ETG-Australian Therapeutic Guidelines 2020 (Part 1)

Clinical assessment of pain
Introduction to assessing pain

A patient’s pain needs to be accurately evaluated in the context of their presentation. Pain may be acute,
recurrent or chronic. The aims of assessment are to determine the cause of the pain, its nature and severity,
and the effect of the pain on the patient. A comprehensive assessment forms the basis for appropriate
management.
Pain is a personal experience, occurring when and where the patient says it does. Pain perception and the pain
experience are influenced by a number of factors including the patient’s mood (especially depression, anxiety
and delirium), past pain experiences, and other symptoms (eg insomnia, nausea) (see Figure 1.1). It is
important to listen to, and believe, the patient’s description of their pain experience and the meaning that the
patient ascribes to it. Explore the patient’s interpretation of their symptoms, particularly if similarities to
previous experiences may have resulted in false implications being ascribed to the pain. Consider the
patient’s symptoms in light of the underlying disease process, but understand that there is no direct
correlation between the severity of pathology and the severity of pain.
Factors influencing the perception of pain (Figure 1.1)
Defining pain
Pain is defined by the International Association for the Study of Pain as ‘an unpleasant sensory and
emotional experience associated with actual or potential tissue damage, or described in terms of such
damage’ [Note 1].
Nociceptive pain arises from actual or threatened damage to non-neural tissue and is due to the activation of
nociceptors (receptors in skin and deep tissues that are sensitive to potentially noxious stimuli). Nociceptive
pain can be subdivided into somatic (superficial and deep) and visceral, according to the origin of the
nociceptive stimulus (see Table 1.1).
Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system. For information on
assessment of neuropathic pain, see Neuropathic pain: introduction.
Breakthrough pain and incident pain are terms that describe the pattern of pain. These pains can be
nociceptive, neuropathic or both.
Breakthrough pain occurs between regular doses of an analgesic and reflects an increase in the pain level
beyond the control of the baseline analgesia. This may just be an occasional natural fluctuation in pain or, if
frequent, reflect inadequate baseline analgesia or management.
Incident pain occurs with, or is exacerbated by, physical activity or an event such as a wound dressing.
Inadequate stabilisation of a fracture or cough can also cause incident pain.
Other terms that may be used to describe a patient’s response to a stimulus include:
allodynia—a painful experience in response to normally nonpainful stimuli (eg to brushing or cold
stimuli)
hyperalgesia—an increased responsiveness to normally painful stimuli (eg to pinprick over skin and
pressure over nerves)
hyperpathia—an abnormally painful experience in response to a repetitive stimulus (eg repetitive
pinprick). It manifests as an explosive increase in pain severity and/or an increased area of pain.
Note 1: Merskey H, Bogduk N, editors for IASP Task Force on Taxonomy. Classification of chronic pain:
descriptions of chronic pain syndromes and definitions of pain terms. 2nd ed. Seattle: International
Association for the Study of Pain; 1994.
Types of pain
Pain is seldom simple, with most pains having both nociceptive and neuropathic components. Pain is
commonly described in terms of these components, which are summarised in Table 1.1. In patients with
entrenched chronic pain, many factors may contribute and these classifications may not be clear.
Pain can also be described practically in terms of its characteristic patterns (eg breakthrough pain, incident
pain).
Classification of pain (Table 1.1)
Nociceptive—
Nociceptive—
superficial Nociceptive—visceral Neuropathic
deep somatic
somatic
bones, joints,
muscles, tendons,
skin ligaments
subcutaneous superficial lymph solid or hollow organs

origin of tissue nodes damage to nociceptive
deep tumour masses
stimulus pathways
mucosa of mouth, organ capsules and
deep lymph nodes
nose, sinuses, mesothelial
urethra, anus membranes
(pleura and
peritoneum)
herpes zoster (shingles)
postherpetic neuralgia
muscular injury appendicitis
osteoarthritis diverticulitis diabetic neuropathy
burns
tendinopathy myocardial infarction post-thoracotomy
wounds syndrome
examples bone fracture endometriosis
malignant ulcers poststroke pain
bone metastases intestinal, biliary or
stomatitis ureteric colic phantom pain
liver capsule
distension or deep abdominal or tumour-related plexus
inflammation mediastinal tumours involvement
spinal cord injury or

compression
dysaesthesia (eg pins and
needles, tingling, burning,
stinging,
lancinating/shooting,
dull radiating)
hot dull deep allodynia (see Defining
description sharp aching pain)
gnawing, cramping,
stinging throbbing colicky hyperalgesia (see Defining
pain)
pressure/tightness
pain in a missing body
part
pain in a numb area

may be perceived in the
localisation (to territory supplied by the
localised poorly defined poorly defined
site of stimulus) affected nerve or
pathway(s)
Pain assessment
Pain assessment: overview
Pain—whether acute, recurrent or chronic—is assessed by obtaining a history and performing a physical
examination. Only perform investigations that will assist in diagnosis or in the management of the patient.
Consider other factors that might influence the experience of pain. Box 1.1 outlines important factors to
consider when assessing a patient who is in pain.
For assessment of pain in children, see Pain assessment in children.

Important factors to consider when assessing the patient with pain (Box 1.1)
Consider the following points in your assessment:
history of event or circumstances surrounding the onset of pain (eg trauma)

nature, location, radiation and severity of pain (use a pain scale to assess severity of pain and
response to therapy, see Severity)
aggravating and relieving factors
previous pain comparisons (eg ‘Is this the worst pain you have had?’)
any analgesia taken before presentation
associated symptoms (eg fatigue, depression, urinary symptoms in renal colic)
psychosocial issues, meaning of the pain to the patient and its impact (see Box 1.3)
general medical and surgical history
medication history (including prescription, over-the-counter and complementary and alternative
medicines) and allergies
use of illicit drugs
physical examination relating to the possible pain cause and other relevant areas
investigations that are relevant to the possible diagnosis.
Pain assessment: history
Introduction
When taking a history, allow adequate time for the consultation. Use open-ended questions so that the patient
can express any fears or concerns in an open and supportive atmosphere.
Some patients may be unable to give an accurate pain history (see People with communication difficulties).
Under these circumstances a collateral history should be sought from relatives or carers.
Location
There is often more than one major site of pain. Identify each painful site and assess separately, as each site
could involve a different pathology or mechanism. Use of a body chart may help monitor the success of
treatments for individual sites of pain.
The ability to localise pain can help in diagnosis. Superficial somatic pain is more easily localised than
visceral pain.
Radiation
The radiation or referral of pain is often characteristic, which can give clues to the cause and type of pain. For
example, shoulder tip pain suggests diaphragmatic pathology or liver capsular (stretch) origin; knee pain or
lateral hip pain suggests hip or lumbar spine pathology; testicular or groin pain may indicate ureteric or
retroperitoneal pathology.
Quality
Quality refers to the words the patient uses to describe their pain (see ‘description’ in Table 1.1).
Pain quality also gives insights into how the patient is reacting to their pain. Pain described as ‘unbearable’,
‘intolerable’ or ‘cruel’ conveys a qualitatively different pain experience than ‘annoying’ or ‘uncomfortable’.
Severity
Pain severity is usually measured using unidimensional scales. These include:
categorical or verbal descriptor scales (using descriptors such as no pain, mild, moderate, severe, worst
ever pain)
numbered scales (0–10 or 0–100)
visual analogue scales (simple lines with word anchors at each end)
faces pain scales (for patients who are unable to use other scales).
See Appendix 1.1 for examples of these pain scales.
Use a scale that works best for the patient. Some patients may not be able to use a pain scale—see People
with communication difficulties for other assessment options.
Pain severity scales offer a subjective measure of pain intensity. They are more accurate than observed
behaviours as they are a more direct measure. Pain scales can be used to guide prescribing decisions (see
Figure 1.2). They can also be used over time to monitor the patient’s response to interventions and adjust
therapy accordingly (see, for example, Figure 1.4).
Be clear when asking the patient a question. Is it:
the average pain over the last 24 hours

the worst pain in 24 hours
the current pain severity
the impact of the pain.
Measuring the pain score at rest and on activity helps to assess the impact of pain on the patient’s function.
There can also be differences in scores for pain at rest and pain on movement. Determine which aspects of
pain severity best help guide management for each patient. Assess the patient’s subjective pain severity score
together with other indicators of pain severity (eg mobility and activity) to gain a complete picture (see the
example below).
Example
One day after surgery a patient is comfortable and reports a pain score of 5/10 on a numerical rating scale
while resting in bed. During a physiotherapy session when the patient gets out of bed and walks to the
bathroom, the score increases to 8/10. Adequate analgesia before the next physiotherapy session allows the
patient to complete the activity without an increase in their pain score.
Do not use pain severity scales as the only basis for prescribing, particularly for chronic pain (see Chronic
pain: pharmacological management). They do not provide a reliable guide to the severity of tissue pathology
and they can be influenced by a variety of factors including mood, anxiety and fatigue. Nevertheless, a
downward trend in a visual or numerical scale score over time in a single patient suggests successful therapy.
Aggravating and relieving factors
Information about what makes the pain better or worse may help in diagnosis (eg pain on breathing with rib
fracture) and in treatment (eg application of heat for pain on movement). Strategies developed by the patient
for managing their pain can be integrated into the treatment plan.
Ask about any previous response to an analgesic to help determine a starting dose, and prevent the use of
previously unhelpful therapy.
Timing
Establish the onset of each pain at each site. Note any fluctuations through the day and how they relate to
movement, sleep or other events such as visits. A record of variations or fluctuations in pain over specific
time frames is helpful. For example, pain with an inflammatory component such as rheumatoid arthritis or
polymyalgia rheumatica is often worse in the morning, pain associated with osteoarthritis is often worse after
activity at the end of the day, and pain from bony metastases may be worse at night. Other factors (eg absence
of distractions) could also lead to the pain being worse at night.
Patient’s understanding of the pain
Find out what the patient knows and feels about the pain. They might be needlessly worrying about a simple
problem (eg the patient may interpret abdominal pain due to constipation as being due to advancing cancer).
To better understand the patient’s pain experience, ask what associated factors influence the pain.
Impact of pain
Ask the patient about the impact of the pain on their everyday activities (eg how it is affecting their ability to
sleep, mobilise, work, concentrate and enjoy life). Multidimensional scales such as the Brief Pain Inventory
(BPI) [Note 2] provide information about the impact of the pain as well as the pain severity. The BPI can be
used to track the impact of pain over time.
Note 2: A copy of the Brief Pain Inventory is included in: Medical care of older persons in residential aged
care facilities. 4th ed. South Melbourne: The Royal Australian College of General Practitioners; 2006. An
online version is available from the RACGP website [URL].
Pain assessment: examination

Examination is an essential component in the assessment of pain. This includes both physical and mental
state examination. The aim of examination is to:
inform diagnosis
provide insight into the impact of pain on current functioning
provide a baseline against which future clinical change can be measured.
The focus and extent of examination should be tailored to the clinical context. Examination of a patient who
presents to the emergency department with acute ankle pain following a fall differs from that of a patient
presenting to the chronic pain clinic with chronic neck pain.
The components of physical examination and mental state examination are well covered by basic medical
texts and resources. Some additional considerations that are particularly relevant to the patient with pain are
listed in Box 1.2.
Additional examination components to consider when assessing the patient with pain
(Box 1.2)
Physical examination
The sensory examination may help to map and clarify the patient's sensory experience. Assess whether
there is a stimulus that is provoking the pain and if the patient's response to it is appropriate.
Assess the function of the painful part or system—this involves observing spontaneous activity and testing
on maximal tolerated effort. For example, a patient with chest pain due to fractured ribs should have their
chest excursion examined and be asked to demonstrate maximal forced expiration. This can then be used to
measure functional improvement with analgesic interventions.
Assess the function of the whole person—this involves assessing surrogates for activities of daily living and
vocation. For example, a patient with chronic low back pain due to resolving discitis could be observed to
assess transfers (lying to sitting to standing), mobility (with and without mobility aids), standing and
walking tolerance, balance, dressing and carrying loads.
Mental state examination
Mood and affect—chronic pain is known to be associated with depression so it is important to recognise
and quantify altered mood states if present.
Thought content—assess for thoughts of suicide, particularly if considering prescribing medication that
could cause harm in overdose. Catastrophic thoughts about occult pathology and fear-avoidance thoughts
are also important to consider, particularly when assessing chronic pain.
Cognition—severe pain is known to impair cognition and memory; many medications used to treat chronic
pain also impair cognition.
Insight—assess the patient's insight into their condition, prognosis and expectations of treatment.
Pain assessment: investigations

Restrict investigations to those useful for confirming clinical impressions and influencing management
decisions. Avoid screening batteries—target investigations to the specific patient. Review previous
investigations before ordering further tests. Inappropriate ‘over-investigation’ often results in unrealistic
expectations of therapy and unnecessary costs.
Pain assessment: acute pain
Initial assessment
When a patient presents with acute pain, assess whether there is serious pathology needing urgent attention.
Even when there is serious underlying pathology, control of distressing symptoms such as pain often allows a
more comprehensive assessment.
When a patient presents with acute pain, assess whether there is serious pathology needing urgent attention.
Use a visual or verbal analogue scale as a guide to both severity of the pain and response to therapy (see
Appendix 1.1 for examples of pain scales).
Once adequate pain relief or control is obtained, perform a more comprehensive assessment (see Box 1.1 and
Box 1.2 for important factors to consider). This must be relevant to the presentation and may be focused in
situations such as trauma and localised pain.
Continuing assessment
Once initial pain control is achieved, regularly monitor the patient’s response to treatment. Repeated
analgesia is often required. Advice about pain management, expectations of pain control, medication
reduction and potential problems should be discussed with the patient, carer and/or family before they leave
the consultation.
Documentation
Document the initial pain level using whatever assessment tool is appropriate at the time. Repeat the
assessment using the same tool each time to monitor the response to treatment and analgesia.
Pain assessment: recurrent or chronic pain
Initial assessment
When a patient presents with recurrent or chronic pain, follow the general approach to assessment outlined in
Box 1.1 and Box 1.2. Also:
reassess the original diagnosis or pathology

review previous analgesic treatment and pain management strategies, as they may influence choice and
dosage of subsequent treatment
consider if the pain could be drug induced (eg musculoskeletal pain with statins, medication-overuse
headache)
conduct a psychosocial assessment (see Box 1.3)
consider assessment of cognition
perform a systems examination, including a complete neurological examination. Check for associated
neurological features such as hypo/hyperalgesia, paresis and dysaesthesia.
Psychosocial assessment (Box 1.3)
When conducting a psychosocial assessment of a patient in pain, develop rapport and adopt an active
listening position. Briefly detail the current situation. Establish relevant patient demographics (eg family,
culture/language, work status, compensation status).
Ask the patient specific questions about:
the context/history of the pain (eg gradual versus sudden or traumatic onset, treatments received and
outcomes)
the pattern of pain (always present or intermittent, when does it get worse/better and the relationship
to the patient’s activities)
significance of the pain (their concerns, worries, and beliefs about the pain)
their mood state (eg fear/anxiety, depression, acceptance)
their responses to the pain (eg passive versus active coping style. Passive includes avoidance of
activities that increase pain, reliance on analgesics or hands-on treatments, waiting to get better.
Active includes attempting to maintain as many normal activities as possible, being self-reliant, using
problem-solving skills)
effects of the pain on relationships, work life and responses of significant others (family, workplace,
other health care providers)
their expectations about the pain and treatments
context of the pain in the patient’s life—both past and present.
Continuing assessment
Regularly assess the patient’s response to therapy, especially with respect to functional outcome and their
level of distress. There may be an identifiable pattern to complaints of recurring pain that may be contextual.
Documentation
Document pain assessment in the medical record. It can influence decision-making both at the time of the
assessment and in the future. Three levels of pain documentation are relevant:
screening—especially in patients with cancer, as pain is a common consequence of advanced disease

initial assessment—all the components of pain assessment described earlier should be documented for
all patients with pain
ongoing assessment—less comprehensive documentation should focus on the response to treatment,
such as pain severity and effects on mobility. Major changes in pain should trigger a more
comprehensive assessment.
Pain assessment: people with communication difficulties
Introduction
Pain is always a subjective experience; however, the inability to communicate pain does not mean that the
person is not in need of assessment and treatment of pain. People with communication difficulties may
include those with cognitive impairment (eg due to dementia or delirium), intellectual impairment, speech or
hearing impairment, and young children. For assessment of pain in children, see Pain assessment in children.
Appropriate professional interpreters should be organised for patients who are not fluent in English.
Older people
Effective management of pain in an older person requires evaluation of all comorbid medical conditions that
might influence either the selection of therapy or the outcome. The assessment should also include physical,
psychosocial and cognitive function. Older people treated for chronic pain often show a more dramatic
improvement in function than level of pain.
Comorbidities, including neurological disorders, often inhibit the patient’s processing and response times.
Allow the older person adequate time to give a history and their version of events, and to respond to
questions. Additional information may be obtained from a relative or carer. If the patient is asked to stand and
walk, they may acknowledge pain that they denied while at rest. Older people may use words such as
‘soreness’ and ‘aching’ instead of ‘pain’.
People with impaired cognition
The clinical approach in patients with impaired cognition (eg due to dementia or delirium) depends on the
severity of cognitive impairment. Dementia makes assessment and management of pain more complex. In the
early to moderate stages of dementia, the ability to report pain is often preserved, although the ability to give
an accurate history of the pain including onset and response to past therapies may be impaired. A
collaborative history should be sought. At this stage patients often find verbal descriptor scales (ie mild,
moderate, severe) easier to complete than numerical or visual analogue scales.
As dementia progresses, the individual becomes less capable of understanding, interpreting and reporting
pain. Language skills are lost. The approach to pain assessment moves from subjective report to surrogate or
observational assessment. Reports from families and carers, direct observation, and observation instruments
such as the Abbey Pain Scale or the DOLOPLUS-2 scale [Note 3] are essential when assessing pain in these
patients.
Behavioural disturbances such as agitation, resisting care, aggression and abnormal vocalisations may be due
to pain but misinterpreted as simply being associated with dementia. In patients who are unable to verbalise
effectively, moaning, grimacing, rubbing of an affected part, or being reluctant to mobilise or participate in
usual activities can be indicators of pain. A time-limited trial of analgesia should be considered.
Detailed information about assessing pain in people in residential aged care facilities has been developed by
The Australian Pain Society [Note 4]. A kit to help implement pain management practices in aged care
facilities is also available [Note 5].
Patients close to death and in a semiconscious state can still be assessed for their pain. Facial expressions (eg
grimacing) or stiffening of the body when moved are indicators of distress, of which pain is one cause.
Note 3: The DOLOPLUS-2 scale for behavioural pain assessment in the elderly is available at [URL]
Note 4: Australian Pain Society. Pain in residential aged care facilities: management strategies. Sydney:
The Australian Pain Society; 2005. [URL]
Note 5: Edith Cowan University. The PMG kit for aged care. An implementation kit to accompany The
Australian Pain Society’s pain in residential aged care facilities: management strategies. Australian
Government Department of Health and Ageing; 2007. [URL]
When uncertainty remains
If review of the situation does not lead to adequate clarity, the practitioner may:
seek further information from family and/or friends and/or the usual health care provider
ask for a second opinion
seek specialist advice, especially if the pain is unusual, the story is inconsistent, or the patient is not
improving.
Key references
Pain assessment: people with communication difficulties
Husebo BS, Ballard C, Sandvik R, Nilsen OB, Aarsland D. Efficacy of treating pain to reduce behavioural
disturbances in residents of nursing homes with dementia: cluster randomised clinical trial. BMJ 2011;343:d4065.
21765198 .
Royal College of Physicians, British Geriatrics Society and British Pain Society. The assessment of pain in older
people: national guidelines. Concise guidance to good practice series, No. 8. London: RCP; 2007. [URL]
Published November 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Acute pain: a general approach
Introduction to acute pain
Acute pain is pain of recent onset that can usually be related to an injury or a disease. There is an expectation of
recovery and return to usual circumstances. Acute pain is generally of nociceptive type in response to tissue injury,
with familiar ‘classical’ presentations—the location, type, pattern and radiation being strongly suggestive of the
underlying pathology. However, both central and peripheral neuropathic pain can also present in the acute phase, and
acute pain presentations can be atypical.
Acute pain usually serves a positive biological function, drawing attention to illness or injury, and stimulating
responses to minimise further damage. In any patient with pain, the focus should be on diagnosing and managing the
underlying cause. Specific treatment for the underlying condition may be required in addition to symptomatic
management of the pain. Acute pain usually resolves with healing of the underlying illness or injury.
While acute pain is often a symptom of serious pathology, the absence of pain as a major symptom does not exclude
serious pathology (eg silent myocardial infarction is well recognised in older people).
Acute pain can arise following trauma (see Acute pain: traumatic) or surgery (see Acute pain: perioperative). The
following discussion relates to the symptomatic management of nontraumatic, nonsurgical pain.
For management of pain in opioid-tolerant patients, see Acute pain in opioid-tolerant patients.
For detailed information about managing pain in children, see Pain in children.
Pain management strategies for some specific indications are given elsewhere in the guidelines (see Box 1.4 for
examples).
The responses to acute pain include immediate reflex responses that:
are behavioural (eg withdrawal, exclamation, checking, protection and rest)

indicate increased autonomic activity (eg pallor, sweating, tachycardia, tremor).
These features give the observer an objective indication that the person is likely to be experiencing pain, although this
should not be taken for granted. There is no absolutely reliable feature that can ‘prove’ another person is in pain or, in
the absence of these features, that they are not in pain.
The person’s subsequent responses may include apprehension, checking for safety and explanation, speculation about
the cause (including thoughts of catastrophe), recall of past experiences, and seeking relief. As well as being
stimulated by the intensity of the pain, this subsequent response depends on its significance to the person in their
current context.
A person’s subsequent response to acute pain depends on its intensity and its significance to them.
Tolerance of pain varies between individuals, and for each individual, depending on duration, context and experience.
People tolerate and distract from acute pain until they regard it as a sufficient threat to their normal activities to warrant
attending to it, or seeking help.
Acute pain does not always abate (see The transition from acute to chronic pain). One reason may be that the disease
process responsible does not resolve. Other factors that favour continuation of pain, and difficulty tolerating it, include:
inadequate initial pain relief

neuropathic nature of the pain (eg herpes zoster)
patient factors, such as a poor understanding of the cause of the pain and uncertainty, fears and anxieties about
its significance
inappropriate treatment options, such as prolonged immobilisation and inappropriate medication
comorbidities.
Pain management strategies for some specific indications (Box 1.4)
Management strategies for the following painful conditions are provided elsewhere in eTG complete:
acute chest pain

biliary colic
dysmenorrhoea
headache and facial pain
inflammatory musculoskeletal pain (see gout, calcium pyrophosphate deposition, viral arthritis, rheumatoid
arthritis, ankylosing spondylitis, reactive arthritis, enteropathic arthritis, psoriatic arthritis, inflammatory
connective tissue diseases, polymyalgia rheumatica, limb conditions)
irritable bowel syndrome
migraine
noninflammatory joint and muscle pain (see osteoarthritis, neck pain, back pain, limb conditions, fibromyalgia)
orofacial pain
pain in patients receiving palliative care.
Stepwise approach to acute pain management

Introduction
In many people with pain it is difficult to predict their analgesic requirements. People with mild pain may not require
an analgesic and nonpharmacological approaches may be adequate.
If analgesics are required, use a stepwise approach starting at a step that corresponds to the severity of the patient’s
pain. When deciding on treatment, also consider other assessment findings (eg comorbidities, effect of the pain on
function) and the clinical context in which the patient presents (see Figure 1.2).
Commence each analgesic with a dose towards the lower end of the range, and titrate upwards depending on the
patient’s response and/or development of adverse effects. If pain is not relieved with the maximum daily dose, reassess
the aetiology before moving to the next step.
If the pain is thought to be neuropathic, see Neuropathic pain for management options.
Deciding where to start when prescribing analgesics for new-onset acute pain (Figure 1.2) [NB1]
IN = intranasal; IV = intravenous; NSAID = nonsteroidal anti-inflammatory drug; SC = subcutaneous
NB1: Use a validated, age-appropriate pain intensity scale (see Appendix 1.1 and Table 1.16). Consider the pain intensity score in the context of other
assessment findings and the clinical environment before deciding which analgesic ‘step’ to start from. See text for recommended doses. Further assessment,
investigations and definitive management can be performed in parallel with symptom management.
Step 1. Mild acute pain

Mild pain may respond to nonpharmacological approaches, without the need for analgesics. Adults may benefit from
reassurance, rest (if nonmusculoskeletal pain), or an ice or heat pack. For children, see Nonpharmacological
management of pain in children.
For mild acute pain not relieved by nonpharmacological measures, oral paracetamol may provide adequate pain relief.
In adults, use:
paracetamol 1 g orally, 4- to 6-hourly, up to a maximum of 4 g daily. For dosing of

paracetamol in children, see Table 1.19.
Reduce the dose in people who have significant liver disease, are malnourished, of small size, or in frail older patients.
Paracetamol is available under many brand names, both alone and as combination preparations. To avoid inadvertent
overdose, advise patients to consider the paracetamol content of all medications.
The paracetamol content of all medications must be considered.
Step 2. Moderate acute pain
Nonsteroidal anti-inflammatory drugs
If symptom relief is not sufficient with paracetamol and there are no contraindications to their use, a nonsteroidal anti-
inflammatory drug (NSAID) can be used instead of, or in addition to, paracetamol. Suitable options include:
1 ibuprofen 200 to 400 mg orally, 3 times daily. For dosing of ibuprofen in children, see Table
1.20
OR (depending on patient comorbidities)
2 diclofenac 25 to 50 mg orally, 2 or 3 times daily. For dosing of diclofenac in children, see

Table 1.20
OR
2 naproxen 250 to 500 mg orally, twice daily. For dosing of naproxen in children, see Table
1.20.
The potential benefit of NSAIDs should be weighed up against potential harms (see Table 1.2 for major adverse effects
of NSAIDs), particularly in high-risk patients. Ibuprofen is recommended first line because of widespread experience
with its use. Adverse effects are dose dependent. At the time of writing, naproxen appears to confer the least
cardiovascular risk but a high risk of gastrointestinal adverse effects. Diclofenac has a lower risk of gastrointestinal
effects but a higher risk of adverse cardiovascular effects. When selecting an NSAID, consider patient comorbidities.
Use the minimum effective dose of the NSAID for the shortest possible time, for a period usually not exceeding 2
weeks. Review the patient at 2 weeks if the acute pain has not resolved.
Use ibuprofen, diclofenac and naproxen with caution and at the lower end of the dose range in older people and in
those with kidney disease (avoid if estimated glomerular filtration rate [eGFR] is less than 30 mL/min), a history of
peptic ulcer disease (avoid if patient has active peptic ulcer disease or bleeding), hypertension or heart failure.
Low-dose aspirin may reduce the increased cardiovascular risk associated with NSAIDs, but it will increase
gastrointestinal adverse effects. However, patients requiring low-dose aspirin for cardiovascular protection should
continue to take it regardless of their need for NSAIDs.
Small quantities of these NSAIDs can be purchased over-the-counter without a prescription. With the exception of
low-dose aspirin, do not use more than one NSAID at a time.
Major adverse effects of nonsteroidal anti-inflammatory drugs (Table 1.2) [NB1]
System Adverse effects Comments

rise in blood pressure, fluid
except for low-dose aspirin, use NSAIDs with caution
retention, myocardial
cardiovascular in patients with cardiovascular disease
infarction, stroke,
cardiovascular death
relative risk of a serious gastrointestinal effect varies
between NSAIDs and is dose-related
upper abdominal pain, gastric over-the-counter NSAIDs appear to have a lower risk
erosions, peptic ulcers (gastric of causing ulcers and bleeding than prescribed NSAIDs
and duodenal), oesophageal because of their lower dose, shorter half-life and
gastrointestinal [NB2] ulceration, gastrointestinal generally shorter duration of use
bleeding, perforation, small selective cyclo-oxygenase-2 (COX-2) NSAIDs (eg
bowel mucosal ulceration celecoxib, etoricoxib) reduce, but do not abolish, the
risk of ulcer disease and complications (concomitant
aspirin negates this effect)
risk factors include perioperative use in older and

sicker patients, pre-existing renal impairment, heart
failure, cirrhosis, a salt-reduced diet, coadministration
renal renal impairment with diuretics, angiotensin-converting enzyme
inhibitors, angiotensin II receptor blockers, aspirin or
other nephrotoxic drugs
NB1: Older people are more at risk of NSAID-related adverse effects; assess their need for NSAID therapy carefully.
NB2: For information on risk factors for, and prevention of, NSAID-induced ulcers, see NSAID-induced ulcers.
Oral opioids
If a patient presents with moderate pain that is not adequately relieved by paracetamol and/or an NSAID, and the pain
is interfering with the patient’s quality of life, consider adding an oral opioid. The most appropriate regimen depends
on the patient’s response to previous therapy.
For selection of opioids in children and appropriate dosing, see Pharmacological management of pain in children:
opioids. Suitable options for adults include:
1 codeine 30 to 60 mg orally, 6-hourly as necessary [Note 1]
OR
1 tramadol immediate-release 50 to 100 mg orally, up to 4 times daily as necessary
OR
2 oxycodone immediate-release 2.5 to 15 mg orally, 4-hourly as necessary. Use the lower end
of the dose range in older people, and the higher end only in fit, otherwise healthy, young
adults. Titrate the dose to response.
Always consider the potential benefits, harms and regulatory requirements before prescribing an opioid (see Table 1.3
for adverse effects with short-term use of opioids). Advise patients to start at the lower end of the dose range and
increase gradually as needed according to response (ie ‘start low and go slow’). Older patients may be particularly
sensitive to opioids (see Opioid sensitivity) and they require careful monitoring. Constipation is a frequent adverse
effect of opioids—advise patients to take a laxative (eg docusate with senna) concurrently.
There is evidence that a lower dose of codeine, less than 30 mg 6-hourly, is no more effective than simple analgesia.
Codeine is a prodrug and requires conversion by the cytochrome P450 (CYP) 2D6 isoenzyme to morphine. This
conversion is dependent on the patient’s individual pharmacogenetics, which are unpredictable. Approximately 6 to
10% of Caucasians and 1 to 2% of Asians lack the CYP2D6 isoenzyme and derive no analgesic benefit from codeine.
Conversely, some people (up to 10% of Caucasians, up to 30% of North Africans) are ultrarapid metabolisers and are
at higher risk of morphine toxicity; codeine should not be used in patients known to be ultrarapid metabolisers or in
breastfeeding women (see the TGA Medicines Safety Update and Drugs and their categories in pregnancy and
breastfeeding for more detail).
Always consider the potential for drug interactions with tramadol before prescribing. A maximum daily dose of 300
mg tramadol is recommended in people aged over 75 years. The usefulness of tramadol is limited by the frequency of
adverse effects, especially in older people who are frail or have cognitive impairment.
Review all patients taking an oral opioid plus paracetamol and/or an NSAID within 48 hours if pain has not resolved.
Always have a discontinuation plan for patients receiving opioid analgesics for acute pain.
Adverse effects with short-term use of opioids (Table 1.3) [NB1]
System Adverse effects—short term

respiratory depression (excessive sedation +/– a decrease in respiratory rate [NB2]) or
respiratory apnoea (which is more marked during sleep or with concomitant sedatives, hypnotics,
alcohol, cannabis and general anaesthetics), bronchospasm
bradycardia, vasodilation and hypotension during intravenous opioid administration,
cardiovascular
postural hypotension
dose-dependent confusion, delirium, sedation, dysphoria, euphoria, cough suppression,
neurological miosis, impaired cognition (requires careful monitoring and patients should be warned
not to drive)
dermatological sweating, flushing, urticaria, pruritus
nausea, vomiting, anorexia, decreased gastric motility, increased antral tone, delayed
gastrointestinal gastric emptying, slowed digestion, prolonged large bowel transit time, increased anal
sphincter tone, constipation
musculoskeletal myoclonus (with higher doses and in patients with renal impairment)
urinary retention and difficulty with micturition, increased external sphincter tone,
urinary
decreased detrusor muscle tone
NB1: See also Table 1.15 for adverse effects with long-term use of opioids.
NB2: A decrease in respiratory rate is a very unreliable indicator of respiratory depression (high blood carbon dioxide levels), which can coexist with a normal
respiratory rate. Sedation is a more sensitive indicator of respiratory depression.
Note 1: Codeine should not be used in breastfeeding women, patients known to be ultrarapid metabolisers, in
children younger than 12 years, and in children 12 to 18 years who have recently had a tonsillectomy and/or
adenoidectomy for obstructive sleep apnoea. For more information, see the TGA Medicines Safety Update.
Step 3. Severe acute pain
General considerations
In patients who present with severe acute pain, the route of analgesic administration depends on the severity of the
pain and the need for rapid analgesic effect. In some cases, oral analgesics may be adequate. Paracetamol and
nonsteroidal anti-inflammatory drugs can be used as opioid-sparing analgesics in patients with severe acute pain. If the
patient is already taking oral analgesics and has not reached maximum doses (see Step 2. Moderate acute pain), a dose
increase may be appropriate. Multimodal analgesia may be appropriate in certain circumstances (see Acute
perioperative pain: introduction). There is no role for transdermal opioid preparations in the management of acute pain.
Intravenous opioids
In most cases of severe acute pain (eg myocardial infarction, renal colic), the intravenous route is indicated to achieve
a rapid and predictable effect. Morphine is commonly used. Fentanyl is an effective alternative in patients who have a
history of adverse effects to morphine. Oxycodone and hydromorphone are also used but prescribers must be aware of
the relative potencies of these opioids (see Table 1.8). If hydromorphone is used, be aware that it is FIVE times more
potent than morphine, and inappropriately high doses have been fatal.
While effective relief of pain is necessary, opioid overdose carries serious risks (see Table 1.3). Rapid dose titration
seeks an acceptable compromise between prompt analgesia and safety. A small dose is given and doses repeated at
intervals of about 5 minutes until analgesia is achieved or sedation and/or respiratory depression contraindicate further
opioid administration. An example of such a process of titration to effect is detailed in Figure 1.3.
Appropriate monitoring and resuscitation facilities are required when patients are given intravenous opioids. Regularly
monitor sedation score (see Figure 1.3), respiratory rate, and arterial oxygen saturation (if possible). It is not
appropriate to write ‘PRN’ orders for intravenous opioids in the ward setting. Most patients who receive parenteral
opioids for acute pain in a community setting should be transferred to hospital for further management.
Carefully monitor the sedation score in all patients receiving intravenous opioids.
Initial intravenous opioid ‘titration to effect’ for acute pain in adults (Figure 1.3) [NB1]
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NB1: This figure provides a guideline for the initial management of severe acute pain in adults using intermittent intravenous opioid analgesia, and assumes
that the patient is not currently on an opioid (ie does not have opioid tolerance). It is not appropriate for maintenance analgesia in continuing pain.
NB2: There is marked individual variation in sensitivity to opioids, so a low initial dose is generally recommended. A higher initial dose (eg up to 10 mg IV
morphine or up to 150 micrograms IV fentanyl) may be appropriate in some situations (eg if given by experienced emergency physicians in clinically urgent
situations to fit, otherwise healthy, young adults).
NB3: The peak effect of an intravenous dose of morphine may not occur for over 15 minutes.
NB4: If within an hour, a patient less than 70 years of age requires more than 20 mg morphine (or 400 micrograms fentanyl), or a patient 70 years of age or
more requires more than 10 mg morphine (or 200 micrograms fentanyl), the patient’s clinical condition should be reviewed.
NB5: Diluted solutions can be used when giving small doses. In a 10 mL syringe, draw up 10 mg morphine (or 200 micrograms fentanyl) and make up to
10 mL with sodium chloride 0.9%.
Subcutaneous opioids
If obtaining intravenous access will unreasonably delay analgesia and care, the subcutaneous route may be considered.
The subcutaneous route is preferred to intramuscular administration because it is less painful and less likely to cause
damage to muscle and other structures. The subcutaneous route is not appropriate in patients with poor peripheral
perfusion or oedema.
Peak analgesia occurs about 30 minutes after subcutaneous injection.
The dose depends on the patient’s age, the clinical context (eg comorbidities, concomitant drugs, history of opioid use
and/or adverse effects) and the ability to closely monitor the patient. After taking these factors into account, a suitable
dose for adults would be:
morphine 2.5 to 10 mg SC, as a single dose.
Use the lower end of the dose range in patients aged 70 years or more. Only use the higher end of the dose range in fit,
otherwise healthy, young adults with acute severe pain in an environment with appropriate monitoring and
resuscitation facilities (including the availability of naloxone for opioid reversal).
Because absorption after subcutaneous injection may be delayed (particularly in patients who have poor peripheral
perfusion), adverse effects may also be delayed. If a patient receives a subcutaneous opioid for acute pain in a
community setting, monitor pain and sedation score (see Table 1.25), respiratory rate, and arterial oxygen saturation (if
possible) for at least 2 hours or until transferred to hospital for further management (ideally via ambulance).
Consider other methods of delivering maintenance opioid if more than one dose of subcutaneous morphine is required.
Intranasal fentanyl
Fentanyl is a highly lipophilic opioid that is well absorbed into the highly vascular nasal mucosa, thus bypassing first-
pass metabolism. This route of administration has a bioavailability of approximately 70% compared with intravenous
administration. Intranasal administration is an off-label use. It has been evaluated as an alternative to intravenous
administration in burns, paediatric emergencies and sometimes in paediatric postoperative patients (see Table 1.22),
and in palliative care. It is also widely used by paramedics in the prehospital setting.
An intranasal delivery device is required to deliver a fine mist of solution quickly into the nasal cavity. The intranasal
route avoids the need for intravenous cannulation and may provide more rapid analgesia than intravenous
administration if an intravenous line is not available. Intranasal administration should be avoided in patients with nasal
congestion, occlusion or epistaxis.
Methoxyflurane
Methoxyflurane is a volatile anaesthetic, with good analgesic properties in concentrations that do not generally
produce loss of consciousness. It is used to produce short-term analgesia and may be of use in acute trauma, patient
transport and wound dressing.
Methoxyflurane can be self-administered, via inhaler or vaporiser, by conscious haemodynamically stable patients,
under the supervision of personnel trained in its use. Methoxyflurane devices are used by ambulance services to
provide analgesia when intravenous access may not be attainable. However, as safer and more effective agents are
available, the clinical use of methoxyflurane is limited. It should only be used where appropriate resuscitation facilities
are available. The activated carbon scavenging unit should be used with the inhaler and occupational health and safety
procedures followed to limit staff exposure to exhaled methoxyflurane.
Methoxyflurane can occasionally produce loss of consciousness, hypotension, and nausea and vomiting. There is an
increased risk of renal toxicity with repeated dosing, related to accumulation of the fluoride ion, and it is
contraindicated in patients with pre-existing kidney disease. Hepatotoxicity has been reported after analgesic doses.
Methoxyflurane is a trigger for malignant hyperthermia and should be avoided in patients with known or suspected
susceptibility to malignant hyperthermia. Not more than 6 mL of methoxyflurane should be administered to adults in a
24-hour period, and not more than 15 mL in a week.
For more information on availability and method of administration, see ‘Methoxyflurane (Penthrox) for analgesia
(doctor’s bag listing)’ in NPS RADAR [Note 2].
Note 2: Methoxyflurane (Penthrox) for analgesia (doctor’s bag listing). NPS RADAR 2010 November. [URL]
Ongoing analgesia
Following the initial treatment, ongoing oral analgesics for severe pain are often required. Use the lowest dose for the
shortest possible time, but take care to ensure adequate analgesia. An understanding of the natural history of the
painful condition and usual speed of resolution may help to determine the likely duration of analgesic use. It is often
appropriate to switch to oral opioids, working back down the analgesic steps outlined in Figure 1.2. See also Figure
1.4.
Liaise with the patient’s primary care provider to ensure appropriate follow-up and regular medication review.
If long-term use of analgesics is likely to be necessary, see Chronic pain: pharmacological management for treatment
options.
Acute pain in older people
Undertreatment of pain
The prevalence of pain increases with age, but it is often under-reported, under-recognised and undertreated in older
people. Both patient and clinician factors contribute to undertreatment of pain:
Older patients are more reluctant than younger patients to report unrelieved pain. This may be due to stoicism or
not wishing to bother busy health professionals.
Older patients may deny ‘pain’, but use other terms such as ‘ache’, ‘soreness’ and ‘stabbing’ to describe what
they are feeling.
Poor pain control may be the result of inadequate administration of medications prescribed on an ‘as necessary’
basis. Dementia, delirium and other forms of cognitive impairment affect reporting of pain.
Studies have shown that patients with cognitive impairment receive significantly lower doses of analgesics than
cognitively intact individuals with similar painful conditions. This may be related to concerns regarding the cognitive
effects of strong analgesics. If there is suspicion that a nonverbal person with dementia has pain (see Pain assessment:
people with communication difficulties), analgesic selection and dosage should be similar to other older people with
the same condition (see Stepwise approach to acute pain management). If there is no clear improvement over several
days, analgesics should be discontinued.
Opioid sensitivity
There is greater physiological heterogeneity among older adults than at other times of life, so caution is required when
making generalisations based on age alone. However, in general, older adults need lower opioid doses (compared to
the usual adult doses) to achieve equivalent analgesia. Age-related physiological changes do not fully explain this
observation. Although more rapid accumulation of active opioid metabolites may result from reduced kidney function
in older people, the major factor contributing to their reduced dose requirements is an increase in brain sensitivity to
the effects of opioids. This applies to both the analgesic effects and adverse effects such as respiratory depression and
nausea.
In older people, it is common practice to start with 25% to 50% of the usual adult dose and titrate carefully according
to response. Older patients should be monitored frequently, both for the effectiveness of the analgesia and the presence
of adverse effects.
Opioid doses in older people must be carefully titrated to effect.
Key references
Introduction to acute pain
Macintyre PE, Scott DA, Schug SA, Visser EJ, Walker SM, eds. Acute pain management: scientific evidence. 3rd ed.
Melbourne: Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine; 2010.
Ready LB, Edwards WT. Management of acute pain: a practical guide. Taskforce on Acute Pain. Seattle: IASP
Publications; 1992.
Stepwise approach to acute pain management
Analgesia: mild-to-moderate pain. Clinical Knowledge Summaries, UK; 2010. [URL]
HYDROmorphone: high-risk analgesic. Safety Alert number 004/11. Sydney: Clinical Safety, Quality and Governance
Branch, NSW Health; 2011. [URL]
Methoxyflurane (Penthrox) for analgesia (doctor's bag listing). NPS RADAR 2010;(November). [URL]
Paracetamol use. [Policy directive]. North Sydney: NSW Health; 2009. [URL]
Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA. Use of nonsteroidal antiinflammatory drugs: an
update for clinicians: a scientific statement from the American Heart Association. Circulation 2007;115(12):1634–42. [
]
Borland ML, Jacobs I, Geelhoed G. Intranasal fentanyl reduces acute pain in children in the emergency department: a
safety and efficacy study. Emerg Med (Fremantle) 2002;14(3):275–80. [ ]
Borland M, Jacobs I, King B, O'Brien D. A randomized controlled trial comparing intranasal fentanyl to intravenous
morphine for managing acute pain in children in the emergency department. Ann Emerg Med 2007;49(3):335–40. [
]
Fosbol EL, Folke F, Jacobsen S, Rasmussen JN, Sorensen R, Schramm TK, et al. Cause-specific cardiovascular risk
associated with nonsteroidal antiinflammatory drugs among healthy individuals. Circ Cardiovasc Qual Outcomes
2010;3(4):395–405. [ ]
Grindlay J, Babl FE. Review article: Efficacy and safety of methoxyflurane analgesia in the emergency department and
prehospital setting. Emergency Medicine Australasia: EMA 2009;21(1):4–11. [ ]
Madadi P, Koren G. Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use.
Pharmacogenomics 2008;9(9):1267–84.
Madadi P, Ross CJ, Hayden MR, Carleton BC, Gaedigk A, Leeder JS, et al. Pharmacogenetics of neonatal opioid toxicity
following maternal use of codeine during breastfeeding: a case-control study. Clin Pharmacol Ther 2009;85(1):31–5. [
]
McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-
based controlled observational studies. PLoS Med 2011;8(9):e1001098. [ ]
O'Rourke KM, McMaster S, Lust KMC. A case of hepatitis attributable to repeated exposure to methoxyflurane during its
use for procedural analgesia. The Medical Journal Of Australia 2011;194(8):423–4. [ ]
Schjerning Olsen AM, Fosbol EL, Lindhardsen J, Folke F, Charlot M, Selmer C, et al. Duration of treatment with
nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior
myocardial infarction: a nationwide cohort study. Circulation 2011;123(20):2226–35. [ ]
Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, Egger M, Jüni P, et al. Cardiovascular safety
of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011;342:c7086. 21224324 .
Acute pain in older people
Coldrey JC, Upton RN, Macintyre PE. Advances in analgesia in the older patient. Best Pract Res Clin Anaesthesiol
2011;25(3):367–78. [ ]
McLachlan AJ, Bath S, Naganathan V, Hilmer SN, Le Couteur DG, Gibson SJ, et al. Clinical pharmacology of analgesic
medicines in older people: impact of frailty and cognitive impairment. Br J Clin Pharmacol 2011;71(3):351–64. [ ]
Published November 2012. Amended March 2018. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Acute pain: traumatic
Introduction to acute traumatic pain
All patients with acute traumatic pain require appropriate analgesia—not only for humane reasons, but also
because it allows more effective evaluation and treatment of injuries, and greater patient satisfaction. Pain
specialists also believe that rapid control of trauma pain is necessary to help prevent central sensitisation and
development of chronic pain syndromes (see The transition from acute to chronic pain: chronic postinjury pain).
The amount of analgesic required for relief of pain due to trauma can be underestimated, and the route of
administration used may be inappropriate. For minor trauma, oral analgesics may be adequate. For severe pain due
to traumatic injuries, titrated intravenous opioid administration is preferred for initial pain relief. This is because of
the rapid onset of action, ease of dosing, and predictability of response, particularly in situations of altered
circulation. Subcutaneous and intramuscular routes lack these advantages and the rate of absorption is slow and
variable. However, if intravenous administration is not possible, the subcutaneous or intramuscular route can be
used. Morphine is the most commonly used opioid, although other opioids can be used. Avoid the use of pethidine.
Dose reduction is required for older patients.
Reassessment is necessary for continuous or recurrent pain following acute trauma.
Analgesia for patients who are on regular therapeutic doses of opioids, who have substance use disorders, or who
are in methadone, buprenorphine or naltrexone programs requires additional consideration (see Analgesia for acute
pain in opioid-tolerant patients).
Analgesia for acute pain in patients who are opioid tolerant requires additional consideration.
Acute pain: minor trauma

Introduction
Consider nonpharmacological methods of pain management as first-line therapy for adults and children with minor
traumatic injuries (eg lacerations, minor burns, soft tissue injuries). Simple measures such as splinting, elevation
and the application of ice can be valuable (see also Nonpharmacological management of pain in children). Inhaled
analgesics (eg methoxyflurane [see Stepwise approach to acute pain management for cautions with use], nitrous
oxide+oxygen mixtures [see Pharmacological management of pain in children: inhalational agents for cautions
with use]) can relieve pain quickly and efficiently.
Reassurance and a calm, confident and empathetic approach by the treating clinician helps to reduce the impact of
pain.
Wounds and lacerations
Early closure of wounds and lacerations often reduces pain by preventing the effects of air currents and thermal
gradients.
For repair of simple low-tension lacerations, tissue adhesives or adhesive skin closures (eg Steristrips) are less
painful than suturing, quick to use and have a similar cosmetic outcome to sutures. Hair apposition technique
(‘HAT’) should be considered for scalp lacerations as it is less painful, doesn't require shaving and produces a
similar outcome compared to suturing.
For wound closures requiring sutures, local anaesthetic, either by direct infiltration or via peripheral nerve block, is
required (see also Local anaesthetics in children). Nitrous oxide (see Pharmacological management of pain in
children: inhalational agents) is sometimes used in children. Debride and thoroughly clean contaminated wounds
and give antibiotics if indicated (see Post-traumatic wound infections).
For more complicated lacerations in children, consider general anaesthesia, or sedation with ketamine with or
without midazolam (see Procedure-related pain in children). Deep sedation and anaesthesia require an appropriate
environment, experienced staff, and monitoring, recovery and resuscitation capabilities.
After closure of the wound, cover with an appropriate dressing (see Ulcer and wound dressings). Simple analgesia
(see Step 1. Mild acute pain and Step 2. Moderate acute pain) is usually sufficient to control the pain.
With contaminated wounds, tissue damage is often significant and the subsequent inflammatory response is more
marked than with clean wounds. Oral analgesics are usually sufficient (see Step 2. Moderate acute pain), but doses
need to be titrated to effect, and reviewed frequently.
Review wounds after 48 hours. If more analgesia is required, evaluate for infection or retained foreign body.
Hospitalisation may be necessary for patients who require more potent analgesics, or who have extensive wounds
or severe infections. See Antibiotic guidelines for management of post-traumatic wound infections.
Sprains and strains
Pain from sprains and strains is usually managed using rest, ice, compression and elevation (RICE therapy) for the
first 48 hours (see Table 12.22). Immersion in ice/water slurries is more effective than the external application of
ice packs. Compression is as effective as ice packs. Never apply ice directly to skin.
Paracetamol should provide sufficient analgesia. If pain persists despite paracetamol, reassess the patient and
consider using a nonsteroidal anti-inflammatory drug (NSAID). See Step 1. Mild acute pain and Step 2. Moderate
acute pain for dosages.
Advise the patient to start mobilisation and passive movement of the injured area as soon as pain permits. Follow-
up is recommended 48 hours after injury. If the pain and dysfunction are out of proportion to the injury, reassess
and consider other diagnoses (eg missed injuries, early complex regional pain syndromes). Referral for early
physiotherapy may be useful.
Dislocations and fractures
Simple
Patients with simple closed dislocations or fractures require initial pain relief before reduction and immobilisation.
If trained staff and appropriate equipment are available, use intravenous morphine or fentanyl (see Intravenous
opioids for appropriate doses in adults and Table 1.22 for children). Regional limb anaesthesia or local nerve
blocks should also be considered.
In nonhospital settings, subcutaneous or intramuscular morphine (see Subcutaneous opioids) and inhalational
agents (eg methoxyflurane) are effective alternatives. Splinting often reduces pain.
Procedural sedation, in addition to analgesics, may be needed (see Procedure-related pain in adults). For severe
pain in children over 2 years of age, consider analgesia with moderate to deep sedation (see Procedure-related pain
in children). Ensure that the child, environment, staff experience, and monitoring, recovery and resuscitation
capabilities are suitable for managing deep sedation or inadvertent anaesthesia. For children under 2 years and
others for whom sedation is contraindicated, consider referral for orthopaedic care under general anaesthesia.
Following reduction, the painful stimulus is removed—this may result in sedation, respiratory depression,
hypotension and bradycardia, and possible airway compromise due to the continuing combined effect of the opioid
analgesic and the sedative required for the procedure. Watch for these potential problems and correct as necessary.
After reduction of the fracture or dislocation, carefully monitor patients who have received procedural sedation.
Following reduction, analgesia is often required for the next 5 to 7 days. Adequate splinting and immobilisation
are essential. Injuries with significant swelling are often better managed with plaster slabs rather than
circumferential casts, which may lead to ischaemic complications.
Fractures and dislocations can cause severe pain. If paracetamol in standard doses (see Step 1. Mild acute pain) is
not sufficient, it is reasonable to add oxycodone:
oxycodone immediate-release 2.5 to 15 mg orally, 4-hourly as necessary. Use the lower

end of the dose range in older people, and the higher end only in fit, otherwise healthy,
young adults. Titrate the dose to response. For dosing of oxycodone in children, see Table
1.21
WITH OR WITHOUT
an NSAID orally, see Step 2. Moderate acute pain for adult dosages and Table 1.20 for
children.
Always consider the potential benefits, harms and regulatory requirements before prescribing an opioid (see Table
1.3 for adverse effects with short-term use of opioids).
The potential benefit of NSAIDs should be weighed up against the potential harms, particularly in high-risk
patients (see Table 1.2). Consider avoiding NSAIDs in patients with long bone fractures as there is conflicting
evidence as to whether the use of NSAIDs impairs fracture healing and increases the risk of nonunion.
Review all fractures and dislocations at 24 hours. If pain is not improving, consider a complication (of the injury,
the reduction, or a previously applied full cast). If pain is increasing or failing to improve within 48 to 72 hours
after treatment, consider conditions such as a compartment syndrome and exclude. If signs of ischemia are present,
urgent referral to an orthopaedic surgeon or emergency department is recommended.
Complicated
Compound dislocations or fractures, or those resulting in neurovascular compromise, should be reduced as soon as
possible, even before radiological examination in certain cases. Initial analgesic requirements may be more than
expected, exceeding the usual doses. Use titrated intravenous opioids (see Step 3. Severe acute pain).
Procedural sedation, in addition to analgesia, is often needed (see Procedure-related pain in adults and Procedure-
related pain in children).
After initial reduction, further procedures are frequently necessary—such as open reduction and internal fixation,
or surgical wound debridement, irrigation and external fixation. Continuing analgesia is often required, but usually
at a lower dose than needed initially. See Acute perioperative pain: postoperative phase for treatment options.
Minor chest injuries

All patients with chest trauma require continuous physiological monitoring during assessment and stabilisation.
Patients with isolated blunt chest trauma may benefit from application of ice water slurry packs to chest injuries to
reduce pain. Early physiotherapy and incentive spirometry to maintain and monitor respiratory function is
essential, as it reduces the risk of segmental lung collapse and subsequent pneumonia. Do not strap or splint the
chest wall to reduce pain, because it increases the risk of hypoventilation and subsequent segmental collapse.
In patients with simple unilateral fractures of one or two ribs, chest wall contusions or sternal bruising, pain may
be controlled with paracetamol (see Step 1. Mild acute pain). However, requirements for paracetamol often exceed
the maximum possible doses for a 24-hour period. In this situation, after discharge from immediate acute care, use
paracetamol at the maximum dose of 4 g per 24 hours and add a nonsteroidal anti-inflammatory drug (NSAID) at
night.
The potential benefit of NSAIDs should be weighed up against their potential harms, particularly in high-risk
patients (see Table 1.2).
An oral opioid such as oxycodone is frequently necessary. Use:
oxycodone immediate-release 2.5 to 15 mg orally, 4-hourly as necessary. Use the lower

end of the dose range in older people, and the higher end only in fit, otherwise healthy,
young adults. Titrate the dose to response. Larger and more frequent doses may be
necessary. For dosing of oxycodone in children, see Table 1.21.
Always consider the potential benefits, harms and regulatory requirements before prescribing an opioid (see Table
1.3 for adverse effects with short-term use of opioids and Table 1.15 for adverse effects with long-term use of
opioids).
Acute pain: major trauma

Head injuries
Patients presenting with head injuries should be managed according to standard trauma protocols and in a facility
capable of managing trauma.
Opioids should only be prescribed after consultation with a senior emergency department physician or
neurosurgeon. The sedating effects of opioids can be confused with a deteriorating neurological condition.
Sedation from opioids also increases arterial carbon dioxide levels and intracranial pressure, which can worsen the
brain injury and outcome.
Major chest injuries
Successful analgesia is an important component of the comprehensive care required for patients with major chest
injuries. Good pain relief permits adequate respiratory movements, which decreases the risk of atelectasis and
pneumonia.
Patients with chest injuries such as penetrating trauma, multiple fractured ribs, flail segment or severe chest wall
contusions, frequently have impaired ventilation secondary to restricted chest wall movement from the degree of
pain. Initial analgesic requirements are high. Ventilatory support is often needed to maintain pulmonary function,
particularly in older people, so consider early referral if any respiratory compromise is evident. Mortality is 11% to
17% in reported case series, with highest rates for patients aged 65 years or more and for those with more than two
rib fractures.
In adult patients who do not require ventilatory support, intravenous bolus doses of morphine or fentanyl should be
used initially (see Figure 1.3). Continuing analgesia can be achieved using morphine or fentanyl. For adults, use:
patient-controlled analgesia (PCA)
OR (if PCA is not possible)
1 morphine 1 to 2 mg/hour IV, by continuous infusion
OR
2 fentanyl 20 to 40 micrograms/hour IV, by continuous infusion.
In older people, it is common practice to start with 25% to 50% of the usual adult dose and titrate according to
response.
For fentanyl and morphine loading doses, PCA and infusion settings in children, see Pharmacological management
of pain in children: opioids and Table 1.22.
A patient who has received high doses of opioids must be observed for sedation and respiratory depression,
because effective pain relief decreases the stimulus for breathing. Closely monitor the sedation score (see Table
1.25) and respiratory function.
Effective pain relief decreases the stimulus for breathing—observe the patient carefully.
Epidural local anaesthetic infusions improve outcomes in patients with multiple rib fractures, and should be
considered early. Intercostal nerve blocks may also be a suitable alternative if analgesic control is proving difficult.
These techniques should only be performed by qualified and trained clinicians. Significant complications include
pneumothorax, haemothorax, intercostal neurovascular damage and spinal cord injuries.
Abdominal injuries
There is no place for withholding analgesics in patients with acute abdominal pain. Providing adequate analgesia
will not mask signs and symptoms in abdominal injuries; abdominal examination is enhanced by adequate
analgesia.
Adequate analgesia will not mask signs and symptoms in abdominal injuries.
For both blunt and penetrating abdominal injuries, intravenous morphine is the drug of choice (see Stepwise
approach to acute pain management for adult dosage, and Pharmacological management of pain in children:
opioids and Table 1.22 for dosing in children).
Fractured hip
Fracture of the hip complex or anterior pubic ring is a common presentation in older people. These fractures,
whether femoral or pelvic, are painful, particularly with movement. The patient requires analgesia even if not
obviously complaining of pain. Pain is often undertreated in older people with fractured hips, especially those who
are cognitively impaired. Special attention is required to ensure optimal pain management.
Immediate pain relief is best achieved using intravenous opioids (see Figure 1.3 for initial dose titration).
Caution should be used with additional and/or continuing doses of opioids.
Suitable patients should also receive a nerve block (eg three-in-one or fascia iliacus block), as these provide
excellent opioid-sparing analgesia. The nerve block may need to be repeated if surgery is delayed.
Early fixation of the fracture is important for pain relief and better patient outcomes.
Multiple injuries
Multitrauma patients require a specific approach to management in a resuscitation facility with appropriate
equipment and staff—typically a trauma team response in a major tertiary centre.
The primary survey with stabilisation and assessment should be performed and analgesia should not be withheld.
Following the primary survey and stabilisation, analgesia should again be considered, especially in patients who
are intubated and ventilated.
A secondary survey (head to toe examination) should follow, including back and rectal examination. Reassessment
is essential, usually every 15 to 30 minutes. The need to assess a patient's neurological status is not a reason to
withhold the use of appropriate analgesics.
Neurological status can be assessed even after opioid use.
Morphine or fentanyl in intravenous boluses should be used initially (see Figure 1.3 for initial dose titration).
Continuing analgesia can be achieved using morphine or fentanyl. For adults, use:
patient-controlled analgesia (PCA)
OR (if PCA is not possible)
1 morphine 1 to 2 mg/hour IV, by continuous infusion
OR
2 fentanyl 20 to 40 micrograms/hour IV, by continuous infusion.
In older people, it is common practice to start with 25% to 50% of the usual adult dose and titrate according to
response.
For morphine and fentanyl loading doses, PCA and infusion settings in children, see Pharmacological management
of pain in children: opioids and Table 1.22.
Fractures and dislocations should be reduced, if possible, and splinted. Regional limb anaesthesia and nerve blocks
are particularly useful, but neurovascular assessment must be made before using any local anaesthetic. Examples
of useful nerve blocks are femoral nerve blocks for fractured femur, intercostal blocks for fractured ribs, and
brachial plexus blocks for upper limb injuries.
Procedural sedation may be needed, particularly in agitated patients with head injury (see Procedure-related pain in
adults and Procedure-related pain in children).
Key references
Introduction to acute traumatic pain
Jao K, Mc DTD, Taylor SE, Khan M, Chae J. Simple clinical targets associated with a high level of patient satisfaction
with their pain management. Emerg Med Australas 2011;23(2):195–201. [ ]
Acute pain: minor trauma
Boursinos LA, Karachalios T, Poultsides L, Malizos KN. Do steroids, conventional non-steroidal anti-inflammatory
drugs and selective Cox-2 inhibitors adversely affect fracture healing? J Musculoskelet Neuronal Interact 2009;9(1):44–
52. [ ]
Burd TA, Hughes MS, Anglen JO. Heterotopic ossification prophylaxis with indomethacin increases the risk of long-
bone nonunion. J Bone Joint Surg Br 2003;85(5):700–5. [ ]
Dodwell ER, Latorre JG, Parisini E, Zwettler E, Chandra D, Mulpuri K, et al. NSAID exposure and risk of nonunion: a
meta-analysis of case-control and cohort studies. Calcif Tissue Int 2010;87(3):193–202. [ ]
Giannoudis PV, MacDonald DA, Matthews SJ, Smith RM, Furlong AJ, De Boer P. Nonunion of the femoral diaphysis.
The influence of reaming and non-steroidal anti-inflammatory drugs. J Bone Joint Surg Br 2000;82(5):655–8. [
]
Acute pain: major trauma
Initial management of closed head injury in adults. [Policy directive]. Sydney: NSW Health; 2007. [URL]
Bergeron E, Lavoie A, Clas D, Moore L, Ratte S, Tetreault S, et al. Elderly trauma patients with rib fractures are at
greater risk of death and pneumonia. J Trauma 2003;54(3):478–85. [ ]
Bulger EM, Edwards T, Klotz P, Jurkovich GJ. Epidural analgesia improves outcome after multiple rib fractures.
Surgery 2004;136(2):426–30. [ ]
Carrier FM, Turgeon AF, Nicole PC, Trepanier CA, Fergusson DA, Thauvette D, et al. Effect of epidural analgesia in
patients with traumatic rib fractures: a systematic review and meta-analysis of randomized controlled trials. Can J
Anaesth 2009;56(3):230–42. [ ]
Flagel BT, Luchette FA, Reed RL, Esposito TJ, Davis KA, Santaniello JM, et al. Half-a-dozen ribs: the breakpoint for
mortality. Surgery 2005;138(4):717–23; discussion 23–5. [ ]
Morrison RS, Siu AL. A comparison of pain and its treatment in advanced dementia and cognitively intact patients with
hip fracture. J Pain Symptom Manage 2000;19(4):240–8. [ ]
Published November 2012. Amended February 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Acute pain: perioperative
Introduction to perioperative pain
Perioperative pain is the pain due to the process of having surgery. This can include pain before, during and after the patient has their
surgery.
Relief of pain is essential for rapid and successful recovery from surgery and major illness. Optimal use of analgesics relieves patient
suffering, assists nursing care, promotes patient mobilisation and recovery, reduces postoperative complications and enables earlier
discharge from hospital. Improvements in care have resulted from:
awareness of the deleterious physiological and psychological effects of severe unrelieved pain
establishment of organisational structures (eg acute pain services, perioperative services) to address postoperative pain
improved knowledge of the pharmacokinetics and pharmacodynamics of analgesics
education to allay the fear of opioid dependence and to reduce complications, including sedation and respiratory depression
additional or alternative use of nonopioid medications to provide analgesia
evidence of the link between acute pain and the development of chronic pain conditions.
Standard methods of pain management include the use of patient-controlled analgesia (PCA) and the administration of epidural or
intrathecal opioids (which may be combined with a local anaesthetic). Regional local anaesthetic blocks are also often provided,
using infusion devices. The oral route of drug administration is preferable to other routes, and should be employed as soon as
practicable.
Multimodal analgesia involves the use of specific drugs and techniques in combination, aiming to:
diminish the inflammatory response to surgery

block afferent painful sensory input
modulate the cascade of events that promote the transmission of pain signals in the spinal cord
promote the descending inhibition of pain.
Multimodal analgesia relies on combining the effects of analgesic drugs with techniques that have different modes of action (eg
nonopioid combined with opioid, local anaesthetic block combined with a systemic analgesic). This approach improves analgesia due
to additive or synergistic effects, and has the added advantage of reducing individual drug doses and therefore decreasing adverse
effects.
Preventive and pre-emptive analgesia involve the administration of analgesics or local anaesthetic blocks before the painful
stimulus. This decreases stress responses, improves analgesia, and decreases subsequent analgesic requirements. Although it is
difficult to completely block all nociceptive input to the central nervous system, and thus prevent central sensitisation, this may be
possible in some circumstances, provided the analgesics are continued well into the postoperative period. There is evidence that
improved acute pain management results in a lower likelihood and intensity of chronic pain developing after surgery (see The
transition from acute to chronic pain: postsurgical pain syndromes).
Optimal postoperative analgesia depends on establishing pharmacological control initially. This process involves appropriate
analgesic administration during the preoperative, intraoperative and postoperative periods.
This topic discusses the management of perioperative pain in adults. For management in children, see Acute pain in children:
perioperative pain.
Preoperative pain
Preoperative education is essential to help allay fear and anxiety associated with surgery. As most patients are now admitted on the
day of surgery, education is the responsibility of all health professionals involved in the patient's care. Discussion should include
details of the procedure, the options for postoperative analgesia, and an emphasis on the need for patients to report their pain to their
carers. The patient's visit to the preoperative assessment clinic is an excellent opportunity to discuss the analgesic plan and give
written information to the patient.
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided before any surgery where postoperative bleeding would be of
concern. If the patient is in pain preoperatively, do not withhold other regular (including oral) analgesic medication. Oral analgesics
can be safely taken with sips of water.
For emergency surgery, any prescribed analgesics should be continued as required.
In adults, an oral premedication, if considered necessary, may be given 60 to 90 minutes before surgery. A typical regimen is:
paracetamol 1 g orally
PLUS (for more major surgery)
oxycodone immediate-release 5 to 10 mg orally.
Intramuscular premedication is seldom required and this route should be discouraged.
With the increasing incidence of day surgery, premedication is often omitted, and sedative and analgesic medications are given
intravenously by the anaesthetist shortly before induction.
In anxious or needle-phobic adults, local anaesthetic cream (eg lidocaine+prilocaine eutectic mixture—EMLA) can be helpful. It is
applied under plastic dressing to the skin intended as an intravenous (or other procedural) site, at least 60 minutes preoperatively.
Intraoperative pain
Good anaesthetic technique can greatly reduce the intensity of the surgical stimulus and the consequent postoperative stress response.
This will help the patient emerge from anaesthesia with minimal postsurgical pain.
Analgesia is established intraoperatively using a multimodal approach with paracetamol (if not given preoperatively), intravenous
opioids such as fentanyl or morphine and, where possible, a local anaesthetic. Nonsteroidal anti-inflammatory drugs (NSAIDs), such
as ketorolac or the selective COX-2 inhibitor parecoxib, can also be used. NSAIDs should only be given if there are no patient- or
surgery-specific contraindications (see Acute postoperative pain: nonsteroidal anti-inflammatory drugs).
Postoperative pain
The type of surgery and individual patient variables influence the intensity, character and duration of postoperative pain. Age,
previous medical history and concurrent medications must be considered when choosing analgesics. Caution should be observed in
patients who are debilitated, are at the extremes of age, have a history of opioid use, or organ dysfunction. The personality and
sociocultural background of patients are also important. Anxiety, fear, communication difficulties and unfamiliarity with hospital
processes are associated with higher postoperative pain intensity, which can influence analgesic requirements. Strategies to lessen
anxiety, including patient education, may be beneficial.
Surgical procedures involving major body cavities, large joint surfaces, and deep tissues are considered ‘very painful’, but this varies
in individual patients. Relatively minor procedures such as split skin grafting or arthroscopic surgery can also induce intense pain.
Pain from upper abdominal or thoracic surgery can impair respiratory function and can increase the risk of respiratory complications
after surgery.
Increasing pain after surgery could indicate the development of a surgical complication (eg compartment syndrome, bleeding) and
should trigger the need for re-evaluation of the patient rather than simply increasing the dose of analgesia. Failure to do so could
result in avoidable patient harm.
If pain increases after surgery, re-evaluate the patient rather than simply increasing the dose of analgesia.
After minor surgery (including some day-surgery procedures), effective analgesia can usually be obtained without using opioids, thus
avoiding their adverse effects.
After major surgery, a multimodal approach should be continued postoperatively. Opioids are the mainstay of perioperative analgesia.
Regular paracetamol is useful and when combined with opioids, improves the quality of analgesia and increases patient satisfaction.
The addition of a nonsteroidal anti-inflammatory drug (NSAID), other adjuvants, or regional techniques using local anaesthetics, may
be appropriate.
A key principle of effective pain management is measuring pain using the patient's own self-report. A common method is for the
patient to score pain using a 0 to 10 verbal score; with 0 representing no pain, and 10 being the most severe pain imaginable (see Pain
assessment: severity and Numerical pain scale). The pain score can be used to assess the efficacy of analgesia and as the basis for
adjusting the patient's analgesic prescription (see Figure 1.4).
The principles of managing postoperative pain are shown in Box 1.5.
Principles of managing moderate to severe postoperative pain (Box 1.5)
Postoperative pain should be controlled whenever possible by using a combination of drugs and strategies (ie multimodal
analgesia).
The patient's self-report of pain is the most reliable, but in its absence there are other ways of assessing pain (see Pain assessment:
people with communication difficulties). An inability to report pain does not mean that the patient does not need adequate
analgesia.
Postoperative analgesics should be tailored to the patient's requirements, the severity of their pain and the level of clinical
observation.
Local anaesthetic techniques have a valuable role.
Constant reassessment of clinical response, liaison between staff, and common sense are important.
Deciding how to adjust the analgesic prescription for acute postoperative pain (Figure 1.4) [NB1]
IV = intravenous; LA = local anaesthetic; NSAID = nonsteroidal anti-inflammatory drug; PCA = patient-controlled analgesia; PRN = as necessary
NB1: Use a validated, age-appropriate pain intensity scale (see Appendix 1.1 and Table 1.16). Consider the pain intensity score in the context of other assessment findings and
the clinical environment before deciding how much to adjust the prescription.
Paracetamol
Paracetamol is useful for almost all patients with acute postoperative pain. When combined with opioids, paracetamol improves the
quality of analgesia and increases patient satisfaction. Intravenous paracetamol provides a similar quality of analgesia to the oral
route and can be used when alternative routes are unavailable or inappropriate. Absorption of paracetamol after rectal administration
may be unreliable.
Paracetamol should be prescribed as a routine medication (rather than ‘as necessary’) while the intensity of postoperative pain is still
moderate to high. Use:
paracetamol 1 g orally or IV, 6-hourly.
Reduce the dose in patients with low body weight. Paracetamol may rarely cause liver injury—risk factors include excessive dose,
coexisting liver disease, prolonged fasting and malnutrition. Regularly reassess the need for ongoing administration.
Opioids
Introduction
In the immediate postoperative period (eg in the recovery room), the most appropriate route of opioid administration is intravenous.
This allows rapid dose titration for the individual patient. Other routes commonly used are subcutaneous, intramuscular, epidural and
intrathecal. The subcutaneous route is preferable to the intramuscular route because it is less painful.
Any opioid (except pethidine) can be used provided the dose is titrated to individual needs. As a general rule, a dose increase should
be no more than 50% of the previous dose. Pethidine should be avoided because of its serotonergic properties, its neurotoxic
metabolite (norpethidine), and its association with drug-seeking behaviour.
Avoid using pethidine for perioperative pain.
Opioids cause impairment of ventilation by several mechanisms, which may interact. Opioids cause central nervous system sedation
directly, depression of respiration, and decreased tone in upper airway muscles causing airway obstruction. Hypercarbia from
respiratory depression may further exacerbate the direct sedative effects of opioids. These risks are greater in obese patients and those
with sleep apnoea.
Carefully consider the use of opioids in patients with significant respiratory disease (including obstructive sleep apnoea), obesity,
head injury, raised intracranial pressure, or renal or hepatic impairment. If unsure about safety, seek specialist advice. There is no
evidence that the use of an opioid for limited periods in the treatment of acute postoperative pain is associated with an increased risk
of addiction.
All patients receiving parenteral opioids should have regular (initially hourly) assessment of their level of sedation (see Table 1.25)
and respiratory rate, to detect opioid-induced central depression. Appropriately trained staff and equipment for resuscitation (eg bag–
mask ventilation with supplemental oxygen, naloxone) must be available.
Sedation is a more sensitive indicator of respiratory depression from opioids than the respiratory rate.
Coadministration of opioids and other sedative drugs (eg benzodiazepines, sedating antihistamines, antipsychotics) increases the risk
of sedation and respiratory depression. Avoid concurrent use if possible, or monitor closely for sedation.
Older adults have the highest rates of surgical procedures but many have their postoperative pain inadequately treated. Opioid
analgesia should not be withheld for fear of aggravating cognitive impairment in older people. Many studies have reported lower
opioid dose requirements for older adults in the immediate postoperative period. It is common practice to start with 25% to 50% of
the usual adult dose. Doses must be carefully titrated to effect in older people—monitor frequently, both for the effectiveness of the
analgesia and the presence of adverse effects.
Analgesia for patients who have been on long-term opioid therapy is discussed in Analgesia for acute pain in opioid-tolerant patients.
Intravenous opioids
The intravenous route has a more rapid onset of action than other routes of administration. As optimal doses vary, doses should be
titrated to response. This is best achieved using intermittent, age-based bolus doses given at 5-minute intervals until satisfactory pain
relief is achieved. An environment that allows close and frequent observation of the patient is required. Once satisfactory pain relief
is achieved, it is best maintained using patient-controlled analgesia (PCA).
A typical regimen [Note 1] is:
morphine 1 to 2 mg IV, in bolus doses at 5-minute intervals until satisfactory pain relief is achieved
FOLLOWED BY
patient-controlled analgesia (PCA).
If PCA is not available, an opioid infusion can be used but requires regular review and adjustment. Continuous opioid infusions can
result in inadequate treatment of breakthrough pain. This is due to variations in patient response, the changing intensity of acute pain,
and delays between alteration of the infusion rate and the resulting analgesic effect. An increase in adverse effects such as sedation
and respiratory depression can also occur. If opioid infusions are used, drug concentrations should be standardised within institutions
to reduce the chance of administration errors.
Subcutaneous infusion is an alternative if there are difficulties with the intravenous route.
Note 1: In older people, it is common practice to start with 25% to 50% of the usual adult dose and titrate according to response.
Patient-controlled analgesia (PCA)
Patient-controlled analgesia (PCA) refers to any method of pain relief that allows a patient to self-administer small doses of an
analgesic as required. The most common form involves the use of a programmable intravenous pump.
The PCA pump allows patients to self-administer fixed bolus doses of opioid in response to pain. PCA is typically delivered
intravenously, but can be used with the subcutaneous or epidural route. The intravenous route allows rapid titration by the patient and
a shorter lockout interval (usually 5 minutes).
The rationale for PCA is that patients, being the best judge of their pain, can administer opioids as often as required, within the limits
preset by the prescriber. This provides improved comfort, by avoiding the peaks and troughs of analgesia associated with other
methods of parenteral administration. It also allows the patient to anticipate and treat incident pain (eg pain associated with
mobilisation or physiotherapy). There is a lower incidence of hypoxaemia in patients receiving PCA opioids than in those receiving
intramuscular opioids.
On pushing a button, a preset bolus dose is administered. An initial loading dose can be set; however, as PCA is a maintenance
therapy, the patient's pain should be controlled with individually titrated doses before starting PCA. This would normally occur
during surgery and in the recovery room.
A continuous background infusion can also be set, but there is little evidence that, when combined with PCA, this improves pain
relief—and patients are more likely to experience adverse effects. In opioid-tolerant patients, a background infusion should be
considered as a replacement for ‘baseline’ opioid requirements if the oral route is not available. Single intermittent bolus doses have a
higher margin of safety than continuous intravenous infusion.
Drug concentrations used in PCA devices should be standardised within institutions to reduce the chance of programming errors.
Standardise drug concentrations used in PCA devices within institutions to reduce programming errors.
Morphine is the opioid most commonly used for PCA because it is effective, cheap and there is most experience with its use. Typical
settings for use of morphine and fentanyl in PCA devices are given in Table 1.4. Tramadol, oxycodone and hydromorphone can also
be given by PCA if local protocols are in place. The approximate relative potencies of the various opioids are given in Table 1.8. If
hydromorphone is used, be aware that it is FIVE times more potent than morphine, and inappropriately high doses have been fatal.
Efficacy is limited by the patient's ability to fully understand the concept and the instructions, their ability to push the PCA button
and, possibly, by their aversion to adverse effects. Efficacy and safety depend on:
familiarity of prescribers and nursing staff with the technique and device (staff education)
patient education
properly functioning equipment
appropriate monitoring (including pain and sedation scores (see Table 1.25), and respiratory rate)
immediate availability of supplemental oxygen.
Use of PCA devices can be less successful at extremes of age. PCA is not advised for patients who are cognitively impaired.
Nurse-initiated bolus dosing may be considered for patients unable to press the button, but this requires the development of clear
practice guidelines. Relatives must be firmly instructed not to press the delivery button on the patient's behalf.
Using opioids by PCA does not eliminate the potential for adverse events. Sedation and respiratory depression have been reported,
with an incidence less than intramuscular but similar to epidural opioid administration. Risks are greater in the presence of a
background maintenance infusion. Mechanical faults can occur. Programming errors and other human errors in setting up the delivery
system or understanding the equipment can be reduced by staff education programs and competency assessments. The involvement
of an acute pain service improves the safety and efficacy of PCA.
Typical intravenous PCA settings for adults (Table 1.4) [NB1]
Drug Bolus dose Lockout interval (minutes)

morphine 1 mg 5
fentanyl 20 micrograms 5
NB1: Drug concentrations should be standardised within institutions to reduce the chance of programming errors.
Subcutaneous opioids
Opioids can be given subcutaneously by intermittent doses or as a continuous infusion through a 25 gauge butterfly needle or a 22 or
24 gauge cannula, provided peripheral perfusion is adequate. The time to peak effect is typically about 30 minutes, so sufficient time
must elapse before deciding to administer further doses.
Avoid subcutaneous administration in patients with poor peripheral perfusion.
With sterile precautions, a single cannula or needle (eg a butterfly device) can be left in situ for 48 to 72 hours.
Morphine, hydromorphone, oxycodone and fentanyl [Note 2] can be given subcutaneously. The approximate relative potencies of the
various opioids are given in Table 1.8. If hydromorphone is used, be aware that it is FIVE times more potent than morphine, and
inappropriately high doses have been fatal.
Older people are more sensitive to the effects of opioid analgesics than younger people and should be started on lower doses and
titrated carefully. See Table 1.5 for examples of dose titration using subcutaneous morphine in two different age groups.
If the doses in Table 1.5 provide acceptable analgesia for at least 2 hours, the total loading dose has been determined to be 7.5 mg in
the 70-year-old female and 20 mg in the 25-year-old male.
Thereafter, approximately 50% of the loading dose—3 mg in the 70-year-old female and 10 mg in the 25-year-old male—is
prescribed every 2 to 4 hours, depending on the time interval at which pain returns.
Establishing the required dose, as outlined in these examples, is the key to instituting satisfactory postoperative analgesia using
intermittent subcutaneous opioid dosing.
Suggestions for dose titration using subcutaneous morphine for severe postoperative pain (Table 1.5) [NB1]
70-year-old opioid-naive female 25-year-old opioid-naive male

initial SC dose 2.5 mg 10 mg
further SC dose at 30 minutes if pain persists 2.5 mg 5 mg
further SC dose at 60 minutes if still significant pain
2.5 mg 5 mg
and no other apparent cause (eg a distended bladder)
NB1: If the pain is not brought under control within 1 hour, seek expert advice.
Note 2: Fentanyl is available as a 50 micrograms/mL injection, so use by the subcutaneous route can be limited by large injection
volumes.
Intramuscular opioids
Intramuscular administration of opioids is the least preferred parenteral route, due to variable absorption rates, pain associated with
the injection, and injury to muscle from repeated administration at the injection site. It was traditionally thought that the
intramuscular route was safer than other routes, but data show that respiratory depression and hypoxaemia also occur with this route.
Patients who require more than one or two intramuscular injections should have their analgesic administered via a patient-controlled
analgesia device, an intravenous infusion, or an indwelling subcutaneous needle.
Oral opioids
An early change from parenteral to immediate-release oral opioids in patients with reliable oral absorption facilitates a smooth
weaning process that can extend beyond discharge from hospital. Typical starting doses are given in Table 1.6. Higher doses may be
needed in patients on long-term opioid therapy or if high parenteral doses have been needed to control the patient's postoperative
pain.
Oxycodone is commonly used for acute postoperative pain. Prescribers should be aware of the abuse potential.
Morphine mixture or immediate-release tablets may be used. There is variable oral bioavailability between patients and this can
make dose titration more problematic than with other opioids in the acute pain setting.
Tramadol may be useful as an alternative to other opioid analgesics after minor procedures (eg day surgery). It has a reduced
incidence and severity of opioid adverse effects (particularly respiratory depression, ileus and constipation), and there is limited
potential for tolerance, physical dependence and addiction, even with long-term use. However, adverse effects such as nausea,
sweating, dizziness and sedation (which are attributable to its serotonergic effect) preclude its use in some patients. Concurrent use of
tramadol with other serotonergic drugs (eg selective serotonin reuptake inhibitor antidepressants [SSRIs]) can cause serotonin
toxicity that is potentially dangerous. Daily doses in excess of 300 mg are not recommended in patients over 75 years.
Codeine is a widely used weak opioid analgesic. It is usually combined with another drug such as paracetamol. The efficacy and
safety of codeine have been questioned. Codeine is a prodrug and requires conversion by the cytochrome P450 (CYP) 2D6
isoenzyme to morphine. This conversion is dependent on the patient's individual pharmacogenetics, which are unpredictable.
Approximately 6 to 10% of Caucasians and 1 to 2% of Asians lack the CYP2D6 isoenzyme and derive no analgesic benefit from
codeine. Conversely, some people (up to 10% of Caucasians, up to 30% of North Africans) are ultrarapid metabolisers and are at
higher risk of morphine toxicity. Codeine should not be used in patients known to be ultrarapid metabolisers or in breastfeeding
women (see the TGA Medicines Safety Update and Drugs and their categories in pregnancy and breastfeeding for more detail).
Modified-release opioid formulations have a limited role in the management of persisting pain after surgery. If a prolonged duration
of pain is anticipated and the patient has been stabilised on an immediate-release opioid, it may be appropriate to convert to an
equivalent daily dose of a modified-release opioid. This can be combined with an immediate-release opioid for breakthrough pain. Do
not use modified-release opioids in the unstable or high-risk patient (ie patients with significant respiratory disease, head injury,
raised intracranial pressure, or renal or hepatic impairment). Administration of a modified-release opioid to a deteriorating patient can
be dangerous.
Serious adverse effects can occur if the wrong formulation is used. To reduce such errors, prescribers must be familiar with the
various opioid formulations and clearly specify the formulation intended. Some hospitals may use only immediate-release
formulations for acute postoperative pain to further reduce the potential for confusion, and to minimise problems with diversion of
modified-release opioids.
Modified-release formulations should never be crushed or chewed, as this destroys their release properties and can result in a large
dose being absorbed over a short period. This presents an opportunity for abuse.
Modified-release formulations should never be crushed or chewed. This could cause an opioid overdose.
Regardless of the formulation used, prescribers should specify the cessation date and/or the date for review by the parent unit or the
patient's general practitioner (GP). A letter should be sent to the GP outlining a discharge analgesic plan including the duration of
further opioid use and a regimen for weaning.
There must be an opioid cessation plan for all patients discharged on oral opioids after surgery.
Typical starting doses for oral opioids for the treatment of postoperative pain (Table 1.6) [NB1]
Oral opioid [NB2] 70-year-old opioid-naive female 25-year-old opioid-naive male

oxycodone immediate-release 5 mg 10 mg
morphine immediate-release 10 mg 30 mg
100 mg (maximum of 400 mg/24
tramadol immediate-release 50 mg (maximum of 300 mg/24 hours)
hours)
NB1: Review the patient at 2-hourly intervals and adjust dose if pain relief is inadequate or adverse effects occur. Implement a plan for early weaning of oral opioids.
NB2: Codeine has a number of limitations (see above) and is not recommended for postoperative use.
Naloxone
Naloxone is a mu-opioid antagonist used in the treatment of opioid-induced central nervous system effects (eg sedation and
respiratory depression). Naloxone should always be available when opioids are administered in the perioperative period, regardless of
the route of administration.
If reversal of opioid action is necessary, small incremental doses are best, to avoid excessive reversal with possible acute withdrawal
syndrome and the return of pain. This can be achieved by diluting one ampoule of naloxone 400 micrograms/mL to 10 mL with
sodium chloride 0.9% and titrating the dose to response:
naloxone 40 micrograms IV, initially and titrate with further 40 microgram increments until the effects of
excessive sedation or respiratory depression are reversed.
If the situation is urgent, a suitable regimen is:
naloxone 100 to 200 micrograms IV, every 2 minutes until the effects of excessive sedation or respiratory
depression are reversed.
If the situation is critical (eg medication administration error causing massive overdose, unconsciousness and respiratory arrest),
larger doses may be required.
The onset of action of naloxone after intravenous administration is about 1 minute. The duration of action is relatively short (15 to 30
minutes) compared to that of most opioids. Continued observation of the patient (looking for a return of the opioid-induced central
nervous system effects) is essential, and repeat administration of naloxone may be necessary. Rapid, complete reversal by naloxone
can potentially cause serious adverse effects such as pulmonary oedema and cardiac arrhythmias.
Small doses of naloxone can be helpful for treating opioid-induced pruritus. Low doses are used so that the analgesic effect of the
opioid is not antagonised. The use of a sedating antihistamine to treat pruritus should be avoided due to the risk of causing excessive
sedation when combined with opioid use.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have an opioid-sparing analgesic effect and may reduce opioid-related adverse
effects. They provide additional anti-inflammatory actions, particularly where there is considerable somatic tissue damage (eg with
orofacial and orthopaedic procedures). However, NSAIDs should not be used routinely in all postoperative patients. Their harms and
benefits need to be assessed before they are prescribed (see Table 1.2 for major adverse effects of NSAIDs), and in most cases
treatment should be reviewed after 2 or 3 days postoperative use. Where oral administration is inappropriate, the intravenous,
intramuscular or rectal routes can be used for some NSAIDs.
Care should be taken with NSAID therapy in older people and where there is a history of gastrointestinal erosion, platelet
dysfunction, aspirin-induced asthma, cardiovascular or cerebrovascular disease, or when the patient has renal impairment or
hypovolaemia. The risk of acute renal failure is increased if NSAIDs are given with diuretics and angiotensin converting enzyme
inhibitors or angiotensin II receptor blockers.
All nonselective NSAIDs have antiplatelet effects, and their use should be avoided in patients with impaired haemostasis or recent
haemorrhage, and before any surgery where postoperative bleeding would be of concern. The antiplatelet effect of aspirin on exposed
platelets is irreversible, persisting for the lifetime of the platelets (5 to 7 days).
Selective cyclo-oxygenase-2 NSAIDs (COX-2 inhibitors or coxibs) are effective analgesics, may be tolerated in patients with aspirin-
induced asthma, and have a lower risk of gastric adverse effects with short-term use. COX-2 inhibitors have no effect on platelets and
will not adversely affect postoperative bleeding. However, they have similar renal risks, and can increase the risk of cardiovascular
and cerebrovascular complications.
Recent evidence shows that COX-2 inhibitors and nonselective NSAIDs (except aspirin) have a risk of cardiovascular and thrombotic
adverse effects. These can occur in healthy people during short durations of use. NSAIDs should be used cautiously in the
perioperative period in patients with cardiovascular disease.
Regional and local administration of local anaesthetics and opioids
Introduction
Local anaesthetics are commonly used in the perioperative period. Direct injection of local anaesthetics close to peripheral nerves,
major nerve trunks or nerve roots produces analgesia by blocking conduction of afferent nociceptive impulses. Continuous regional
analgesia can be achieved by infusing a local anaesthetic via epidural, interpleural, paravertebral, nerve sheath, or simple wound
catheters. This minimises the need for systemic analgesics (especially opioids with opioid-related adverse effects), and can provide
profound analgesia for many hours to days postoperatively. A limiting factor is the associated motor nerve block, particularly major
nerve blockade of the limbs.
Dosing of local anaesthetics must not exceed safe limits (see Table 1.7).
In addition to local anaesthetics, opioids are often given by the epidural or intrathecal route in the perioperative setting.
Other adjuvant drugs, notably clonidine, act at spinal or supraspinal sites and may be used to enhance and prolong local anaesthesia.
Maximum safe single doses of local anaesthetic in adults (Table 1.7)
Example of maximum volume for 70 kg healthy adult

Maximum single bolus
Drug Strength of local
dose [NB1] Volume
anaesthetic [NB2]
bupivacaine with or without adrenaline 2 mg/kg 0.5% 28 mL
levobupivacaine 2 mg/kg 0.5% 28 mL
lidocaine without adrenaline 3 mg/kg 2% 10 mL
lidocaine with adrenaline 7 mg/kg 2% 24 mL
ropivacaine 3 mg/kg 0.75% 28 mL
NB1: These doses are a guide only and will vary with different sites of injection, vascularity, type of block, age and health of the patient. Intravenous access and equipment for
treating adverse effects must be available before instituting a major local anaesthetic block. The lowest dose necessary should be used.
NB2: To convert a percentage concentration to mg/mL, multiply by 10 (eg 2% = 20 mg/mL).
Choosing an infusion device
Infusions in hospitals can be delivered by most infusion devices although a rate-limited pump, with unique identification, provides
important safety when using local anaesthetic. The giving set should also be uniquely identified to avoid confusion with intravenous
lines and it should have no injection ports. There are also a number of disposable elastomeric infusion devices available, but their use
is limited in some settings because of the cost. See Subcutaneous drug administration in palliative care for further information about
continuous subcutaneous drug administration with a syringe driver.
Epidural administration
Direct administration of local anaesthetics and/or opioids into the epidural space using an indwelling catheter is an effective analgesic
technique for acute postoperative pain from a wide variety of procedures.
Safe and effective epidural therapy requires:
specially trained staff—comprehensive education and competency assessment are essential for medical and nursing staff
comprehensive practice guidelines—for postoperative management and monitoring of patients, and for the treatment of
complications
appropriate equipment—including a rate-limited infusion device and giving sets with no injection ports. The pump and
administration line should be uniquely identifiable for epidural use only.
Drugs used
Fentanyl is the opioid of choice for epidural infusion. The combination of epidural fentanyl with local anaesthetic improves the
quality of epidural analgesia compared to local anaesthetic alone.
Less fat-soluble opioids (eg morphine) have a slower onset, a more prolonged duration of action, and a more extensive spread of
analgesia than fentanyl. Morphine spreads cranially in the cerebrospinal fluid. When administered as a single dose it can provide
prolonged postoperative pain relief (12 to 24 hours) without the need for an indwelling catheter. It also has the potential for delayed
respiratory depression (onset may be delayed for 12 to 24 hours). This can be hazardous if additional centrally acting drugs are given
during this period—do not give concomitant systemic opioids without specialist advice.
Respiratory depression after epidural morphine can occur for up to 24 hours.
Proprietary combinations of opioids and local anaesthetics for epidural infusion are available. Standardising solutions reduces the
incidence of dosing errors. The local anaesthetics most commonly used for epidural analgesia are bupivacaine (0.125%) and
ropivacaine (0.2%); levobupivacaine (0.125%) is also available. The opioid most commonly used in these proprietary combinations is
fentanyl. Typical concentrations of fentanyl used in combination with epidural local anaesthetic are from 2 to 5 micrograms/mL. The
usual rate of infusion for effective analgesia with these mixtures is 5 to 15 mL/hour, titrated to produce an area of analgesia that
covers the site of the surgical wound. Using this method can produce adequate analgesia even in the absence of a clearly definable
sensory block (measured, for example, by applying ice to the skin to test for cold sensation).
Adverse effects
Epidurally administered opioids can cause sedation, respiratory depression, pruritus, urinary retention and nausea. Local anaesthetics
block the conduction of nerve impulses. Their actions are not confined to pain fibres; they can cause sympathetic block with
hypotension (particularly if the patient is hypovolaemic), and can produce sensory and motor block. The patient should be observed
for significant motor block and warned to protect an anesthetised part of the body from injury. Unusual and pronounced motor block,
especially when persisting beyond the normal duration of effect of local anaesthetics, requires prompt neurological review of the
patient.
Using a combination of an opioid and a dilute local anaesthetic gives, compared with using either drug alone, comparable or
improved analgesia with fewer adverse effects.
Permanent neurological damage from an epidural haematoma or abscess is a serious potential complication of epidural analgesia.
Epidural abscess is a serious but extremely rare complication. The incidence from large audits is about 1 in 50 000. It also occurs
spontaneously in patients without epidural analgesia at a similar rate. Risk factors include prolonged use (greater than 2 to 3 days)
and immunocompromise (eg diabetes, corticosteroid use). The incidence of epidural haematoma is approximately 1 in 50 000 to 100
000 patients and is related to the patient population studied. Early diagnosis and treatment increases the likelihood of partial or full
neurological recovery. If surgical decompression is required, the best outcome occurs if this is done within 8 hours of the onset of
neurological symptoms.
In a patient who has recently had an epidural block (even after removal of an epidural catheter), the occurrence of back pain plus
fever, with or without a neurological abnormality, could indicate an epidural abscess. This represents a medical emergency, and
requires early investigation with magnetic resonance imaging (MRI). This, together with urgent referral to a neurosurgeon, is
essential to preserve neurological function. Delay reduces the chance of neurological recovery.
Back pain plus fever in a patient who has recently had an epidural block represents a medical emergency.
Intrathecal administration
Intrathecal administration (ie injection into the cerebrospinal fluid) of very small doses of an opioid (eg morphine 100 to 300
micrograms) combined with a local anaesthetic is particularly suitable for surgical procedures on the lower body (eg caesarean
section). Pain relief from a single dose of morphine typically lasts for 12 to 24 hours, depending on the dose.
The opioid is administered at the time of the spinal anaesthetic, and the same postoperative vigilance, precautions and monitoring as
for postoperative epidural analgesia is required (see Epidural administration: adverse effects). Single-dose intrathecal morphine may
cause late-onset (up to 24 hours) respiratory depression, particularly in opioid-naive patients and if high doses (eg more than 300
micrograms morphine) are given. Patients require monitoring for sedation and respiratory depression for at least 24 hours, and this
must be made clear to recovery room and ward staff. Do not give concomitant systemic opioids without specialist advice. Severe
pruritus, nausea and urinary retention can limit the use of intrathecal morphine.
Caution should be exercised when giving any drug by the intrathecal route, as neurotoxicity and central nervous system adverse
effects are more likely than with intravenous administration. Particular care must be taken to avoid drug dosing errors.
Continuous peripheral nerve blockade
Continuous peripheral nerve blockade extends the duration of postoperative analgesia beyond that of a single injection. It is a useful
adjunctive technique for selected surgical procedures, and in some cases provides a less invasive alternative to epidural
administration. The anaesthetist usually positions the catheter before the procedure, although sometimes the catheter is inserted by the
surgeon. Local anaesthetic is then delivered by continuous infusion for 1 to 4 days, as part of a multimodal approach. This might also
include administration of an opioid using a patient-controlled analgesia device, paracetamol and a nonsteroidal anti-inflammatory
drug.
Brachial plexus infusion
Brachial plexus infusion of local anaesthetic can be used for surgery involving the arm and hand. This technique allows pain relief
and induces a sympathetic block that improves limb perfusion. Interscalene brachial plexus blockade (by either single shot or
continuous infusion) provides effective analgesia for 24 to 48 hours after shoulder surgery.
Surgical wound infiltration and infusion
Long-acting local anaesthetic injected into a wound provides analgesia for up to 6 hours following superficial procedures. The
evidence for the effectiveness of continuous wound infusions to provide analgesia for major procedures including abdominal surgery
is less convincing, although some techniques using deep and superficial infusion catheters may be helpful. Care must be taken to
ensure that the total dose of local anaesthetic infused is within safe limits (see Table 1.7).
Acute postoperative pain: ketamine

Ketamine has a role, in low doses, as an adjunct for acute postoperative pain management, by helping to prevent central nervous
system ‘wind-up’ or hyperalgesia. It is used to treat acute pain that is poorly responsive to opioids (including neuropathic pain, and
pain in opioid-tolerant patients). Ketamine should only be used after specialist consultation.
Nonsurgical postoperative pain

Bladder distension
Following lower limb and abdominal surgery, and prolonged procedures, urinary retention can cause profound discomfort. In the
immediate postoperative period, patients may be too drowsy to clearly identify the source of their distress, which can also result in
restlessness, tachycardia and hypertension. Bladder distension should always be considered in patients with lower abdominal
discomfort. Urinary catheterisation is the treatment of choice.
Muscle spasm
Reflex muscle spasm often accompanies painful orthopaedic procedures, and can be exacerbated by the use of a tourniquet during the
operation (eg thigh spasm after knee joint surgery). Physical therapies (heat, massage, positioning) and nonsteroidal anti-
inflammatory drugs can be helpful.
Persistent postsurgical pain

In many patients, pain persists for many months after the surgical procedure, well past the time by which ‘normal’ healing would be
assumed to have occurred. This may be for a number of reasons, including incomplete surgical correction of the original problem.
However, other reasons for this persistence should be considered. See The transition from acute to chronic pain: postsurgical pain
syndromes for a detailed discussion on prevalence, risk factors and possible strategies to reduce the occurrence of persistent
postsurgical pain.
Key references
Acute perioperative pain: introduction
Macintyre PE, Scott DA, Schug SA, Visser EJ, Walker SM, eds. Acute pain management: scientific evidence. 3rd ed. Melbourne:
Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine; 2010.
Acute perioperative pain: preoperative phase
Acute perioperative pain: intraoperative phase
Acute postoperative pain: general considerations
Acute postoperative pain: paracetamol
Acute postoperative pain: opioids
HYDROmorphone: high-risk analgesic. Safety Alert number 004/11. Sydney: Clinical Safety, Quality and Governance Branch, NSW
Health; 2011. [URL]
Cashman JN, Dolin SJ. Respiratory and haemodynamic effects of acute postoperative pain management: evidence from published data.
Br J Anaesth 2004;93(2):212–23. [ ]
Latta KS, Ginsberg B, Barkin RL. Meperidine: a critical review. Am J Ther 2002;9(1):53–68. [ ]
MacDonald N, MacLeod SM. Has the time come to phase out codeine? CMAJ 2010;182(17):1825. [ ]
Macintyre PE, Loadsman JA, Scott DA. Opioids, ventilation and acute pain management. Anaesth Intensive Care 2011;39(4):545–58. [
]
Acute postoperative pain: naloxone
Kjellberg F, Tramer MR. Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials. Eur J
Anaesthesiol 2001;18(6):346–57. [ ]
Murphy JD, Gelfand HJ, Bicket MC, Ouanes JP, Kumar KK, Isaac GR, et al. Analgesic efficacy of intravenous naloxone for the treatment
of postoperative pruritus: a meta-analysis. J Opioid Manag 2011;7(4):321–7. [ ]
Acute postoperative pain: nonsteroidal anti-inflammatory drugs
Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA. Use of nonsteroidal antiinflammatory drugs: an update for
clinicians: a scientific statement from the American Heart Association. Circulation 2007;115(12):1634–42. [ ]
Fosbol EL, Folke F, Jacobsen S, Rasmussen JN, Sorensen R, Schramm TK, et al. Cause-specific cardiovascular risk associated with
nonsteroidal antiinflammatory drugs among healthy individuals. Circ Cardiovasc Qual Outcomes 2010;3(4):395–405. [ ]
Schjerning Olsen AM, Fosbol EL, Lindhardsen J, Folke F, Charlot M, Selmer C, et al. Duration of treatment with nonsteroidal anti-
inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide
cohort study. Circulation 2011;123(20):2226–35. [ ]
Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, Egger M, Jüni P, et al. Cardiovascular safety of non-steroidal
anti-inflammatory drugs: network meta-analysis. BMJ 2011;342:c7086. 21224324 .
Acute postoperative pain: regional and local administration of local anaesthetics and opioids
Horlocker TT, Wedel DJ. Infectious complications of regional anesthesia. Best Pract Res Clin Anaesthesiol 2008;22(3):451–75. [
]
Neal JM, Bernards CM, Hadzic A, Hebl JR, Hogan QH, Horlocker TT, et al. ASRA practice advisory on neurologic complications in
regional anesthesia and pain medicine. Reg Anesth Pain Med 2008;33(5):404–15. [ ]
Wulf H. Epidural anaesthesia and spinal haematoma. Can J Anaesth 1996;43(12):1260–71. [ ]
Acute perioperative pain: nonsurgical postoperative pain
Acute postoperative pain: ketamine
Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic
review. Anesth Analg 2004;99(2):482–95. [ ]
Persistent postsurgical pain
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature, interpreted and distilled by
Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Acute pain in opioid-tolerant patients
Introduction to acute pain and opioid tolerance
An increasing number of patients who present for acute pain management are taking long-term opioids. Most
are taking the opioid for chronic cancer or noncancer pain and others have an addiction to opioids. Most will
be opioid-tolerant, that is, the effect of the drug decreases over time so higher doses are needed to obtain the
same analgesic effect. Physical dependence is also a normal physiological response to long-term opioid use
and is associated with withdrawal symptoms on sudden reduction, cessation or reversal of the drug. This
differs from opioid addiction, which is also associated with aberrant drug-seeking and drug-taking behaviours
—people with addiction disorders may be stabilised by an opioid substitution program and/or have ongoing
use of illicit opioids.
In opioid-tolerant patients with acute pain, treatment should aim to provide effective analgesia while
minimising tolerance and preventing withdrawal. Underestimation of pain and undertreatment is common in
these patients. A previous experience of insufficient analgesia coupled with withdrawal symptoms on
presentation with acute pain can make an individual distrustful of medical staff. Adequate time should be
taken to discuss these issues openly and honestly. Clinicians should discuss the harms and benefits of
increasing the opioid dosage, and other multimodal and multidisciplinary strategies that may be introduced to
help manage the pain.
There is limited evidence to guide management of acute pain in opioid-tolerant patients. Most strategies are
based on case reports and case series, clinical experience and expert opinion. For detailed discussion on
management of the opioid-tolerant patient and the patient with an addiction disorder, see Acute Pain
Management: Scientific Evidence, 4th edition [URL].
Acute pain in patients prescribed opioids for chronic pain

Oral opioids (morphine, oxycodone, methadone, hydromorphone) or transdermal opioids (buprenorphine,
fentanyl) are used in patients with chronic pain (see Analgesics used in chronic nonmalignant pain: opioids).
When a patient taking an opioid for chronic pain presents with increased pain, determine from the history
whether this is an exacerbation of their usual pain or something new. Examples of ‘new’ pains that need to be
investigated and treated include an acute myocardial infarction, bowel obstruction or trauma.
It is important to verify the dose of opioid that the patient is taking. If possible, continue the usual opioid
(using the same formulation and dosage) so that withdrawal symptoms do not occur, and add other analgesics
or adjuvants as required. For mild to moderate acute pain, paracetamol or nonsteroidal anti-inflammatory
drugs may provide adequate pain relief (see ‘Stepwise approach to acute pain management’, Step 1. Mild
acute pain and Step 2. Moderate acute pain for dosages). For moderate to severe acute pain, patients may
require admission to hospital for treatment with an intravenous opioid. Doses needed may be higher than
usual (see Figure 1.3 for standard initial doses).
It is important to verify the dose of opioid that the patient is taking.
If the usual opioid cannot be given (eg the patient is unable to take medication orally), use an alternative
opioid to cover the usual dose and then titrate to response to establish additional requirements. An equipotent
dose should be calculated (see Table 1.8) and incorporated as background dosing using a patient-controlled
analgesia (PCA) device. Alternatively, if PCA is not available, a continuous intravenous or subcutaneous
opioid infusion could be given, but extra monitoring is required. Early advice from a pain specialist or acute
pain service may be required.
Parenteral opioids should be given in a closely monitored environment, so medication can be ordered,
response assessed, and dosing changed rapidly as necessary. There is a reduced incidence of nausea and
vomiting in opioid-tolerant patients, but there may be an increased risk of excessive sedation and respiratory
depression if opioid doses suddenly and rapidly exceed baseline requirements.
Maintenance analgesia using PCA (or a closely monitored continuous infusion if PCA is not available) is a
useful modality until the acute situation has resolved. Other techniques of pain management should also be
explored (eg local anaesthetic blocks, or adjuvant therapy such as nonsteroidal anti-inflammatory drugs,
tricyclic antidepressants, low-dose ketamine infusions). For more information about pain management
techniques, see Acute perioperative pain: introduction.
If pain is difficult to control, consider consultation with an acute pain service.
Approximate potencies of various opioids relative to 10 mg parenteral morphine (Table 1.8)

[NB1]
Opioid Parenteral [NB2] Oral

morphine 10 mg IM/IV/SC 30 mg
buprenorphine 400 micrograms IM/IV 800 micrograms sublingual
codeine [NB3] — 240 mg
fentanyl [NB4] 150 to 200 micrograms IM/IV/SC —
hydromorphone 1.5 to 2 mg IM/IV/SC 6 mg
methadone [NB5] [NB5]
oxycodone 10 mg IV/SC 20 mg
tramadol [NB6] 100 mg IM/IV 150 mg
NB1: These are average equivalent doses because of pharmacokinetic variation between individuals. When changing from one opioid to another,
commence with 50% to 75% of the calculated equianalgesic dose and then titrate to response.
NB2: Administration by different routes results in different times to peak concentration. When using the IV route, start with lower doses and titrate
to effect. Intramuscular administration should be avoided in patients receiving palliative care because of their irregular absorption and the pain that
occurs on administration.
NB3: Codeine is not suitable for patients with severe pain.
NB4: For conversion of transdermal fentanyl patches to morphine, or morphine to transdermal fentanyl patches, see fentanyl product information.
NB5: When changing from morphine to methadone, conversion ratios vary considerably depending on the morphine dose. Methadone should only
be prescribed for chronic pain by practitioners experienced in its use.
NB6: Tramadol may not be suitable as the sole analgesic for patients with moderate to severe pain.
Acute pain in patients with an opioid addiction

When managing acute pain in patients with an opioid addiction, seek early advice from a pain or addiction
medicine specialist and liaise closely with the patient’s usual care providers. The aims of treatment are to
provide effective analgesia, to minimise opioid tolerance and to prevent withdrawal.
Management of patients with an addiction disorder is complicated by:
tolerance, physical dependence and risk of withdrawal

psychological and behavioural characteristics of addiction
the presence of the drug (or drugs) of abuse
other medicines used in the treatment of drug withdrawal or rehabilitation (see Patients in opioid
substitution programs or taking naltrexone)
sequelae of drug abuse including organ impairment and infectious diseases
misuse of other substances such as alcohol, benzodiazepines and cannabis
pejorative attitudes of some staff towards the patient with an addiction disorder.
Identifying patients with an addiction disorder can be problematic, and an accurate history difficult to obtain.
Ask the patient about their current drug usage. Management is more complex if there is polysubstance abuse.
Central nervous system stimulants (cocaine, amphetamines, ecstasy) do not exhibit cross-tolerance with
opioids.
In acute situations (eg trauma or a surgical emergency) or in other situations where the total daily dose of
opioid is not known, patient-controlled analgesia (PCA) may be the best treatment option. This is best
achieved in a closely monitored inpatient environment, so medication can be ordered, response assessed, and
dosing changed rapidly as necessary.
Maintenance analgesia using PCA (or a closely monitored continuous infusion if PCA is not available) is a
useful modality until the acute situation is resolved. Other techniques of pain management should also be
explored (eg local anaesthetic blocks, or adjuvant therapy such as nonsteroidal anti-inflammatory drugs,
tricyclic antidepressants, low-dose ketamine infusions). For more information about pain management
techniques, see Acute perioperative pain: introduction.
Associated affective disorders and behavioural disturbances need to be managed and drugs should be
administered in a secure environment. Beware of drug diversion tactics.
Pregnant women with addiction disorders should be managed by a team with experience in dealing with
addiction problems and pain.
Patients in opioid substitution programs or taking naltrexone
Introduction
Methadone and buprenorphine are used in the treatment of opioid addiction via opioid substitution programs.
Naltrexone, an opioid antagonist, is used to reinforce abstinence in the treatment of opioid and alcohol
dependence. If patients taking methadone, buprenorphine or naltrexone present with acute pain, close
communication with usual care providers is essential to ensure appropriate initial and ongoing management.
Methadone
Methadone is commonly used for the treatment of opioid addiction. It is a long-acting mu-opioid receptor
agonist (mean half-life 22 hours, range 4 to 190 hours), but also has effects on the N-methyl-D-aspartate
(NMDA) and serotonin (5-HT) receptors. Methadone suppresses craving and withdrawal symptoms. Usual
daily oral doses are up to 100 mg. In the once-daily doses used in the management of opioid addiction, it does
not provide adequate analgesia for 24 hours. Chronic use of methadone may heighten sensitivity to pain,
which can develop within a month of starting therapy.
If the patient on methadone presents with a new acute pain problem, contact the patient’s methadone provider
to verify the dose and discuss management plans. Consider early consultation with an acute pain service.
Continue the patient’s usual methadone dose and add additional opioid on a ‘PRN’ basis for pain
management. If unable to take medication by mouth, seek specialist advice. Liaise with the patient’s
methadone provider regarding resumption of dosing on discharge.
Buprenorphine
Buprenorphine is a long-acting opioid (half-life 28 hours) that is a mu-receptor agonist and a kappa-receptor
antagonist. Buprenorphine is used in high dose in opioid substitution programs to reduce craving and suppress
withdrawal symptoms. It is taken sublingually in doses of 8 to 32 mg (Subutex) once a day or second daily.
Buprenorphine is also available combined with naloxone (Suboxone) to reduce potential for parenteral abuse.
Sublingual buprenorphine is about 30 times more potent than oral morphine.
Managing acute pain in patients stabilised on buprenorphine requires specialist input. The patient’s
buprenorphine provider should also be contacted to verify the dose and discuss management plans.
Naltrexone
Naltrexone is an opioid antagonist used in the prevention of relapse in opioid and alcohol dependence. It
prevents the user from experiencing pleasurable effects with subsequent opioid or alcohol use by blocking the
mu-opioid receptor. The half-life of naltrexone is 14 hours, but it remains bound to opioid receptors for over
24 hours. The usual dose is 25 to 50 mg orally, daily.
Opioid analgesia is frequently ineffective in naltrexone recipients. Conversely, when naltrexone is wearing off
users may be supersensitive to opioids, and opioid adverse effects can develop rapidly. This may be due to
mu-opioid receptor upregulation.
Managing acute pain in patients maintained on naltrexone requires specialist input, because the pharmacology
of naltrexone is complex and pain control often requires multimodal therapies.
Acute pain in patients recovering from an opioid addiction

Patients recovering from opioid addiction pose another problem. They will be appropriately concerned about
relapse if opioids are administered. Effective communication and planning are essential. Reassure the patient
that the risk of relapse is small if opioid medication is used appropriately, and it could be higher if inadequate
doses of analgesic are used. Where possible, use alternative methods of analgesia and explore nondrug
alternatives. Treatment must include regular reassessment and appropriate changes if pain relief is inadequate.
For hospitalised patients, careful discharge planning is important to ensure appropriate weaning of analgesics.
Key references
Acute pain in opioid-tolerant patients: introduction
The opioid-tolerant patient (section 11.7). In: Macintyre PE, Scott DA, Schug SA, Visser EJ, Walker SM, editors.
Acute pain management: scientific evidence. 3rd ed. Melbourne: Australian and New Zealand College of
Anaesthetists and Faculty of Pain Medicine; 2010.
Carroll IR, Angst MS, Clark JD. Management of perioperative pain in patients chronically consuming opioids. Reg
Anesth Pain Med 2004;29(6):576–91. [ ]
Huxtable CA, Roberts LJ, Somogyi AA, Macintyre PE. Acute pain management in opioid-tolerant patients: a
growing challenge. Anaesth Intensive Care 2011;39(5):804–23. [ ]
Mehta V, Langford RM. Acute pain management for opioid dependent patients. Anaesthesia 2006;61(3):269–76. [
]
Acute pain in patients prescribed opioids for chronic pain
Anesth Pain Med 2004;29(6):576–91. [ ]
Hadi I, Morley-Forster PK, Dain S, Horrill K, Moulin DE. Brief review: perioperative management of the patient
with chronic non-cancer pain. Can J Anaesth 2006;53(12):1190–9. [ ]
]
Acute pain in patients with an opioid addiction
Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or
buprenorphine therapy. Ann Intern Med 2006;144(2):127–34. [ ]
Anesth Pain Med 2004;29(6):576–91. [ ]
Gibson AE, Degenhardt LJ, Hall WD. Opioid overdose deaths can occur in patients with naltrexone implants. Med
J Aust 2007;186(3):152–3. [ ]
Lintzeris N, Lee S, Scopelliti L, Mabbutt J, Haber PS. Unplanned admissions to two Sydney public hospitals after
naltrexone implants. Med J Aust 2008;188(8):441–4. [ ]
]
Roberts DM, Meyer-Witting M. High-dose buprenorphine: perioperative precautions and management strategies.
Anaesth Intensive Care 2005;33(1):17–25. [ ]
Roberts LJ. Managing acute pain in patients with an opioid abuse or dependence disorder. Aust Prescr
2008;31(5):133–5. [URL]
Vickers AP, Jolly A. Naltrexone and problems in pain management. BMJ 2006;332(7534):132–3. [ ]
Weschules DJ, Bain KT. A systematic review of opioid conversion ratios used with methadone for the treatment of
pain. Pain Med 2008;9(5):595–612. [ ]
Acute pain in patients recovering from an opioid addiction
Anesth Pain Med 2004;29(6):576–91. [ ]
]
Procedure-related pain in adults
Interventions for painful procedures
Many patients undergo painful procedures such as lumbar puncture, bone marrow aspiration, dressings, computer
tomography–guided biopsies, drainage procedures and difficult peripheral or central venous cannulation. Any
procedure requiring intravenous or inhaled analgesia, with or without accompanying sedation, must be performed
by suitably trained staff in an area with adequate monitoring facilities and resuscitation equipment. Detailed
information about staffing requirements, facilities and equipment, and monitoring requirements is provided in
guidelines prepared by the Australian and New Zealand College of Anaesthetists and seven other specialty
societies or colleges [Note 1].
Patients often experience unnecessary pain and distress at the time of interventions. Providing satisfactory pain
management during a procedure helps to improve patient cooperation and satisfaction, and minimises fear and
anxiety during any subsequent procedures.
Management will depend on the type of procedure, the need for immobility, the anticipated level of pain, and the
patient’s age, physical condition, medical comorbidities and emotional state. Some procedures can be performed
with use of nonsedating analgesics (see Procedures without sedation). For more painful procedures or more
distressed patients, sedation may be required (see Procedures with sedation).
Definitions for analgesia and the various levels of sedation used during procedures are listed in Table 1.9.
For information on management of procedure-related pain in children, see Procedure-related pain in children.
Definitions for analgesia and levels of sedation used during procedures (Table 1.9) [NB1]
Intervention Definition
absence or reduction of pain in response to stimulation that would
analgesia normally be painful. Analgesia may be induced by drugs that act locally
or systemically. Some systemic analgesics also induce sedation
a state of drug-induced depression of consciousness used to facilitate
procedural sedation tolerance of uncomfortable or painful diagnostic or interventional
medical, dental or surgical procedures
refers to the degree to which consciousness is depressed. This is
determined by monitoring the patient’s ability to respond purposefully to
depth of sedation verbal commands or tactile (innocuous or painful) stimuli. Although
depth of sedation is a continuum, some levels of sedation have been
defined to assist risk management [NB1] and documentation:
the patient is spontaneously awake and responds normally to
minimal sedation (or anxiolysis)
verbal commands
moderate sedation (or conscious the patient can be easily roused and responds purposefully to
sedation) verbal commands, either alone or accompanied by light touch
the patient cannot be easily roused but does respond purposefully

deep sedation after repeated or painful stimulation. Reflex withdrawal from a
painful stimulus is not considered a purposeful response
a drug-induced state characterised by absence of purposeful response to

any stimulus. General anaesthesia is usually associated with impaired
protective airway reflexes, depression of respiration and disturbance of
general anaesthesia
circulatory reflexes. General anaesthesia requires the exclusive attention
of an anaesthetist, or other appropriately trained and credentialed medical
specialist within his/her scope of practice.
NB1: Moderate and deep sedation are associated with progressively higher risk of impairment of protective airway reflexes, central respiratory drive
and circulatory reflexes. The person administering sedation must be able to rescue the patient from adverse events.
Adapted from:
Australian and New Zealand College of Anaesthetists, et al. Guidelines on sedation and/or analgesia for diagnostic and interventional medical, dental or
surgical procedures [PS9]. Melbourne: ANZCA; 2010. [URL]
Merskey H, Bogduk N, editors for IASP Task Force on Taxonomy. Classification of chronic pain: descriptions of chronic pain syndromes and definitions
of pain terms. 2nd ed. Seattle: International Association for the Study of Pain; 1994.
American Society of Anesthesiologists. Standards, guidelines, statements and other documents. Continuum of depth of sedation: definition of general
anesthesia and levels of sedation/analgesia. American Society of Anesthesiologists; 2009.
Note 1: Australian and New Zealand College of Anaesthetists, et al. Guidelines on sedation and/or analgesia for
diagnostic and interventional medical, dental or surgical procedures [PS9]. Melbourne: ANZCA; 2010. [URL]
Patient assessment before a painful procedure

All patients should be assessed before a procedure is conducted. Patients requiring sedation in addition to
analgesia must have a comprehensive assessment before any drug is administered. Assessment should include a
medical history, examination and relevant investigations.
The patient’s fasting status should be determined. For emergency procedures that need to be performed
immediately, fasting is not required. However, the most senior staff available should assess the patient and clinical
context, weigh the benefits and risks of proceeding with sedation, and optimise risk management.
For urgent cases requiring a procedure for which some delay is acceptable, a minimum of 2 hours fasting time is
recommended after carefully weighing the benefits and risks of sedation.
For other procedures that can be delayed, the ideal fasting times are:
6 hours from solids

2 hours from clear fluids.
When the fasting time falls short of these recommendations, the most senior staff available should assess the
patient and clinical context, weigh the benefits and risks of proceeding with sedation, and optimise risk
management. This may involve airway protection. Irrespective of the fasting time, the possibility of vomiting and
aspiration must always be considered. Seriously ill or injured patients should be assumed to have a full stomach.
Patients with respiratory or cardiovascular disease, or those with airway compromise, are at higher risk from
sedation. Staff with airway and resuscitation skills and training in sedation should be present to care for such
patients during the procedure. Specific personnel requirements depending on the patient’s physical status and the
type of sedation are outlined in the joint college guidelines [Note 2].
Assessment of the patient and procedure must be clearly documented in the patient record.
Preparing for a painful procedure

The key to managing procedure-related pain is anticipation. This necessitates assessment of the patient (see
Patient assessment); knowledge of what the procedure will involve and the pain and distress expected; and timely
administration of analgesics that are well matched to the duration of anticipated pain.
General principles include:
Ensure that the planned procedure is essential—Will this diagnostic test change management? Is a less
invasive treatment an option? Can it be performed at the same time as another procedure requiring analgesia
or anaesthesia?
For painful procedures, make an analgesia plan—sedation is not a substitute for analgesia.
Use the least intrusive and least sedating analgesia that will meet the patient’s needs (see Figure 1.5).
Give analgesic long enough before the procedure for optimal analgesia to occur.
Formulate a back-up plan in the event that pain or distress becomes unmanageable during the procedure.
Assess and manage sedation-related risk. Ensure appropriate equipment and staff are available for
monitoring and managing adverse events (see Table 1.10).
Keep an accurate record of the procedure, drugs used and observations made before, during and in the
recovery phase of the procedure. Use of a preformatted form is preferable.
The proceduralist should establish a supportive relationship with the patient. The nature of the procedure, any
risks and what to expect after the procedure should be explained. A written summary is useful. Informed consent
for the procedure, and for sedation if applicable, should be obtained from the patient.
For patients undergoing repeated procedures, adequate ‘procedure-free times’ should be agreed between the
patient and staff. Use of cognitive behavioural techniques, including guided imagery, hypnosis and relaxation may
be appropriate in some cases (see Chronic pain: psychological techniques).
Steps to consider in planning procedural analgesia (Figure 1.5)
Painful procedures without sedation

Techniques that can be employed to minimise pain during procedures not requiring sedation include:
nonsedating oral analgesics (eg paracetamol, nonsteroidal anti-inflammatory drugs)

local anaesthetic infiltration (see Table 1.7 for maximum safe single doses of local anaesthetic in adults)
nerve or plexus block
regional intravenous anaesthesia.
Painful procedures with sedation

Overview
For some diagnostic or interventional procedures (see Box 1.6 for examples), the objective is to produce both
analgesia and a degree of sedation. Procedural sedation is a continuum from minimal, through moderate, to deep
sedation and general anaesthesia (see Table 1.9 for definitions). It is easy to inadvertently proceed from one level
of sedation to another, especially if using potent or intravenous medication. Staff must be skilled and accredited to
manage sedation at least one level deeper than that intended.
Procedural sedation is a continuum from minimal, through moderate, to deep sedation and general anaesthesia.
Sedation might be required to reduce fear and anxiety, to allow a particular analgesic technique to be tolerated, or
to minimise recall of unpleasant events. The level of sedation should be appropriate to the procedure and the
physiological status of the patient, and induced by the most appropriate medication using the safest route.
Adequate analgesia should be a priority. Excessive sedation to compensate for inadequate analgesia is potentially
dangerous.
Deep sedation should not be used as an alternative to adequate pain relief.
Unfortunately no ideal drug for producing sedation exists and patient responses to sedative drugs can be variable
and unpredictable. Therefore most drugs used in procedural sedation are given in small incremental doses titrated
to clinical effect. This may take some minutes to achieve. Techniques and drugs used should have a safety margin
adequate to minimise the risks of complete loss of consciousness.
Patients at increased risk of adverse events include:
older people
patients with obstructive sleep apnoea (or other forms of significant respiratory disease), morbid obesity, or
a difficult airway (eg micrognathia, large tonsils)
patients with reduced kidney or liver function, who may not metabolise drugs normally
patients already on opioids or other central nervous system depressants.
Sedation must not be used for people with raised intracranial pressure (closed head injury, tumour or haematoma)
because hypercarbia exacerbates the raised intracranial pressure.
Do not give sedation to patients with raised intracranial pressure.
There is a potential for airway compromise, respiratory depression, circulatory collapse or drug reactions
following administration of combinations of opioid analgesics and sedatives, and appropriate observations and
monitoring should be maintained. Combined administration of sedatives/analgesics from different drug classes
can produce excessive sedation and additive or synergistic effects on respiratory depression.
Clinicians administering sedation must be competent in airway management and resuscitation skills. When there
is an intention to produce loss of consciousness, an anaesthetist or other appropriately trained and credentialed
medical specialist should be present (see joint college guidelines for required staffing levels [Note 3]). Any
procedure requiring intravenous or inhaled analgesia with accompanying sedation must be performed in an area
with adequate monitoring facilities and resuscitation equipment.
Clinicians administering sedation must be competent in airway management and resuscitation skills.
The technique must be tailored to the physical status of the patient and the level of expertise available. Full
general anaesthesia may be preferable for some procedures (particularly for uncooperative patients, and patients at
high risk, see above), and for patients with significant cognitive impairment. Minimal sedation, with an opioid
and/or local anaesthetic, may be satisfactory for others.
If the procedure cannot be completed under sedation, it must be terminated and rescheduled under general anaesthesia.
Some procedures likely to require sedation (Box 1.6)
Nearly all patients will require sedation for:
cardioversion
reduction of dislocation of large joints (eg shoulders, hips, knees, elbows)
reduction and splinting of long bone fractures.
Some patients will require sedation for:
burns dressings
central line insertion
chest drain insertion
deep foreign body removal
drainage of abscess
lumbar puncture
suturing (especially in anxious and cognitively impaired adults).
Minimal sedation
Inhaled analgesics (nitrous oxide [50% to 70% in oxygen] or methoxyflurane) can be used when minimal to
moderate analgesia is required rapidly for short painful procedures. Monitoring requirements and
contraindications for nitrous oxide are similar in adults and children (see Pharmacological management of pain in
children: inhalational agents). For cautions with use of methoxyflurane, see Stepwise approach to acute pain
management.
For patients requiring minimal sedation and analgesia for a planned procedure, an oral opioid may be adequate.
Oxycodone is commonly used. A suitable dose is:
oxycodone immediate-release 5 to 10 mg orally, as a single dose 30 minutes before the

procedure.
The lowest dose possible should be used, especially in older people.

Patients already receiving long-term opioids will require supplemental analgesia, and their analgesic requirements
may be higher than anticipated. It is important to continue any regular analgesia both before and after the
procedure.
Moderate sedation
Various drugs are available to produce moderate sedation. The clinician administering analgesia and/or sedation
should maintain appropriate verbal contact with the patient.
Intravenous sedation is commonly achieved with titrated small doses [Note 4] of an opioid. A suitable regimen is:
fentanyl 50 to 100 micrograms IV, followed if necessary by 25 to 50 micrograms every 5

minutes up to a maximum total dose of 200 micrograms. Use lower doses in older or frail
patients.
Morphine has a slower onset of action than fentanyl but may be used if postprocedural pain is expected.
The addition of a benzodiazepine may be required to provide adequate sedation. Midazolam is commonly used
but patient response can be variable, so it should only be used by appropriately trained staff. The combination of
opioids and benzodiazepines has a synergistic effect on respiratory depression. Appropriate monitoring (see Table
1.10) is essential and resuscitation facilities must be immediately available. A suitable regimen is:
midazolam 2 mg IV over 1 to 2 minutes, followed if necessary by 1 mg every 2 minutes

until patient is adequately sedated. Total doses of more than 5 mg are rarely needed. Older
patients may respond to 0.5 to 1 mg.
Other drugs may be required to counteract adverse or prolonged effects of the sedation and analgesia. See Drugs
used for benzodiazepine and opioid reversal for information on opioid and benzodiazepine reversal.
Other drugs (eg ketamine, propofol) may be used to provide deeper levels of sedation where appropriately trained
staff, equipment and protocols for their use are available. Propofol is an anaesthetic agent—there is only a small
margin between the sedative dose and the anaesthetic dose.
Note 4: For patients undergoing multiple/repetitive procedures, the effectiveness of the timing and dose of
analgesic used last time is a guide to dose requirements on subsequent occasions.
Monitoring and managing sedation-related adverse events

The majority of adverse events with sedation relate to loss of airway control, respiratory compromise and
hypoxia.
Adverse events are more likely with deeper levels of sedation, if two or more types of sedative drugs are used, and
if the sedative drug effects outlast the stimulating procedure.
It is essential that an appropriately trained person be assigned to exclusively monitor the patient throughout
sedation until recovered. Staff must be able to assess sedation level, manage sedation at least one level deeper than
that intended, and have resuscitation skills relevant to the patient’s age and condition (see Table 1.10).
Monitor according to the depth of sedation actually achieved (see Table 1.10). If sedation deepens during
monitoring, escalate care accordingly. If the patient is to remain undisturbed (sedation level not being evaluated),
staff and monitor as for deep sedation.
Staffing and monitoring for different levels of sedation (Table 1.10)
Sedation depth [NB1] Personnel [NB2] Monitoring

staff in clinical area should have ALS
minimal sedation level [NB3] and pain
skills
specified staff member with ALS skills
to exclusively monitor the patient (no
other tasks) + an assistant available if sedation level [NB3] and pain, airway
moderate required patency, rate and depth of breathing,
and pulse oximetry continuously
staff in clinical area able to provide
bag–mask ventilation if required
if deep sedation is unintended, call
specified staff member with advanced for help and escalate care
airway and resuscitation skills to
deep exclusively monitor the patient (no sedation level [NB3] and pain, airway
other tasks) + a skilled assistant at all patency, rate and depth of breathing,
times pulse oximetry, ECG, BP and expired
CO2 continuously
if loss of consciousness is
unintended, call for help and
specified staff member with advanced
escalate care
unconscious airway and resuscitation skills and
ability to manage and exclusively sedation level [NB3] and pain, airway
(reflex response to pain only) monitor the patient (no other tasks) + a patency, rate and depth of breathing,
skilled assistant at all times pulse oximetry, ECG, BP and expired
CO2 continuously
ALS = advanced life support; BP = blood pressure; CO2 = carbon dioxide; ECG = electrocardiogram
NB1: See Table 1.9 for definitions of sedation depth.
NB2: For more detailed information on personnel requirements, see Australian and New Zealand College of Anaesthetists, et al. Guidelines on sedation
and/or analgesia for diagnostic and interventional medical, dental or surgical procedures [PS9]. Melbourne: ANZCA; 2010. [URL]
NB3: See Table 1.25 for an example of a sedation score classification.
Drugs used for benzodiazepine and opioid reversal
Flumazenil
If oversedation occurs, escalate monitoring and manage as for a deteriorating patient. If flumazenil is required to
reverse midazolam, a suitable regimen is:
flumazenil 0.1 to 0.2 mg IV, with increments every 1 to 2 minutes titrated to effect up to a
maximum of 1 mg.
The effect commences within 1 minute of the injection. The duration of the flumazenil’s effect is approximately
45 minutes, after which time re-sedation may occur depending on the midazolam dose and route of
administration.
Naloxone
Naloxone may be used to reverse opioid effects if required. For detailed information on naloxone dosing, see
Acute postoperative pain: naloxone.
Key references
Procedure-related pain in adults: introduction
American Society of Anesthesiologists. Standards, guidelines, statements and other documents. Continuum of depth
of sedation: definition of general anesthesia and levels of sedation/analgesia. American Society of Anesthesiologists;
2009.
Australian and New Zealand College of Anaesthetists, et al. Guidelines on sedation and/or analgesia for diagnostic
and interventional medical, dental or surgical procedures [PS9]. Melbourne: ANZCA; 2010. [URL]
Merskey H, Bogduk N, editors for IASP Task Force on Taxonomy. Classification of chronic pain: descriptions of
chronic pain syndromes and definitions of pain terms. 2nd ed. Seattle: International Association for the Study of Pain;
1994.
Procedure-related pain in adults: patient assessment
Procedure-related pain in adults: preparing for the procedure
Procedure-related pain in adults: procedures without sedation
Procedure-related pain in adults: procedures with sedation
Bell A, Taylor DM, Holdgate A, MacBean C, Huynh T, Thom O, et al. Procedural sedation practices in Australian
emergency departments. Emerg Med Australas 2011;23(4):458–65. [ ]
Holdgate A, Taylor DM, Bell A, MacBean C, Huynh T, Thom O, et al. Factors associated with failure to successfully
complete a procedure during emergency department sedation. Emerg Med Australas 2011;23(4):474–8. [ ]
Taylor DM, Bell A, Holdgate A, MacBean C, Huynh T, Thom O, et al. Risk factors for sedation-related events during
procedural sedation in the emergency department. Emerg Med Australas 2011;23(4):466–73. [ ]
The transition from acute to chronic pain
Mechanisms and precipitants in the transition to chronic pain
Adequate early pain management may prevent the transition from acute to chronic pain.
The International Association for the Study of Pain defines chronic pain as pain which has been present daily
for 3 months. However, this definition gives no information about the severity of the pain or the inciting
event. The process of central sensitisation was described in a seminal paper in 1983 and provided the first
insights into the mechanisms by which an acute pain state could transition into a chronic pain state.
Central sensitisation is mediated by activities that not only increase excitability but also decrease inhibitory
inputs at the level of the dorsal horn of the spinal cord. Some of these activities may be targets for therapeutic
interventions (eg with local anaesthetics, the gabapentinoids, N-methyl-D-aspartate [NMDA]-receptor
antagonists, and serotonin and noradrenaline reuptake inhibitors [SNRIs]).
There is increasing evidence that a number of mechanisms contribute to the transition from an acute to a
chronic pain state. These include (but are not limited to):
an upregulation of NMDA receptors at the level of the dorsal horn in the spinal cord—this has been
implicated in the processes of wind-up and increased excitability thereby augmenting sensory nerve
transmission
changes in the peripheral sensory afferent neurone resulting in ‘hyperalgesic priming’ either by
prolonged inflammation or opioid exposure—the latter may help to explain the mechanisms that are
common to both the transition of acute to chronic pain and the development of opioid tolerance
ectopic activity in transected nerves producing the spontaneous pain characteristic of some neuropathic
pain states—this may be, at least in part, due to alterations in sodium channel expression in neural
damage.
Chronic pain may be precipitated by:
acute pain following surgery or injury

acute pain associated with illnesses such as herpes zoster, HIV
stroke resulting in central poststroke pain syndromes
spinal cord injury resulting in radicular ‘at level’ pain, distal neuropathic pain and various
musculoskeletal pain syndromes
therapy with antineoplastic drugs.
It remains uncertain why only some patients develop chronic pain after an acute illness, injury or trauma. A
number of psychosocial factors common to patients who have experienced different pathophysiological insults
may be implicated. Increasingly, genetic factors are thought to have a role in the development and expression
of some chronic pain syndromes and in the future may provide targets for analgesic therapies.
Risk factors for postsurgical pain syndromes

Definitions for persistent postsurgical pain vary across the literature and criteria are poorly defined.
Comparative studies are therefore difficult to interpret. An early definition required that the pain be of at least
2 months duration postoperatively, that there be no other cause for the pain (eg progressive malignancy or
chronic infection), and that there be no pre-existing problem to explain the ongoing pain. However, other
definitions have been employed. The relatively novel technique of using mesh in surgical repairs of inguinal
hernias has also confounded the issue, as the inflammatory response generated by the mesh may persist for
longer than the 2 months required to meet the original definition.
The prevalence of postsurgical pain syndromes is variably related to different procedures, with amputation,
postherniorrhaphy, post-thoracotomy and postmastectomy pain syndromes being the most common (see Table
1.11). These occur with different frequencies and at different times (eg postherniotomy pain syndromes
decrease in frequency over the first 12 months, as does phantom limb pain). This suggests that prolonged pain
following certain surgical procedures may be ameliorated by aggressive treatment within the first 12 months.
Many studies on postsurgical pain are limited by poor study design. Many are retrospective questionnaires
that rely on patient recall months to years after surgery. Other confounding factors include the use of different
surgical techniques and the failure to account for improvements in surgical technique over time.
The risk factors for the transition of acute to persistent postsurgical pain can be divided into preoperative,
intraoperative and postoperative factors (see Table 1.12).
The one unifying predictive factor shown to be important in the transition of acute to persistent pain in the
postsurgical population is severe acute pain. The adoption of acute pain services in many hospitals has
improved postoperative analgesia, coupled with better patient satisfaction. The Cochrane Collaboration is
currently reviewing the role of pharmacotherapy for the prevention of chronic pain after surgery in adults
[Note 1].
Severe acute postoperative pain is the most important risk factor for persistent postsurgical pain.
It is now recognised that many surgical procedures inadvertently or unavoidably result in injury to peripheral
nerves and that this injury can become the focus for the development of neuropathic pain. A meta-analysis of
perioperative administration of a gabapentinoid (gabapentin or pregabalin) concluded that these drugs can
reduce the incidence of persistent postsurgical pain, but better-designed clinical trials are needed to confirm
this [Note 2].
Neuropathic pain may be under-recognised in the perioperative setting. It can present as pain with
dysaesthetic features such as burning, shooting or numbness in the area of pain. It is not consistently
responsive to opioids and other specific drugs may be needed. Once identified, neuropathic pain should be
treated specifically and not by increasing the dose of opioid. Suitable drugs include tricyclic antidepressants
and antiepileptics (including pregabalin and gabapentin) (see Neuropathic pain). Expert advice should be
sought.
Other factors that could potentially be modified to reduce the transition of acute to persistent postsurgical pain
include:
changes in surgical technique to reduce the potential for neural trauma—for example, light-weight mesh
in hernia repairs; endoscopic versus traditional surgical techniques for inguinal herniorrhaphy,
cholecystectomy and thoracotomy
education of patients about postoperative expectations—potential adverse outcomes of a procedure
(including persistent postoperative pain) should be explained as well as potential benefits. This is
particularly important where patients may have relatively few symptoms or indications for a procedure
(eg the asymptomatic hernia found incidentally on ultrasound examination, cosmetic breast surgery,
elective caesarean section)
adequate psychological preparation of patients—with shorter hospital stays and increasingly complex
surgery being performed on a day-stay basis, patients have fewer opportunities to discuss issues of
concern such as return to work. Recognising anxiety and depression and attempting to allay these (by
empathic dialogue and truthful discussion about the expected risks and benefits of a given procedure)
are important in patient preparation for surgery
involvement of patients in their postoperative care—encourage patients to be proactive with their
management and not passive participants. Set daily goals and explain to the patient the importance of
achieving these goals, with improved function the primary objective. Goals include normalising
behaviour with a timetable for the patient to get dressed, shower, attend physiotherapy, go to the
hospital cafeteria or for a walk outside. Patients should not stay in bed unless medically unstable
better counselling of patients about their analgesic therapy—many patients remain confused about why
and when they should take medications. For example, clearly explain to the patient that the purpose of
analgesics is to reduce their pain so they can get out of bed and maximise their rehabilitation. Also
caution about the problems of long-term analgesic use
staff attitudes—for patients who are not progressing due to pain, staff accountability and
multidisciplinary meetings are essential to avoid conflicting messages being given to the patient. A
thorough multidisciplinary assessment should be done and a management plan formulated.
Future work will examine pharmacogenomics as a predictor for the development of persistent postoperative
pain syndromes. Certain gene polymorphisms have been associated with less efficacious acute pain
management and hence an increased risk of the patient developing persistent postsurgical pain. A number of
gene mutations have been identified that alter pain perception or sensitivity. Drug metabolism may also be
affected by genetic polymorphisms and this may have implications for better acute pain management with
analgesics tailored to a patient’s genetic make-up.
Persistent postoperative pain has significant implications for patients. If their functional state is severely
compromised they may be unable to undertake rehabilitation programs. For example, following total joint
arthroplasty, persistent pain around the affected prosthesis may lead to secondary deconditioning, venous
thromboembolic disease and, eventually, loss of independence.
Estimated prevalence of postoperative pain by procedure (Table 1.11)
Prevalence of severe
Prevalence of Prevalence of persistent
Surgical procedure persistent postoperative
preoperative pain postoperative pain
pain
Pain new in location or character [NB1]
stump pain 62%
lower extremity very common if ischaemic
phantom pain 70% 5% to 10%
amputation disease
phantom sensations 82%
breast surgery:
augmentation
mammoplasty rare 20% 2.3%
simple mastectomy rare 30% 5% to 10%

mastectomy +
axillary node rare 50% up to 10%
dissection
thoracotomy:
posterolateral
approach rare 33% 5% to 13%
VATS rare 25% 1% to 5%

radical prostatectomy rare 32% N/A
62%, associated with
hysterectomy 32% 6%
uterine pathology
sternotomy:
CABG angina common 30% 3% to 5%
valve replacement rare 32% 3% to 5%
colectomy rare 28% N/A
common and usually
laparoscopic
associated with 23% 2%
cholecystectomy
cholelithiasis
vasectomy rare 15% 1% to 5%
inguinal hernia repair incident pain common 12% 2% to 4%
caesarean section (labour pain) 6% 1%
lens implantation rare less than 1% N/A
Persistence of pre-existing pain [NB2]
pelvic fracture open almost universal and
48% N/A
fixation associated with fracture
lumbar spinal surgery:
common and associated
spinal stenosis with nerve root N/A 31%
impingement
discectomy with nerve root 44% N/A
impingement
almost universal and
total hip replacement associated with joint 20% 3%
disease
root canal surgery with tooth decay 12% N/A
CABG = coronary artery bypass graft; N/A = not available; VATS = video-assisted thoracoscopic surgery
NB1: Most common syndromes of persistent or chronic pain, surgery was not undertaken for pain relief, pain is usually neuropathic.
NB2: Pain severe and present longer than expected, surgery was for pain relief, pain multifactorial and often associated with original condition (eg
continued inflammation).
Adapted with permission from: Perkins F, Ballantyne J. Postsurgical pain syndromes. In: Stannard CF, Kalso E, Ballantyne J, eds. Evidence-based
chronic pain management. Oxford: Blackwell Publishing Ltd; 2010. p.195. © 2010 by Blackwell Publishing Ltd.
Risk factors for the development of postsurgical pain syndromes (Table 1.12)
Preoperative factors
pre-existing pain of more than 1 month in duration (not necessarily related to the operative site)
repeat surgery
psychological vulnerability
preoperative anxiety
female gender
younger age (adults)
worker’s compensation (? secondary gain)
genetic predisposition
inefficient diffuse noxious inhibitory control (DNIC)
Intraoperative factors
surgical approach especially with regard to the risk of nerve damage—minimally invasive surgical
approaches have demonstrated improved outcomes as have surgical approaches that seek to identify
and preserve the nerves
infection and haemorrhage—increase the rate of reoperation and consequently the likelihood of
developing postsurgical pain syndromes
anaesthetic techniques—retrospective data for hysterectomy and caesarean section demonstrate a risk
reduction of approximately 50% when spinal anaesthesia versus general anaesthetic techniques are
employed
Postoperative factors
acute pain (moderate to severe) [NB1]
radiation therapy to the surgical area
neurotoxic chemotherapy
depression
psychological vulnerability
anxiety
NB1: most important risk factor

Adapted with permission from: Macintyre PE, Scott DA, Schug SA, Visser EJ, Walker SM, eds. Acute pain management: scientific evidence. 3rd
ed. Melbourne: Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine; 2010. p.11.
Note 1: Gilron I, Moore R, Wiffen P, McQuay H. Pharmacotherapy for the prevention of chronic pain after
surgery in adults (protocol). Cochrane Database Syst Rev 2010;(1):CD008307. [URL]
Note 2: Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic
postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis. Anesth
Analg 2012;115(2):428-42. [URL]
Causes of chronic low back pain

Low back pain is common in Western societies. Most patients with low back pain seen in primary care will
have a nonspecific mechanical cause and a self-limited clinical course. Before a diagnosis of ‘nonspecific’
back pain is made, it is important to exclude causes of back pain that are associated with other disease states
(eg multiple myeloma, ankylosing spondylitis, metastatic malignancy), or that have primary pathology of the
anatomical structures of the back (eg discitis, osteoporotic crush fractures).
The outcome of a single episode of low back pain is generally favourable. However, for many patients there is
a recurrent and variable course, with individual patient characteristics accounting for a substantial variation in
outcome. Some patients will have severe chronic levels of pain.
Risk factors for the transition from acute to chronic nonspecific low back pain are not well understood.
Nonspecific low back pain discusses the most consistent factors associated with poor outcomes and gives
detailed information about treatment strategies.
Risk factors for chronic postinjury pain

Chronic pain is common at 12 months following severe major trauma with consequences including poor
functional outcomes and increased psychological distress. Nearly 17% of these patients will report pain scores
of 5 or more (on a 0 to 10 numerical rating scale) at the 12-month mark. The ability to accurately predict those
patients who are likely to transition from acute to chronic pain states following injury would allow early triage
into chronic pain management services with the resources to adopt a biopsychosocial management approach.
Patients who transition from an acute to a chronic pain state following trauma tend to be male (in contrast to
many other chronic pain conditions where females predominate). They are, on the whole, younger than
patients who develop persistent postsurgical pain. The pain tends to involve the limbs (especially the upper
limb, where complex regional pain syndromes and brachial plexus lesions predominate), and the spine.
Chronic pain secondary to whiplash injuries is common in this group of patients, as is low back pain.
Factors that contribute to the transition from acute to chronic pain following injury include:
pre-injury unemployment
severe injury
high acute pain scores
low expectations about being able to control the pain (ie low self-efficacy).
Similarly, the severity of chronic pain following an injury is associated with worse pre-injury health, pre-
injury unemployment, high acute pain scores, strong beliefs about the need for analgesics, and a compensable
injury. As is the case in patients who transition from acute to persistent postsurgical pain, more severe acute
pain predicts poorer pain outcomes in the postinjury group.
These patients should be counselled about their medications and encouraged to be active participants in their
rehabilitation.
Overview of complex regional pain syndromes

Complex regional pain syndromes (CRPS) are increasingly recognised following often quite trivial injury or
surgery. Less commonly, they are secondary to primary lesions of the nervous system. CRPS may be divided
into two major types—CRPS I usually occurs following trauma, of which a Colles fracture is a common
precipitant, while CRPS II develops after partial injury to a peripheral nerve.
CRPS affects the limbs (upper limbs more frequently in adults and lower limbs in children) with the worst
pain felt in the most distal part of the extremity. The pain is not limited to the distribution of a peripheral
nerve or root, and its severity is out of proportion to that expected. The pain is often described as a
spontaneous burning sensation distally which increases when the limb is drooping. Stimulus-evoked pain and
deep somatic pain elicited by pressure and movement of the joints distally are common findings. Additionally,
CRPS II by definition is associated with a loss of sensory and motor function in the distribution of the affected
nerve.
If pain in the distal limbs is disproportional to the injury, consider CRPS.
Exaggerated activity in the sympathetic nervous system may produce early symptoms and signs of
overactivity with temperature change, colour change (rubor, cyanosis or pallor), diaphoresis and oedema of
the affected limb. Trophic changes, change in hair growth patterns, nail abnormalities, skin fibrosis, joint
contracture and osteoporosis may be present in chronic stages.
Abnormalities in motor function may also be seen, ranging from a loss of fine motor movements to a tremor
to frank dystonia. On rare occasions a sensory neglect of the affected limb may be present.
It is not clear why only some individuals develop CRPS following injury or surgery that is often trivial. There
is considerable debate regarding the pathophysiological basis for CRPS with the condition exhibiting both
inflammatory and neuropathic phenomena. Until this is resolved it is difficult to direct treatment appropriately.
Current treatment emphasises early rehabilitation aiming at functional restoration of the affected limb. This
can only be achieved with early analgesia using drugs such as opioids, antidepressants, the gabapentinoids and
carbamazepine. Corticosteroids have also been used with some success in the early phases of CRPS when
inflammation predominates and precludes or impedes physical therapy or functional restoration. Early referral
to a pain management clinic for the full suite of rehabilitation programs including psychological treatments to
provide education and facilitate coping skills is important for patient outcome.
Risk factors for postherpetic neuralgia

Postherpetic neuralgia represents the transition and persistence of the pain of acute herpes zoster (shingles).
Factors that predict an increased risk of postherpetic neuralgia include:
advancing age (especially over 80 years)

presence and severity of the prodromal pain
severity of acute herpes zoster pain.
Postherpetic neuralgia is difficult to manage and can result in patients becoming withdrawn, depressed and
increasingly dependent. This has significant implications for long-term care in older people.
Strategies to prevent the transition from acute herpes zoster to postherpetic neuralgia include:
vaccination of adults to improve natural cell-mediated immunity at an age when it is declining

(although about 350 people need to be vaccinated to prevent one case of postherpetic neuralgia)
early identification of herpes zoster and appropriate antiviral therapy
aggressive analgesic management of patients with developing or established herpes zoster–related
acute pain.
See Postherpetic neuralgia for information on management.
Risk factors for chronic pain syndromes after antineoplastic therapy

Cancer can be associated with pain due to progressive disease or the treatment regimens (including surgery,
chemotherapy and radiotherapy). The increasing efficacy of cancer treatments has led to an increased
prevalence of patients in the community either living with cancer as a ‘chronic illness’ or as cancer survivors.
In addition to therapy-induced pain, other factors may contribute to the burden of chronic pain in these
patients (eg paraneoplastic syndromes, herpes zoster and subsequent postherpetic neuralgia, nonmalignant
causes).
Some chemotherapeutic agents can produce dose-limiting painful peripheral sensorimotor neuropathies. These
symptoms may regress with time, but they continue in a significant number of patients. There is some
evidence that this is not the same entity with all chemotherapeutic agents. Both myelinated and unmyelinated
peripheral nerve fibres may be targeted selectively by different drugs, thus producing different clinical
findings on history and examination.
Risk factors for developing painful peripheral sensorimotor neuropathies secondary to antineoplastic therapies
include:
the chemotherapeutic agent (eg common with vinca alkaloids, taxanes [including paclitaxel and
docetaxel], platinum compounds [eg cisplatin], thalidomide, lenalidomide, bortezomib)
the cumulative dose, dose intensity and duration of treatment
combination therapy with other neurotoxic agents
the patient’s age—younger patients are more likely to receive more aggressive chemotherapeutic
treatment
the presence of a pre-existing neuropathy.
There is little evidence for the pharmacological treatment of chemotherapy-induced peripheral neuropathy
(CIPN), as the current trials are limited by their methodology. Therapies that may be effective for some
neuropathic pain conditions (eg postherpetic neuralgia or painful diabetic peripheral neuropathy) do not
always have the same efficacy in patients with CIPN. Antidepressants, antiepileptic drugs and opioids have
been used, both singly and in combination, with varying and generally poor analgesic efficacy. There is some
evidence that oral vitamin E supplementation can reduce the development of painful peripheral neuropathies
in patients receiving paclitaxel or cisplatin as part of their treatment regimen.
HIV-related chronic pain

Chronic pain is common in patients with HIV, with reports of up to 50% of patients experiencing pain. With
progression to AIDS the incidence of pain increases. In advanced disease, pain has an increasing impact on
the patient’s quality of life. This is similar to the experience of patients with cancer.
The pain in patients with HIV is multifactorial. It may result from the virus itself, opportunistic infections,
immunosuppression (leading to a variety of haematological and solid tumours including Kaposi’s sarcoma) or
as an adverse effect of treatment (including antiretroviral therapy). Lifestyle-related factors (eg intravenous
drug use, increased rates of risk taking and consequent trauma and incarceration) and psychosocial issues (eg
anxiety, depression) may also have a role. In addition, this group can have chronic pain unrelated to their
underlying diagnosis.
Appropriate diagnosis, investigations and specific therapies are required. Patients with HIV may develop
painful distal sensory polyneuropathies, sometimes caused by the older antiretroviral drugs. These
polyneuropathies have been relatively resistant to standard therapy used in the management of neuropathic
pain. Smoked cannabis, lamotrigine and high-dose capsaicin patches (not currently available in Australia)
have some evidence of benefit in treating patients with painful peripheral neuropathy due to HIV. While there
is little evidence that opioid therapy is helpful, it may be appropriate for some patients. A number of
psychosocial risk factors in this patient demographic should suggest caution in the prescription of opioids (see
Analgesics used in chronic nonmalignant pain: before starting an opioid). Mindfulness has been used as a
stress reduction technique to assist with the management of pain (and other symptoms) in patients with HIV.
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Chronic pain: overview
Introduction to chronic pain management
About 20% of Australians suffer chronic pain, and this will increase as the population ages. In up to 5% (or
about one million people), the pain has a significant impact on function and quality of life. Australia's
multidisciplinary pain clinics cannot see this number of patients. Therefore much of the load for managing
people with chronic pain falls on general practitioners (GPs).
Many patients with chronic pain feel disenfranchised and rejected by the ‘medical model’, their families,
their work colleagues and the general community. An important aspect of management is to legitimise and
destigmatise the pain, and these patients need support and time to manage them effectively. A good clinician–
patient relationship is essential and improves health outcomes. GPs who know their patients well can play a
valuable role.
Pain specialists are working with the Royal Australian College of General Practitioners to improve GP access
to education about chronic pain. The aim is to provide GPs with the resources needed to educate patients
about the limitations of drug therapy and the important role of self-management and nonpharmacological
therapies.
Chronic pain is a complex medical condition. It may be caused by ongoing pathology (eg cancer, rheumatoid
arthritis). Often, however, the originating event is no longer active but pain persists because of lasting
changes within the neurological system. In patients with chronic pain, functional magnetic resonance imaging
shows changes in many parts of the brain. These changes can reverse if the pain is successfully treated.
Sometimes pain develops without any easily recognised pathology.
Chronic pain may lead to secondary physical consequences that can have a major impact on the patient's life.
These include deconditioning and postural changes as well as changes to the psyche, sleep patterns, appetite,
behaviours and thoughts. The patient's social and psychological environments contribute to their perception
of pain (see Figure 1.1). Sometimes these factors are more significant determinants of the outcome for the
patient than the underlying disease process. Due to this complexity a ‘biopsychosocial’ approach is
recommended when assessing and managing all pain but particularly chronic pain.
Unpacking this complex situation allows attention to areas that can be improved, particularly when pain
cannot be cured. Treatments may involve just one modality or multiple interventions integrated into a
management package. Interventions range from psychological and physical therapies to pharmacological
therapies and invasive techniques. Pain-relieving surgical treatments such as joint replacement should be
considered as possible options in appropriate circumstances. Educating the patient about the effect of chronic
pain on their lifestyle may lead to improvement in quality of life, particularly when pain cannot be
substantially decreased (see Patient education).
General principles for managing chronic pain

Although some general principles can be applied (see Box 1.7), each patient with chronic pain should have an
individual management plan. The plan should be linked to the patient's assessment (see Clinical assessment
of pain). When designing a treatment plan:
Ascertain a baseline measurement of pain and function and do a psychosocial assessment (see Box
1.3). This information can be used later to analyse and measure treatment responses.
Explore the patient's understanding of their pain problem and any unhelpful or incorrect beliefs they
may have adopted.
Ask the patient about their expectations and goals of treatment to help determine an appropriate
treatment strategy.
Consider the patient's response to previous treatments to help determine what further treatments may
be offered.
Discuss the likelihood of benefit with any intervention and how it can be meaningfully measured. Also,
advise the patient about the chance of harm with the intervention.
It is important to build an empathetic relationship with the patient. When initially seeing a patient with
chronic pain, take time to fully understand all the factors that may be impacting on the presentation. This is
the first step in building a positive relationship with the patient. Patients with chronic pain require more than
a routine short appointment. Unless all the factors contributing to the pain are considered, many hours of
wasted treatments may ensue as well as unnecessary medications, investigations and specialist referrals.
All reasonable attempts should be made to cure chronic pain, but do not persevere when cure is unlikely and
treatment may result in harm or false hope. Stop any treatments or medicines that are unnecessary and
causing adverse effects or expense.
A useful approach is to change the paradigm from ‘pain cure’ to ‘pain management’. This can be one of the
most difficult concepts for the patient to accept—explaining why chronic pain is different to acute pain and
the reasons why standard treatments often fail to cure chronic pain can be helpful. Once this concept is
accepted the patient can change focus and concentrate on treatments that:
improve function and mood despite persisting pain

modify activities within actively considered boundaries
increase body awareness with the aim of reducing the physiological and psychological response to
pain.
For many people with chronic pain, nonpharmacological interventions reduce the pain to a level that is easier
to control. For others, the pain may persist but they may experience an increased ability to cope with the pain
and minimise its effect on their lives.
For management of chronic pain in children, see Pain in children with cancer, Pain in children with chronic
medical conditions and Other chronic pain syndromes in children.
Important principles of chronic pain management (Box 1.7)
When managing patients with chronic pain:
Perform a comprehensive clinical assessment (see Clinical assessment of pain).

Adopt a multidisciplinary approach with a focus on appropriate combinations of physical,
psychological and pharmacological therapies (see Chronic pain: nonpharmacological management
and Chronic pain: pharmacological management).
Consider nonpharmacological therapies first if there is not an immediate need for drug therapy.
Consider drug therapy if nonpharmacological therapies are unsuccessful or inappropriate, or to
facilitate rehabilitation. Pharmacological therapies for chronic pain may work better when combined
with nonpharmacological techniques.
If drug therapy is used, give each drug in an appropriate dose for required effects before adding other
drugs.
Regularly review patients to check their pain control, function and quality of life and their need for
ongoing or change of therapy.
Provide long-term support.
Patient education in managing chronic pain

Take time to educate the patient about their pain and to involve them in decision-making. Some good
resources written by Australian authors who work in pain clinics can be recommended [Note 1]. The National
Prescribing Service also has information for consumers [Note 2].
A written summary can be used to explain the aims of the treatment plan and to help develop goals with the
patient. Some important points to cover are outlined in Box 1.8.
For some patients it is important to explain some neurobiology about chronic pain. Explaining the heightened
pain system in simple terms such as having the ‘volume knob turned up’ can be helpful. Other patients may
understand more complex explanations. Phantom pain can be used as a good example to demonstrate that
pain may not go away when a painful part is removed.
Explaining the efficacy and evidence for various treatments may give the patient an understanding of why
particular strategies are used or not used (eg why back surgery is performed more selectively than
previously).
Explaining the placebo effect can show the patient that there is a ‘brain’ component to their pain experience.
They should be aware of this effect when evaluating any therapy, particularly new costly therapies that are
advertised in the media and may be of no benefit.
Patient information sheet: key points about chronic pain (Box 1.8)
Patient information sheet
Chronic pain is common, occurring in about 20% of the Australian population.
Although there is often no cure, you can learn to manage the pain so that it does not rule your life.
Chronic pain is different to acute pain. Rest may be recommended for acute pain while the underlying cause
(eg a broken bone) heals. For chronic pain, if no cause is found, it is best to slowly increase activity in
small measured steps despite pain (this is called pacing). Remember that ‘hurt’ does not mean ‘harm’.
Return to normal daily activities as soon as possible. Waiting for complete pain relief before resuming
normal activities is unnecessary and can lead to greater disability.
Restarting activity after long periods of inactivity may cause some pain (eg muscle stiffness) but this
improves with activity in the long term.
Medicines are often not very effective for chronic pain and can have adverse effects. Some medicines can
make you sleepy and give you some rest from the pain, but this can form a vicious cycle with more
downtime and resting than needed. This can result in further pain and loss of muscle condition, changes in
posture and weakness (deconditioning).
Investigation results may be normal in chronic pain. Abnormal test results are not always a good indicator
of pain.
Ask your doctor or health care provider about ways to help manage your pain.
Note 1: Butler DS, Moseley GL. Explain pain. Adelaide: Noigroup Publications; 2003. Nicholas MK,
Australian Broadcasting Corporation. Manage your pain: practical and positive ways of adapting to chronic
pain. 3rd ed. Sydney: HarperCollins; 2011.
Note 2: NPS MedicineWise. Chronic pain explained [consumer information website]. Sydney: National
Prescribing Service (NPS); 2017. [URL]
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Chronic pain: nonpharmacological management
Introduction to nonpharmacological chronic pain management
Various strategies are used to treat patients with chronic pain (see Chronic pain: overview). The main
nonpharmacological approaches can be divided into:
physical techniques (passive or active)

mind–body techniques (eg acupuncture, biofeedback, Feldenkrais, mirror therapy)
mind-based techniques (eg cognitive behavioural therapy, hypnosis, relaxation/meditation,
mindfulness, operant conditioning, acceptance and commitment therapies, psychoanalytic and
psychodynamic therapies) (see Psychological techniques)
use of aids/orthotics and occupational therapy (eg home and workplace / work practice modification)
social/environmental interventions (eg community support groups, work retraining)
combinations of any or all of these approaches.
Evidence for use of these treatments is included in this guideline where possible. It is important to note that
evidence for efficacy in one situation does not equate to evidence in another. In addition, systematic reviews
are often inconclusive in this area of medicine because of difficulty combining studies of great diversity and
of locating studies with low bias.
Some of these techniques (eg yoga [see Exercises and functional restoration], acupuncture, hypnosis,
meditation [see relaxation/meditation techniques]) are classified as complementary and alternative medicine
(CAM). CAM is defined by the US National Institutes of Health as ‘a group of diverse medical and health
systems, practices, and products that are not generally considered to be part of conventional medicine’. It is a
broad definition that encompasses treatments used in addition to (complementary) or in place of (alternative)
conventional medicine. Many of the principles of conventional treatment overlap with some CAM
approaches.
CAM is used by many sufferers of chronic pain, with studies reporting that 35% to 63% of these patients use
CAM. CAM is not included in this guideline unless there is clear evidence for meaningful effect.
CAM treatments, like all other treatments, need to be scientifically validated using a rigorous approach.
However, analgesic studies are particularly difficult to perform when treatments are poorly defined, difficult
to blind, difficult to reproduce, and have strong placebo effects. In addition, because of the powerful potential
effects of the ‘clinician’ performing the technique, specific benefits of the entity are often not clear.
The benefit of all treatments for chronic pain should be measured in terms of pain relief and/or improvement
in function, mood and quality of life. The treatment should be cost-effective and encourage a self-
management style rather than reliance on passive strategies. If there is cost involved, the comparison with
cheaper alternatives should be made and adverse effects weighed against benefit.
Chronic pain management: physical techniques

Introduction
Physical techniques can be:
passive—thermotherapy, manual therapies, transcutaneous electrical nerve stimulation (TENS),

acupuncture
passive and/or active—neurofacilitation (includes Feldenkrais, Bobath and proprioceptive
neuromuscular facilitation)
active—general strengthening and aerobic exercise, specific exercises, stretch (may include yoga),
hydrotherapy, functional restoration.
The main focus of physical modalities for chronic pain is to encourage self-management. Physical therapists
of various types can provide a range of interventions, including manual techniques, electrical stimulation and
acupuncture. These passive therapies can be helpful in the short term to help initiate improvement, but
longer-term use should be discouraged unless there is sustained and measurable improvement in function and
quality of life.
Pain management often begins with passive modalities (to assist in desensitisation) and then progresses to
increasingly active approaches, with a view to functional restoration. Therapist-intensive treatments should
be limited to a set time that is agreed with the patient as part of their pain management plan. There may be
grounds for ‘top-up’ therapy to improve longer-term compliance. Studies are sparse in this area. Outcome
should be based on mood and function as well as pain relief over time.
Some physiotherapists, occupational therapists, nurses and psychologists have specialised in chronic pain
management and may be located through pain networks such as the Australian Pain Society [URL] or
recognised pain services.
Thermotherapy
While heat and cold may provide short-term benefits to those with chronic pain, discourage over-reliance on
these passive modalities. Encourage a more active approach. There is limited evidence, often of poor quality,
of the efficacy of hot and cold therapy. Prolonged use of heat can result in burns and skin breakdown.
Manual therapies
Introduction
Manual therapies include manipulation, mobilisation, trigger point therapy and massage. Use of these passive
therapies should be limited, to avoid creating a dependency on the therapist for repeated short-term relief.
Advise patients that these therapies are not a long-term solution to managing their pain. They should be
considered as part of a package of care that provides advice and reassurance about resuming activity,
controlling pain and recognising and minimising psychosocial risk factors.
Manipulation
There are several types of manipulative therapy that can be administered by various therapists who must be
adequately trained in this technique. It is unlikely that manipulation alone will provide long-term benefit.
Serious complications appear to be low but informed consent is an important aspect of therapy.
Spinal manipulation can provide short-term relief of mild to moderate pain in a subgroup of patients with
chronic nonspecific low back pain, but results are no different from other interventions. Mobilisation and/or
manipulation have been effective in the treatment of chronic neck pain when part of a multimodal approach.
Because of the hypersensitive, hyperirritable nature of many chronic neck and low back pain conditions, it
may be hard to justify the use of manipulation when gentler forms of mobilisation or other treatments appear
to be equally effective.
Myofascial trigger point therapy
A myofascial trigger point is a hyperirritable, taut band of muscle that is usually tender and may cause
referred pain in a characteristic distribution, especially on palpation or needling. Myofascial trigger points are
often present in chronic pain states. Trigger point therapy can be provided in a number of ways, including by
digital pressure, dry needling or injection (see Acupuncture). While treatment can be helpful in the short
term, understanding the basis for the existence of the trigger points will provide more options for longer-term
improvements.
Digital trigger point therapy is commonly used by therapists to treat myofascial pain and can readily be
taught to patients to use at home. Self-therapy programs have been used with some success for neck and
upper back pain and myofascial pain.
Massage
There is some evidence for use of massage therapy in the short-term treatment of chronic low back pain.
Therapies vary but may include direct trigger point massage and stretching. Massage is best used as a tool in
a treatment package but not as a long-term therapy.
Transcutaneous electrical nerve stimulation

Transcutaneous electrical nerve stimulation (TENS) is the most common and most accessible form of
hyperstimulation analgesia. There are various theories around mechanism of action and various modes of
stimulation. It is thought that TENS stimulates large myelinated primary afferent fibres (A fibres) activating
inhibitory circuits in the dorsal horn, thus diminishing nociceptive transmission of C-fibre inputs.
TENS is noninvasive and is used for acute and chronic localised pain (including cancer pain) of both
nociceptive and neuropathic types. For TENS to be effective, it must be possible to produce paraesthesia in
the region in which the pain is experienced or in the same or a closely related dermatome.
There is insufficient published evidence to support the use of TENS for the treatment of some chronic pain
conditions including chronic low back pain, neck pain, cancer pain, phantom limb and stump pain, or
osteoarthritic knee pain.
Nonetheless, clinical experience suggests that TENS is effective for some patients with chronic pain that is
unresponsive to other modalities (eg heat and/or trigger point therapy). These patients tend to be moderately
sensitised; highly sensitised patients are often too irritable to tolerate TENS.
TENS is most effective if initially delivered under the supervision of a trained therapist. A trial of 2 weeks is
needed before its outcome can be assessed, so patients should delay purchasing a device until after this
period. Using a TENS device during functional tasks may enable the patient to perform activities that would
otherwise be limited by pain. Initially, stimulation for one hour, three or four times daily is prescribed, but
patients can vary this to suit their needs, increasing up to 16 hours a day.
TENS should not generally be used as a sole treatment.
TENS may interfere with cardiac implanted electronic devices (eg pacemakers, cardioverter defibrillators),
but can sometimes be used safely depending on the type of device, positioning of leads and other factors.
Advice from a specialist with expertise in this area is recommended before TENS is used in the presence of
these devices.
Neurofacilitation
Neurofacilitatory techniques promote normal or efficient movement patterns via neurophysiological

mechanisms. The most notable of these are proprioceptive neuromuscular facilitation (PNF), Bobath and
Feldenkrais. Complex interactions between sensory input and motor output are thought to result in
neuroplastic changes that allow for better coordinated sequencing of movement and improved postural
control.
These specialised techniques may have a place in specific situations where the patient is not responding to
more commonly used approaches. These techniques have been traditionally used to treat neurological
conditions, most commonly stroke. Studies are limited in the chronic pain population. Forms of
neurofacilitation are used in management of complex regional pain syndrome using mirror therapy and
computerised limb recognition programs.
All three modalities involve passive movement (the patient's body part is at rest and moved by the therapist),
active-assisted movement (generated by the combined action of the patient and therapist) and active
movement (where the patient performs the movement independently).
Clinicians may start with passive techniques and progress to more active techniques. In the context of pain
management, these therapies aim to enable pain-free, or more comfortable, functional movement.
While the published evidence for these techniques in the treatment of pain is limited, clinical experience
suggests they can help patients to improve movement patterns and postural awareness and control, resulting
in improved pain management.
Exercises and functional restoration
Strengthening and flexibility exercises can reduce pain in some conditions (eg osteoarthritis, longstanding
spinal pain), but strengthening exercises may increase pain very easily if the pain system is sensitised. As
chronic pain often results in significant deconditioning, reversing this can have a major impact on patient
wellbeing and prevent further deterioration.
Exercise may need to be graded up very slowly and sometimes different approaches (eg Feldenkrais, see
Neurofacilitation) may be more beneficial in some patients. Patient adherence (compliance) to exercise
programs can be poor, and restoration of functional activity often requires more than an exercise prescription.
Dose, careful prescription, modification of exercise, supervision, gentle exercise progression, and
reinforcement by reminders are important for success.
An exercise program is often combined with a cognitive behavioural therapy program or mind-based therapy.
These combined programs (of good quality) generally improve outcome at least in the short term and for up
to 1 year. Some programs can be tailored for specific groups (eg older people). Other programs may help
prevent further pain developing (eg falls prevention / balance).
Specific exercise regimens (eg lumbar stabilising exercises, Pilates, yoga) can be helpful, particularly as a
preventive strategy, but may need to be modified for patients with chronic pain.
The type of exercise program that is best for subacute or chronic low back pain is not clear. For pain that has
been present for 6 to 12 weeks, there is some evidence that a graded-activity program may improve
absenteeism outcomes. For people with chronic low back pain, exercise therapy is effective at improving pain
and function although the overall effects may be small (see Exercise). Stretching programs alone have proven
beneficial, as has yoga. When an exercise plan is initiated, outcomes may be better when exercises are
combined with a cognitive behavioural approach or other reinforcement strategy.
Exercise should form a central part of the treatment of patients with chronic neck pain.
For patients with fibromyalgia, aerobic training improves function and possibly decreases pain and tender
points. Strength training may have beneficial effects on function, pain and depression.
Hydrotherapy
Hydrotherapy is as effective as land-based exercise in treating pain associated with a range of disorders. It
may be used in the short term to improve mobility or weight-bearing when increasing land-based function has
been problematic due to pain. The effects of buoyancy, heat and hydrostatic pressure may provide superior
pain relief and ease of movement in such cases. Patients with chronic pain may have reduced pain while in
the pool but this may be short lived and often followed by increased pain.
There is limited evidence for long-term use of hydrotherapy for chronic back pain. For patients with hip and
knee osteoarthritis, aquatic exercise provides short-term improvement in pain, physical function, mental
health and quality of life. For fibromyalgia, there is moderate to strong evidence that hydrotherapy improves
pain, health status and quality of life in the short term.
Further research is needed to determine the specific types of aquatic exercises and techniques that are most
appropriate for different conditions and their long-term effect.
Chronic pain management: mind–body techniques

Acupuncture
Acupuncture has its origins in traditional Chinese medicine and is based on the concept of meridians and
energy lines. Some researchers have proposed that the mechanisms underlying the treatment effect of
acupuncture may be similar to those in trigger point therapy.
Some patients with pain (malignant or nonmalignant) can benefit from acupuncture, with reduced pain
severity and/or maintenance of function. However, evidence for its effectiveness in different types of pain is
conflicting, even when compared to placebo, sham acupuncture or standard care.
For patients with chronic low back pain, acupuncture is more effective in the short term in improving pain
and function compared to no treatment, but no more effective than other conventional treatments. When
combined with other conventional therapies, acupuncture improves the effectiveness of treatment of chronic
low back pain compared to those therapies alone. Thus, acupuncture and dry needling appear to be useful
adjunctive treatments for chronic low back pain.
There is moderate evidence that acupuncture provides short-term relief of chronic neck pain. There is also
evidence that acupuncture reduces the frequency of onset of episodic acute or chronic tension-type headache.
As with all passive treatments, it is important that acupuncture is time limited and the benefits are measured
and translate to improved function or decrease in dependence on medications.
Biofeedback
Biofeedback refers to the presentation of information about a biological function to the patient, as an aid to
relaxation or to help control that physiological function. It may be a useful tool to help the patient recognise
muscle tightness and to relax or strengthen certain muscle groups. An example is the display of electrical
activity from scalp muscle fibres to help a patient relax scalp and face muscles for the relief of chronic
tension headaches.
Biofeedback is a specialised therapy and should only be undertaken by practitioners with appropriate training
(eg physiotherapists, psychologists, psychiatrists).
There is some evidence supporting the use of biofeedback in combination with relaxation and/or cognitive
behavioural therapy for headache (particularly tension headaches), temporomandibular joint dysfunction and
chronic pain generally. There is evidence of its effectiveness for vulvar vestibulitis when combined with
pelvic floor rehabilitation exercises.
Mirror therapy
Mirror therapy is used in the treatment of phantom limb pain and complex regional pain syndrome. Positive
effects have been seen, but mainly in case series and small randomised controlled trials.
For treatment of upper limb conditions a rectangular box is used that contains one surface with a vertical
sagittal mirror. The normal upper limb is placed inside the box and the abnormal limb on the other side. The
patient attempts to move the abnormal limb while visualising the normal limb. This visualisation of
movement of the normal limb (which appears to be the abnormal limb) has an effect on the movement and
sensation in the abnormal limb. This type of treatment may be combined with other visual feedback
treatments such as limb lateralising programs using a computer-generated program of images.
Chronic pain management: psychological techniques

Overview
Psychological treatments can be used as an adjuvant in the management of pain; sometimes they can be the
primary intervention. Principles of some psychological techniques (eg active listening, reassurance,
encouragement) are used informally in general interactions with patients. Understanding how to use these
more formally can be worthwhile.
Many approaches can be used. For instance a cognitive behavioural therapy approach (CBT approach)
involves helping the patient to identify thoughts, feelings and behaviours that may be contributing to their
pain, and encouraging changes in behaviour to address these. A CBT approach differs from formal cognitive
behavioural therapy.
Most health care providers can (and should) learn to use basic psychological techniques. Some patients,
however, need additional psychological intervention from more highly trained providers.
Identifying patients who might benefit from specific psychological interventions should be based on
assessment. Multidisciplinary pain clinics typically include a psychological assessment as part of their
standard work-up of all patients. However, medical practitioners without those resources can also conduct a
basic psychological assessment of pain (see Box 1.3).
Ask questions in a direct way (eg ‘Tell me how, what, when’). Asking the patient to explain things (eg
questions beginning with ‘Why?’) can result in rationalisations and excuses rather than more factual accounts
that can provide a basis for possible interventions.
If it appears that the pain is being modified by a patient's beliefs, worries, responses, mood state or
interactions with those around them, or if the pain is impacting on mood and behaviours in a negative way,
then psychological interventions should be considered. These should be directed according to the assessment
findings. In some cases referral for more comprehensive, specialist assessment (eg at a multidisciplinary pain
clinic) might be warranted, but local resources (eg clinical psychologists, psychiatrists) should also be
considered [Note 1].
There are many types and combinations of formalised psychological behavioural treatments with good
evidence that they improve pain in conditions such as back pain, at least in the short term. Psychological
approaches have been successfully used in adolescents with clear evidence of efficacy in headache, and
possibly in other painful conditions.
Emphasise to patients that the use of a psychological technique does not mean that their pain is not real or
that the pain is not being taken seriously. This is particularly important for patients with chronic pain.
Encourage patients to use these techniques to maintain a sense of control over their pain experience, and to
reduce their suffering and disability.
Note 1: The Australian Psychological Society website provides contact details for psychologists in
Australia [URL] and click on the tab ‘find a psychologist’. Funded programs for psychological services
may be available and should be explored.
Cognitive behavioural therapy

Cognitive behavioural therapy (CBT) involves the systematic application of psychological principles to assist
patients to change unhelpful thoughts (cognitions), emotions and behaviours. Pain relief is not the goal of
CBT; rather having the patient do things despite pain, and being less troubled by pain, should be the focus of
treatment.
Patients can be treated effectively with CBT methods on a one-to-one basis, or in a group setting. Treatment
is usually led by a psychologist who has been formally trained in this therapy. Other health professionals (eg
physiotherapists, doctors, nurses) can help the patient to apply the principles of CBT in a practical way. If
more than one provider is involved, CBT should be delivered in a coordinated way between the providers.
Most patients require between 5 and 20 sessions. More disabled or distressed patients are likely to need more
sessions, and a group-based, multidisciplinary program is likely to be more effective.
A ‘program’ approach essentially combines CBT with other treatments (eg exercise, stretching, relaxation
techniques). In combination, the efficacy of each component is improved. Not all patients are suited to this
approach. Patients who may be unsuited include those with communication difficulties, cognitive impairment
and psychiatric comorbidities. Patients with substance use disorders and rigid thinkers may also be
unsuitable. The program (individual or group) needs to be appropriate for the patient. There is a sparsity of
literature on CBT programs related to specific age groups and specific pain conditions, apart from low back
pain.
With CBT, the health care provider works with the patient in a collaborative rather than a directive manner.
This requires initial clarification of their respective roles and expectations, and agreement on feasible goals to
work towards. The health care provider should act like a trainer. There should be a clear expectation that the
patient takes an active role in implementing the treatment plan, and in generating ideas and possible
solutions, rather than passively waiting for the health care provider to come up with all the answers. The
health care provider should display a calm and reassuring manner, and encourage the patient to persevere
with the management plan, and work towards their goals. See Box 1.9 for important principles of CBT.
CBT methods can be used to change the ways in which pain sufferers perceive and react to their pain and
other stressors. It can also help them engage in activities and exercises (see Box 1.10 for examples of how
CBT can work in practice). There is strong evidence for the effectiveness of cognitive behavioural techniques
in chronic pain in selected patients. The quality of programs varies considerably. Combination therapies may
be more effective than CBT alone.
The patient must implement the coping (or self-management) strategies and goal-directed tasks at home
between treatment sessions. During the session, the patient should report on their progress towards their
goals, their implementation of agreed exercises and activity plans, and their use of specific skills. It can be
helpful if they keep a diary.
Important principles of cognitive behavioural therapy (CBT) (Box 1.9)
When performing CBT it is important to:
define specific and concrete goals for functional activities and moods
specify steps towards achieving desired goals
consistently reinforce efforts towards goal achievement
actively involve the patient in:
selecting their goals
monitoring their progress
employing necessary skills
identifying and modifying unhelpful patterns of thought and behaviour.
Scenarios using cognitive behavioural therapy (CBT) (Box 1.10)
Example 1
A typical sequence for a CBT intervention is to talk with the patient about their pain experiences, to help
them make sense of what they've experienced, and what might need to change to reduce the impact of that
experience. This often entails education about the likely basis of the pain, and about differences between
acute and chronic pain. Negotiate specific goals with the patient, as they must want to achieve the goals if
they are going to put effort into them. Define these goals in terms of activity (eg walking to the shops and
back, driving for an hour, carrying 10-kilogram weights in each hand for 5 minutes, preparing a meal). The
patient may also need to be taught some specific skills to help them achieve their goals. These skills might
include relaxation (or ways of reducing emotional arousal or tension), and other self-management strategies
(eg pacing of activities, problem solving, thought challenging).
Example 2
Unhelpful responses to pain include a tendency to engage in catastrophic thoughts (eg ‘This pain is killing
me’), and to overdo activities on ‘good days’ (when the pain is not so bad). These often lead to aggravation
of pain. By recognising catastrophic thoughts and finding a way to defuse them, patients can learn to reduce
their sense of helplessness. By moderating activity levels with regular breaks and alternating activities,
patients can maintain most normal daily activities with minimal reliance on analgesics despite continued
pain. Specific skills in problem solving can also be taught to those who repeatedly feel defeated by their
pain and keep waiting for their doctor to solve the problem for them. Typical problem-solving steps include
identifying the problem, developing a number of possible options for dealing with it, selecting and trying
one option, reviewing the outcome and, if this is unsuccessful, considering the next option or reviewing the
original identification of the problem and repeating the other steps.
Hypnosis
Hypnosis shares many of the features of relaxation (see Relaxation/meditation techniques) and imagery. A
common feature of many forms of hypnosis is that one person responds to suggestions made by another on
experiences involving changes in perception, memory and voluntary actions.
There is moderate evidence that hypnosis can be useful for acute pain but evidence for chronic pain is
weaker. For the most effective pain reduction, it is recommended that hypnosis be considered as one part of
an overall treatment plan.
Contraindications to hypnosis include severe mood disturbance, presence of a psychotic illness or thought
disorder, or a diagnosis of personality disorder.
Hypnotherapy, and the assessment of the patient, should be undertaken only by health professionals trained in
the clinical use of hypnosis [Note 2].
Note 2: The Australian Society of Hypnosis (ASH) runs training programs in clinical hypnosis and can
provide contact details of medical practitioners, psychologists and dentists trained and qualified by ASH.
Telephone (02) 9747 4691 [URL]
Relaxation/meditation techniques
A variety of techniques can help to decrease anxiety and muscle tension—these include imagery, distraction,
meditation, controlled breathing, and progressive muscle relaxation and biofeedback. Patients often find
meditation and breathing techniques more helpful than progressive muscle relaxation techniques that include
muscle tensing, as this can aggravate some painful conditions. Relaxation techniques are closely related to,
and often indistinguishable from, forms of meditation and self-hypnosis.
Relaxation methods require frequent practice, and the patient should apply them whenever they feel more
stressed than usual, or in more pain. This might be several times a day. Audiotapes may be helpful, at least
initially. Being able to relax without an audiotape has the practical advantage of ready application.
Relaxation can help cancer patients with pain and nausea. There is evidence supporting its use for recurring
headaches. Relaxation methods are rarely used in isolation, but rather as one element of a more
comprehensive pain management plan. Patients who are not helped by more simple relaxation methods might
benefit from biofeedback.
Attentional techniques
Attentional techniques enable patients to alter their attention in relation to pain. Distraction from the pain can
be through attention to imagined scenes/sensations or to external stimuli such as music, scenes or smells.
Other techniques involve attending to the pain in ways that seem to modify or re-interpret the experience into
something less threatening. For example, mindfulness meditation is aimed at acceptance, rather than control,
of pain. Attempting to alter the patient's emotional state, from stress or fear to comfort or peace, is a common
feature of many of these techniques. Attentional techniques are often combined with relaxation methods, and
at times these may be indistinguishable.
There is moderate evidence that interventions combining relaxation and imagery can achieve changes in the
sensory experience of pain among adults with cancer pain. In this group, the evidence for changes in affective
states, various measures of control (eg perceived control over the intervention), and functional status is more
equivocal.
There is some evidence that rather than shifting attention away from the pain, instructions to focus on the
pain as part of a meditation technique can alter pain perception.
Psychotherapy
Psychotherapy emphasises verbal interactions and the relationship between the therapist and the patient to
produce an alteration in the patient's behaviour, feelings and modes of reacting. Psychotherapy can include
cognitive behavioural therapy, but in Australia psychotherapy usually refers to methods based on
psychodynamic theories of personality. Many of these types of treatment are long term; however, there are
shorter versions with more specific aims. One such approach (which may assist with the maintenance of some
patients with chronic pain) is supportive psychotherapy. In this approach, rather than trying to explore the
whole of a patient's life, therapy is focused on strengthening the patient’s coping mechanisms using
suggestion, advice, reassurance, clarification, abreaction (ie revisiting traumatic past experiences) and
encouragement.
There are no randomised controlled trials on the use of psychodynamic psychotherapy in patients with pain.
Clinical experience supports its use in selected cases, often as an addition to the more action-oriented
approaches.
Chronic pain management: occupational therapy

Occupational therapy aims to restore and maintain a patient's best possible level of daily activity and
function. Patients can be taught ways of managing daily chores and work tasks. This can involve task
simplification, advice about suitable aids to use within the home, car or workplace, and guidance about
changing how some everyday activities are performed. It may involve simulation or practice of normal
activities (eg work tasks, home chores, driving). Lifestyle difficulties can also be addressed by using stress
management and relaxation techniques. Cognitive behavioural therapy principles are often employed in
conjunction with other members of a multidisciplinary team. Workplace assessments and functional capacity
evaluations can also be provided.
Combined nonpharmacological interventions for chronic pain

Overview
There is good evidence that multidisciplinary treatment of chronic pain is effective. Many
nonpharmacological modalities may be more effective in combination (eg improving physical function while
learning factual information about chronic pain and identifying unhelpful thinking, or learning coping
strategies such as relaxation or mindfulness and identifying barriers to change).
These integrated approaches seem to be best done with an integrated team of health professionals. The best
‘dose’ and combination of treatments and delivery method (group or individual) is yet to be determined and is
often influenced by local expertise and availability.
Some centres offer several entry points to programs. These range from a simple education program, to a short
regular exercise and lifestyle program, to more intensive combined cognitive behavioural therapy and
exercise programs (eg ADAPT program, START program). Other centres offer individually tailored
approaches. Sometimes an inpatient rehabilitation–style program is used.
Pain management programs
Not all pain management programs are the same:
Some are CBT-based and others have a rehabilitation focus with fewer psychological strategies.
Some are group based and some are individually tailored.
Some include strategies to remove reliance on medications and passive strategies.
Some are inpatient based and others outpatient based.
Some take place on a part-time basis over several weeks to months while others are concentrated into a
2- to 3-week period.
Different patients may be suited to different types of programs.
Some are aimed at return to work while others focus on improving quality of everyday function and
life.
Some are age specific (eg for older people).
The aim of all pain management programs is to improve the patient's function and quality of life, and reduce
pain if possible. There is little information on whether pain programs are equally effective for neuropathic
pain and musculoskeletal pain. Most studies have been done in people suffering from back pain or other
generalised pain conditions (eg fibromyalgia), but there is less evidence available for neuropathic conditions.
Community support groups

Patients with chronic pain often become socially isolated, and might benefit from joining a local group (eg
health centre, migrant resource centre) or a special interest group (eg public library, art gallery).
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Chronic pain: pharmacological management
Introduction: pharmacological management of chronic pain
Treating patients with chronic pain can be difficult and time-consuming (see Chronic pain: overview). This topic
focuses on management of chronic pain that is not caused by conditions with active destruction or inflammation
(eg cancer, rheumatoid arthritis).
The aim in patients with chronic nonmalignant pain is to improve their function, coping skills and quality of life. A
reduction in pain scores is a bonus, but not necessarily expected. Extended or multiple consultations are often
needed. Drugs used to treat chronic nonmalignant pain work in only about one-third of patients. At best, they
reduce pain by about 30% to 50%; in some patients, the verbal pain score may be decreased by only 1 to 3 points
on a 0 to 10 scale. Pharmacological treatment alone often frustrates the patient and the doctor. As drugs are
unlikely to stop the pain, it is important to assess whether they are improving the patient’s quality of life and
function.
Functional improvement rather than a reduced pain score is the aim of management of chronic nonmalignant pain.
In patients with chronic pain due to an active destructive or inflammatory condition, the same pain management
principles apply, but disease-modifying drugs also need to be considered. In addition, an active process causing or
largely contributing to pain may require a more rapid escalation of pharmacological management than when there
is no active destructive or inflammatory component.
Acute exacerbations of cancer pain or progressive pain need to be managed in a timely manner with attention to
the mechanism of pain. Help from a pain medicine specialist may be needed if the pain does not settle with usual
care. Destructive procedures, radiotherapy and continuous drug infusions delivered by various routes may be
relevant in this patient group. At all times the principles are to improve quality of life and reduce any harm or
adverse effects from analgesics. If the focus of treatment changes to palliation, refer to Pain in patients receiving
palliative care for information on management.
Analgesics for chronic nonmalignant pain management

Introduction
In chronic nonmalignant pain there is no such thing as a ‘pain killer’. Medication modifies the pain only to some
extent. A comprehensive assessment is essential, and nonpharmacological options should be explored before
starting pharmacological therapy. Some pain conditions (eg neuropathic pain) are poorly responsive to regular
analgesics—in these patients analgesic adjuvants (eg antidepressants, antiepileptic drugs) may be a better
treatment choice (see Neuropathic pain).
Escalating the dose of a single drug that has not proven effective in standard doses is more likely to result in
adverse effects than pain control. Substituting or adding a drug from a different therapeutic class may be worth a
trial. If this does not prove effective, then a shift from a unifocal pharmacological approach to a multifaceted or
multidisciplinary approach is recommended (see Chronic pain: nonpharmacological management and Chronic
pain: invasive techniques).
Chronic pain management is multidisciplinary, and takes time.
Paracetamol
Encourage patients to take regular paracetamol as an adjunct to nonpharmacological or other pharmacological

strategies. Use:
1 paracetamol 1 g orally, 4- to 6-hourly, up to a maximum of 4 g daily
OR
1 paracetamol modified-release 1.33 g orally, 8-hourly.
Paracetamol rarely relieves the pain completely but can modify its severity. If there is no evidence of benefit after
an adequate trial, it may be discontinued.
The maximum dose of paracetamol (from all sources) is 4 g daily. Reduce the dose in people who have significant
liver disease, are malnourished, of small size, or in frail older patients.
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be used in as low a dose as possible for the shortest
possible time. Continual daily use in chronic pain is not recommended unless the harms versus benefits have been
discussed with the patient and the patient’s specialist (see Table 1.2 for major adverse effects of NSAIDs).
Opioids
Role in chronic nonmalignant pain
Opioids work well in acute pain, but their role in chronic nonmalignant pain is limited. Randomised controlled
studies of opioid treatment in chronic nonmalignant pain have been of short duration, so evidence for long-term
benefit is lacking.
Experience suggests that opioids work in only one in three patients and that they reduce pain intensity by 30% to
50% at best. In patients taking opioids for chronic nonmalignant pain, about 80% have at least one adverse effect
and only 44% remain on opioids long term (see Adverse effects of opioids).
Opioids may help patients by improving their function and quality of life, without necessarily reducing their pain.
Before starting an opioid
Before starting an opioid in patients with chronic nonmalignant pain:
explore all other treatment options, both physical and psychological

assess the patient using a multidisciplinary approach
discuss the adverse effects (see Table 1.15) and possible harms and benefits of long-term opioid therapy
obtain agreement/acceptance from the patient about the expected outcome of therapy (ie pain reduction
rather than complete abolition of pain, reduced suffering, improved function and quality of life)
explain that the opioid is being used as a trial and treatment will cease if there has not been significant
progress towards achieving treatment goals over 4 weeks
assess the potential for opioid abuse or misuse [Note 1]
obtain agreement about monitoring, treatment adherence (compliance), and the consequences of
nonadherence
define strategies (open and transparent) to monitor adherence
consider the use of an ‘opioid contract’.
Note 1: For an example of an opioid risk tool, see: Webster LR, Webster RM. Predicting aberrant behaviors in
opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med 2005;6(6):432-42. [URL]
Trialling an opioid
If a decision is made to trial an opioid, always observe the rules outlined in Box 1.11. When assessing response:
check for improvement in quality of life (sleep, mood, libido) and function (activities)
record pain scores (for severity and duration of pain).
The opioid should be ceased if there is any evidence of misuse or abuse, if there is no improvement in the patient’s
wellbeing after 4 weeks, or if the opioids are having a detrimental effect.
Rules for use of opioids in chronic pain (Box 1.11)
Once a decision has been made to prescribe an opioid for chronic pain, observe the following rules:
One clinician or team should be responsible for prescribing the opioid.

Do not introduce an opioid at the same time as another drug.
To minimise adverse effects, start with a low dose and adjust slowly according to response, ie ‘start low
and go slow’ (see Table 1.13 for suggested starting doses).
Use lower doses in older people and monitor carefully.
Avoid the use of immediate-release or parenteral opioids.
Advise all patients to take laxatives at the commencement of treatment and then regularly, as needed (see
Functional constipation for treatment options).
Remember all opioids have adverse effects (see Table 1.3 and Table 1.15).
Review all prescription drugs and complementary and alternative medicines the patient is taking and check
for potential interactions.
Avoid the use of concurrent benzodiazepines as the combination can cause severe sedation and impair
cognition and driving ability.
Check what other agents the patient is taking that could potentially interact (eg alcohol, cannabis).
Avoid the use of opioids for breakthrough pain.
Regularly review the patient to monitor progress and to assess if ongoing opioid treatment is needed.
If a decision is made to discontinue an opioid, it should be weaned slowly and under supervision. Seek
specialist advice if uncertain about the weaning procedure.
Opioid dosing
Modified-release oral morphine and oxycodone and buprenorphine patches are suitable first-line opioids for the
management of chronic pain. Start with a low dose. If the response is inadequate, increase the dose slowly. See
Table 1.13 for suggested starting doses, interval between dose increases and maximum daily doses recommended
for the treatment of chronic pain. If a small dose is good it doesn’t follow that a larger dose is better.
When using an opioid for chronic pain, ‘start low and go slow’ and review regularly for ongoing need and adverse effects.
Older people are particularly susceptible to adverse opioid effects, so careful dose titration and close monitoring
are essential. A low dose of an immediate-release oral opioid may occasionally be used initially in frail older
people to gauge response. If tolerated, they should be switched to a modified-release formulation if ongoing
therapy is required.
Modified-release formulations should never be crushed or chewed, as this destroys their release properties and can
result in a large dose being absorbed over a short period. This presents an opportunity for abuse. Modified-release
morphine granules (for reconstitution as an oral suspension) are available for patients who are unable to swallow
solid oral dose formulations or who have percutaneous endoscopic gastrostomy (PEG) tubes.
Modified-release opioid formulations should never be crushed or chewed.
Do not use hydromorphone, transdermal fentanyl, or methadone as first-line opioids in opioid-naive patients with
chronic pain. In general, these opioids should only be prescribed by practitioners experienced in their use or after
consultation with a pain specialist. This is because:
hydromorphone is FIVE times as potent as morphine

fentanyl is potent (12 micrograms/hour of transdermal fentanyl is equivalent to 50 mg per day of oral
morphine). Fentanyl patches should never be commenced in opioid-naive patients unless in a monitored
setting
methadone has complicated pharmacokinetics and a long and variable half-life.
Suggested dosing recommendations for opioids used first line in the treatment of chronic pain
(Table 1.13)
Starting dose in opioid- Minimum interval Recommended maximum

Opioid
naive patients [NB1] between dose increases dose [NB2]
morphine oral modified- 5 to 10 mg orally, daily to
3 days 100 mg daily
release twice daily
oxycodone oral modified- 5 mg orally, daily to twice 3 days 80 mg daily
release daily
buprenorphine
5 micrograms/hour 7 days 20 micrograms/hour
transdermal patch
NB1: If inadequate response, small incremental dose increases are recommended.
NB2: If a higher dose is required, seek specialist advice.
Opioid rotation
If a reasonable dose of the initial opioid is well tolerated but ineffective, it is unlikely that changing to a different
opioid will be effective. If the patient does not tolerate the initial opioid, a different opioid may be tried.
Opioid rotation can be achieved in a number of ways. Opioid rotation has been associated with harm when dose
potencies have not been carefully considered. The prescriber should seek specialist advice if not confident about
changing the opioid regimen.
The approximate relative potencies of the various opioids used in chronic pain are given in Table 1.14. The use of
more than one opioid at the same time is not recommended except under specialist advice.
Approximate relative potencies of various opioids used in chronic pain (Table 1.14) [NB1]
Approximate relative potencies compared to 50 mg/day of

Opioid
oral morphine
morphine oral 50 mg/day
buprenorphine transdermal patch 20 micrograms/hour [NB2]
fentanyl transdermal patch 12 micrograms/hour
hydromorphone oral 10 mg/day
methadone oral [NB3]
oxycodone oral 35 mg/day
NB1: When changing from one opioid to another, commence with 50% to 75% of the calculated ‘equianalgesic’ dose and then titrate to response.
NB2: The maximum dose of transdermal buprenorphine should be 20 micrograms/hour unless under specialist advice.
NB3: When changing from morphine to methadone, conversion ratios vary considerably depending on the morphine dose. Methadone should only be
prescribed for chronic pain by practitioners experienced in its use.
Adverse effects of opioids
There is growing recognition that long-term opioid use, particularly in high doses, can lead to increasing harm. An
opioid-induced adverse effect will develop in about 80% of patients on opioids long term (see Table 1.15).
Always rationalise a patient’s medication before adding opioids to reduce the risk of harmful drug interactions.
Ten to 20 per cent of patients are at risk of misusing opioids. There is a growing awareness that not all patients use
opioids as prescribed. Harm minimisation for both the patient and the community is the responsibility of the
prescriber. The risk of deaths related to misuse of opioids is growing and prescribers need to be vigilant.
Starting a patient on an opioid may seem the humane and appropriate treatment for a person with chronic
nonmalignant pain. However, if function does not improve within 4 weeks, recognise that continued use of opioids
could lead to a number of adverse effects, with minimal improvement in pain.
Adverse effects with long-term use of opioids (Table 1.15) [NB1]
System Adverse effects—long term Comments

average daily dose of oral morphine of
200 mg (or equivalent) is associated
respiratory depression (excessive sedation
with a 3-fold increase in death
+/– a decrease in respiratory rate [NB2])
respiratory depressant effects will be
respiratory
central and/or obstructive sleep apnoea (in exacerbated if the patient uses other
up to 75% of patients) sedatives such as benzodiazepines,
alcohol or cannabis
cardiovascular fluid retention can exacerbate heart failure
sedation
sedation and impaired cognition
impaired cognition require careful monitoring
warn patients not to drive until effects
neurological impaired driving ability (especially with on cognition have stabilised
high doses or when combined with consider need for driving assessment
benzodiazepines—this effect is cumulative and licence suspension in affected
and occurs especially in older people) individuals
impaired coordination (can result in falls and

fractures)
lower limb cellulitis (due to immune
dermatological
compromise)
chronic constipation is a common
problem and requires proactive
management and prevention—always
prescribe laxatives with long-term
opioids and advise patient to use
chronic constipation
according to need
gastrointestinal
nausea and vomiting if constipation is difficult to manage in
patients receiving long-term
oxycodone, consider the oral
modified-release oxycodone+naloxone
combination
may present as a component of opioid-

induced hyperalgesia
musculoskeletal diffuse musculoskeletal tenderness myoclonus is seen with higher doses
and in patients with renal impairment
fluid retention, oedema

long-term use of opioids suppresses
gynaecomastia the hypothalamic pituitary axis,
leading to suppression of all hormones
amenorrhoea osteoporosis can be exacerbated by
neuroendocrine
inactivity due to chronic pain
osteoporosis monitor hormone levels and refer to an
endocrinologist if necessary
low testosterone in men (with resultant
frailty)
urinary retention and difficulty with
urinary micturition, increased external sphincter
tone, decreased detrusor muscle tone
Other
decrease in drug effect over time, such that
increasing doses of drug required—
an increase in dosing is required to have the
many adverse effects are dose
same effect
dependent
tolerance
speed of onset of tolerance seems to depend need to distinguish tolerance from
on the drug’s lipid solubility and route of opioid-induced hyperalgesia
administration
all patients taking long-term opioids will this is not addiction
develop physical dependence—this is a if discontinuing opioids, gradually
physical dependence physiological adaptation such that abrupt reduce the dose to minimise
cessation or reduction in dosing is likely to withdrawal symptoms
cause withdrawal
3% to 4% of the population are at risk of
opioid addiction if exposed to long-term
careful patient selection is important
addiction opioids (15% of these people will also use
illicit drugs, 15% to 20% alcohol and 25%
nicotine)
abnormal behaviour due to undertreatment
pseudoaddiction
or inappropriate treatment of pain
process complex and not fully
patients have increased levels of pain (which explained—if a patient starts on
may be widespread) opioids for a localised pain problem
opioid-induced and then develops total body pain,
increasing the opioid dose does not improve consider OIH
hyperalgesia (OIH) the pain and can increase it (unlike tolerance seek specialist advice if using daily
where increasing the dose leads to reduction doses exceeding 100 mg oral
of the pain); reducing the opioid dose
morphine or 80 mg oral oxycodone
improves the pain
complex and not well understood—

morphine interferes with killer T-cells
immune compromise and can compromise the patient’s
immune system
NB1: See also Table 1.3 for adverse effects with short-term use of opioids.
NB2: A decrease in respiratory rate is a very unreliable indicator of respiratory depression (high blood carbon dioxide levels), which can coexist with a
normal respiratory rate. Sedation is a more sensitive indicator of respiratory depression.
Tramadol
Tramadol is a synthetic weak mu-opioid agonist that also enhances noradrenergic and serotonergic inhibition of
nociceptive transmission. Advantages include analgesia with minimal sedation or respiratory depression and
reduced gastrointestinal adverse effects.
Tramadol has a limited role in chronic pain management. It has limited analgesic activity, and a number of adverse
effects and drug interactions, particularly with the serotonergic drugs that may be beneficial in chronic pain
management.
Tramadol has a limited role in chronic pain management.
Tapentadol has been approved by the Australian Therapeutic Goods Administration, but at the time of writing
experience with use in Australia is limited. It is reported to be a stronger mu-opioid agonist than tramadol, with
noradrenergic but no serotonergic effects.
Other pharmacological treatments for chronic pain

Analgesic adjuvants
Analgesic adjuvants such as tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, and
antiepileptic drugs are sometimes used to treat chronic pain. Many patients with unexplained pain conditions may
have a neuropathic component to their pain. In these patients a trial of adjuvant medications is indicated to assess
the response.
For information on management of neuropathic pain, see Neuropathic pain.
Complementary and alternative medicines

People often use complementary and alternative medicines for chronic pain despite lack of evidence of efficacy (of
the type required for conventional drugs). For information on use of complementary medicines in the treatment of
painful rheumatological disorders, see Complementary medicines.
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Vuong C, Van Uum SH, O'Dell LE, Lutfy K, Friedman TC. The effects of opioids and opioid analogs on animal and
human endocrine systems. Endocr Rev 2010;31(1):98–132. [ ]
Webster L. Update on abuse-resistant and abuse-deterrent approaches to opioid formulations. Pain Med 2009;(10
Suppl 2):S124–33 .
Webster LR, Choi Y, Desai H, Webster L, Grant BJ. Sleep-disordered breathing and chronic opioid therapy. Pain Med
2008;9(4):425–32. [ ]
Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid
Risk Tool. Pain Med 2005;6(6):432–42. [ ]
Weissman DE, Haddox JD. Opioid pseudoaddiction: an iatrogenic syndrome. Pain 1989;36(3):363–6. [ ]
Other pharmacological treatments for chronic pain
Navigating the maze of drug therapy for neuropathic pain. NPS News 2008;(60). [URL]
Attal N, Cruccu G, Baron R, Haanpaa M, Hansson P, Jensen TS, et al. EFNS guidelines on the pharmacological
treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010;17(9):1113–e88. [ ]
de Leon-Casasola O. New developments in the treatment algorithm for peripheral neuropathic pain. Pain Med 2011;
(12 Suppl 3):S100–8 .
Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain
2010;150(3):573–81. [ ]
Chronic pain: invasive techniques
Overview of invasive techniques for chronic pain management
Invasive techniques are procedures that breach the skin to introduce chemical, thermal or electrical stimuli.
When used for chronic pain, the aim is to modify the transmission of nociceptive signals and thereby reduce
the patient's pain experience.
The intent of this guideline is to inform clinicians about the nature, indications, evidence of benefits, risks and
adverse effects of invasive techniques for managing chronic pain, so that clinicians can plan and discuss care
with their patients.
This guideline is not intended to instruct clinicians on the conduct of these procedures. Proceduralists
performing any invasive procedure must be appropriately trained. Informed patient consent must be obtained.
Facilities where such procedures are performed must have adequate space, personnel, imaging, monitoring
equipment, and equipment and protocols for aseptic technique, recovery and resuscitation. Proceduralists
should refer to established guidelines (see Further reading).
Before considering invasive techniques, patients should undergo a comprehensive assessment including
medical and pain history, and physical and psychosocial assessments (see Clinical assessment of pain).
Patients should be informed about all reasonable therapeutic options and encouraged to try those with the best
benefit-to-harm ratio. Patients who elect to undergo invasive procedures have generally obtained inadequate
benefit or experienced intolerable adverse effects from conservative therapies.
After undergoing invasive techniques for pain management, patients need to be monitored by their
practitioners and use other strategies to manage their residual pain (see Chronic pain: nonpharmacological
management). Patients should use any benefits they obtain from procedures to work on improving their
function, self-management strategies and quality of life.
The list of invasive techniques in this topic is not exhaustive. Only procedures for which there is evidence of
benefit, or which have found their way into practice without such evidence, are covered. The evidence for
each indication is outlined in brief.
In this topic, invasive techniques are divided into:
injections without a specific neural target

injections and infusions with a specific neural target
electrical stimulation
neurosurgical procedures.
Contraindications for invasive techniques for pain management

All invasive techniques carry some risk. For certain patients, the risks are so great that the procedure would
be considered unsafe. Contraindications that are relevant to all invasive procedures outlined in this topic
include:
allergy—known allergy to an antiseptic, drug, preservative, contrast medium or latex precludes the use
of the allergenic substance
coagulopathy—whether due to a disease or drug, coagulopathy is a contraindication to invasive
procedures when the harm of potential bleeding (eg uncontrolled blood loss or compression by
haematoma in a contained tissue plane or the spinal canal) outweighs the expected benefit of the
procedure [Note 1]
localised infection in the procedural field
systemic sepsis—precludes the implanting of a foreign body (implanted device)
lack of patient consent.
See specific techniques for additional detail.
Note 1: For guidance on how different anticoagulant drugs and combinations affect regional anaesthesia
risk and decision-making, refer to: Regional analgesia and concurrent anticoagulant medications (section
7.4). In: Macintyre PE, Scott DA, Schug SA, Visser EJ, Walker SM, eds. Acute pain management: scientific
evidence. 3rd ed. Melbourne: Australian and New Zealand College of Anaesthetists and Faculty of Pain
Medicine; 2010.
Or for more detail: Horlocker TT, Wedel DJ, Rowlingson JC, Enneking FK, Kopp SL, Benzon HT, et al.
Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of
Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition). Reg Anesth Pain Med
2010;35(1):64-101. [URL]
Precautions of invasive techniques for pain management

The following conditions are not absolute contraindications. Harms versus benefits need to be discussed with
patients who:
are pregnant
have significant impairment of respiratory or cardiovascular function
are immunosuppressed
are unable to cooperate
have altered anatomy that might compromise the safe and successful conduct of the procedure.
In some cases (eg in patients receiving palliative care), the harm–benefit analysis may favour treatment to
alleviate severe refractory pain.
Adverse effects of invasive techniques for pain management

Possible adverse effects of invasive techniques include:
failure to relieve pain—due to diagnostic error, technical problems, anatomical variation or inadvertent
intravascular injection
pain and/or haematoma at procedure site
inadvertent needling of neural or deep structures
inadvertent spread of injectate to adjacent structures
embolisation of particulate injectate (eg particulate corticosteroid formulations)
systemic toxicity if large doses are used (see Table 1.7 for maximum safe doses of local anaesthetic) or
intravascular injection occurs
allergic reaction to injectate
infection
procedure-related anxiety, distress, vasovagal syncope.
In patients receiving opioids, invasive techniques that produce profound analgesia can lead to unopposed
opioid effects with severe sedation and respiratory depression. This should be anticipated and plans made for
appropriate patient monitoring and opioid titration.
Chronic pain management: injections without a specific neural

target
Trigger / tender point injections
Description: A needle is introduced into the approximate location and depth of a muscle tender point. Dry
needling has been reported, but drug(s) are usually injected. These include local anaesthetics, depot
corticosteroids, hypertonic saline and botulinum toxin.
Possible indications and evidence: There are no established indications for chronic pain. Nevertheless, it
has been/is used for:
tender areas or myofascial trigger points (fibromyalgia, myofascial pain syndrome)—diagnostic criteria
have questionable reliability and there is no consistent evidence of clinically significant benefit
chronic migraine headache—although botulinum toxin type A appears ineffective for non-migraine
headache, it has been approved in several countries for prophylaxis of headaches in patients with
chronic migraine. However, there is debate regarding the strength and bias of evidence for this
indication.
Risks and adverse effects: see Invasive techniques for chronic pain: adverse effects.
Intra-articular injections
Description: A needle is introduced into a painful joint, guided by palpable bony landmarks for most
appendicular joints and radiological guidance for axial joints (atlanto-occipital, atlanto-axial, zygapophyseal,
sacroiliac).
Drugs used include:
local anaesthetic for diagnostic procedures

corticosteroid for therapeutic procedures (see Principles of using local corticosteroid injections for
musculoskeletal conditions in adults for dosing advice)
hyaluronan for supplementing the viscosity of joint fluid (also called viscosupplementation) (see
Osteoarthritis: intra-articular injections).
Possible indications and evidence: Established indications include shoulder pain due to adhesive capsulitis
(frozen shoulder) or rotator cuff disease, lateral and medial epicondylar tendinopathies, carpal tunnel
syndrome, hip pain, knee pain and plantar fasciitis. However, effect sizes diminish within 4 weeks of a single
injection and evidence for repeated injections is limited.
Although hyaluronan is used for knee pain associated with osteoarthritis in patients who have not benefited
from corticosteroids, recent evidence is conflicting.
Intra-articular corticosteroid injections are not recommended for lumbar zygapophyseal joint pain or cervical
zygapophyseal joint pain following whiplash (due to demonstrated lack of benefit), or for Achilles tendinitis
(due to risk of tendon rupture).
Risks and adverse effects: see Invasive techniques for chronic pain: adverse effects. Septic arthritis is a rare
but serious complication. Systemic adverse effects of corticosteroid include transient increase in blood
glucose for up to 48 hours. Local adverse effects following repeated corticosteroid injections include crystal-
induced inflammation, tendon rupture, osteoporosis and osteonecrosis (see also Principles of using local
corticosteroid injections for musculoskeletal conditions in adults).
Chronic pain management: injections and infusions with a specific

neural target
Introduction
This section outlines procedures in current practice that target specific neural structures—various peripheral
nerves, the spinal nerves (within or adjacent to their dural sleeves), the neuraxis or the sympathetic plexuses.
Local anaesthetic blockade provides short-duration, reversible analgesia and is not a therapy per se. The
blocks are used diagnostically to ascertain whether a particular nerve is responsible for the patient’s pain.
Other drugs injected include corticosteroids, analgesics and neurolytic agents (eg alcohol, phenol).
Peripheral nerve blocks
Trigeminal nerve block
The trigeminal nerve and its branches supply the front half of the head, face, mouth, tongue and chin.
Blockade of the peripheral branches is only of short-term benefit for facial pain, and is associated with
adverse effects. Neurolytic blockade of the trigeminal ganglion using glycerol for treatment of refractory
trigeminal neuralgia is supported by low-quality evidence. Referral to a neurosurgeon is recommended.
Greater occipital nerve block
The greater occipital nerve (posterior branch of the C2 spinal nerve) conducts sensation from the skin over
the back of the upper neck and part of the scalp. Blockade of this nerve using local anaesthetic and/or
corticosteroid was previously advocated as a diagnostic test and/or treatment for cervicogenic headache, but
its target specificity and clinical utility are unsupported. Adverse effects were not well reported. Dizziness is
commonly associated with the procedure.
Suprascapular nerve block

The suprascapular nerve supplies two muscles of the shoulder girdle and the shoulder joint. Blockade with
local anaesthetic with or without corticosteroid is used to treat shoulder pain due to conditions such as
adhesive capsulitis (frozen shoulder) and rotator cuff disease. There is limited evidence of short-term efficacy
and a low incidence of complications. However, there is a small but material risk of pneumothorax.
Intercostal nerve block
The intercostal nerves supply intercostal muscles and transmit sensation from the chest and abdominal wall
and parietal pleura. Neurolytic blocks of these nerves are performed for cancer pain but can be associated
with significant morbidity.
Medial branch blocks
Description: The medial branches of the dorsal rami supply the zygapophyseal (‘facet’) joints of the spine,
small sections of multifidus muscle and some have branches to the skin. These nerves are blocked by trained
specialists using fluoroscopic guidance.
Possible indications and evidence: Established indications include investigation of chronic neck pain and
investigation of chronic low back pain.
These investigations are only indicated if the patient seeks target-specific diagnosis and would consider the
option of target-specific therapy. Currently, the only validated treatment is percutaneous radiofrequency
neurotomy of the medial branches. If this therapy is not available, or the patient would not consider it, then
the utility of diagnostic blocks is limited.
For blocks of the thoracic medial branches, there is limited evidence regarding accuracy of the technique and
no evidence of therapeutic utility.
Risks and adverse effects: see Invasive techniques for chronic pain: adverse effects. If performed by trained
proceduralists using fluoroscopic guidance and following established practice guidelines, misadventure due to
needling adjacent or deep structures is rare. Unrecognised intravascular injection may cause false-negative
results.
Sympathetic plexus blocks
Introduction
Peripheral sympathetic pathways transmit nociceptive afferent fibres from viscera as well as sympathetic
efferent fibres. Drugs may be injected to block these pathways temporarily for diagnostic purposes, or for
longer to palliate refractory visceral pain or to modify efferent sympathetic activity (eg in vascular
insufficiency, complex regional pain syndrome). Drugs used include local anaesthetics, with or without
neurolytic agents.
Stellate ganglion block
Stellate ganglion blockade involves injecting local anaesthetic into the region of the stellate ganglion to block
the cervical and upper thoracic sympathetic pathways. Although evidence of efficacy is lacking, it is used in
some centres for complex regional pain syndrome affecting the upper limb. Case reports of serious adverse
effects include cardiac arrest and life-threatening airway obstruction due to haematoma.
Coeliac plexus block
Description: Coeliac plexus block involves inserting needles under fluoroscopic or computerised-
tomographic (CT) guidance into target points for the coeliac plexus. These points can also be accessed
endoscopically. Drugs injected include local anaesthetics and neurolytic agents (eg alcohol or phenol).
Patients are often sedated during the procedure.
Possible indications and evidence: Coeliac plexus block is useful for end-of-life care in patients with
pancreatic cancer pain (80% response rate), or other upper abdominal malignancies. Its use in nonmalignant
pain is not supported by evidence.
Risks and adverse effects: see Invasive techniques for chronic pain: adverse effects. Diarrhoea and
hypotension commonly occur but resolve quickly. Major neurological complications (including paraplegia)
are rare.
Lumbar sympathetic block
Lumbar sympathetic ganglion blockade involves injecting a small volume of local anaesthetic and/or
neurolytic agent into the lumbar sympathetic chain under fluoroscopic guidance. Although evidence of
efficacy is lacking, it has been used for complex regional pain syndrome affecting the lower limb, peripheral
neuropathy, phantom limb pain and postherpetic neuralgia. Neurolytic agents (eg phenol) can provide longer-
term blockade than local anaesthetics, and are mainly used to treat painful peripheral vascular disease. Minor
adverse effects include pain at the injection site, bleeding, infection and irritation of the genitofemoral nerve.
Men may develop failure of ejaculation with a neurolytic block. Spinal or epidural infection is a serious but
rare complication.
Hypogastric plexus and ganglion impar blocks
The hypogastric plexus mediates pain related to lower abdominal and pelvic pathology. The ganglion impar
mediates perineal pain. Neurolytic blocks of these structures have been performed but their limited duration
of effect and potential adverse effects make them only suitable for patients with refractory cancer pain and
limited life expectancy.
Epidural blocks
Introduction
The epidural space surrounds the dural sac that contains cerebrospinal fluid (CSF) and the spinal cord (or
cauda equina below L2). Drugs can be injected into this space to block or modulate neural transmission (see
Figure 1.6A and Figure 1.6B). Drugs used include local anaesthetics, opioids, clonidine and corticosteroids.
Epidural blocks are generally part of a multimodal treatment regimen to provide pain relief in selected
patients with radicular pain or radiculopathy. Epidural blocks may be considered when less invasive therapies
are inadequate, or to defer surgery or allow temporary relief in patients in whom surgery is contraindicated.
Caudal epidural block
Description: A needle is inserted via the sacral hiatus into the caudal epidural space. Outside the
perioperative context, the most common drug injected via the caudal route is a corticosteroid.
Possible indications and evidence: Observational studies of caudal epidural corticosteroid for treatment of
lumbosacral radicular pain (radiating leg pain, ‘sciatica’) have reported success rates of various magnitudes.
However, in controlled studies, the short-term and long-term outcomes appear no better than for caudal saline
injection. Although caudal epidural block has also been employed for spinal stenosis and chronic low back
pain, current evidence does not support its use in these conditions.
Risks and adverse effects: see Invasive techniques for chronic pain: adverse effects. It is important to
prepare patients for possible transient increased back and leg pain, and systemic effects of the corticosteroid.
Infection is rare but has significant consequences and may present days or weeks after the procedure.
Interlaminar epidural block
Description: A special epidural needle is introduced to reach the posterior epidural space approximately in
the midline. Fluoroscopic guidance and radiographic confirmation of position is recommended outside the
perioperative/obstetric context. Local anaesthetic and corticosteroid are administered. While there are many
reports of this procedure in the lumbar spine, there are few for cervical or thoracic levels.
Possible indications and evidence: There is medium-quality evidence that lumbar interlaminar epidural
corticosteroid is effective for treating lumbosacral radicular pain (radiating leg pain, ‘sciatica’), but only in
the short term (up to 4 weeks). The balance of evidence does not support use of interlaminar epidural steroid
for treating chronic low back pain, and there is insufficient evidence for chronic neck pain, cervical radicular
pain (‘cervicobrachialgia’) or thoracic pain.
Risks and adverse effects: see Invasive techniques for chronic pain: adverse effects. Rare and serious
complications can occur, including paraplegia as a result of bleeding or infection in the epidural space.
Transforaminal epidural block
Description: Under fluoroscopic guidance, a fine needle is inserted into the lateral recess of the intervertebral
foramen adjacent to the target nerve root. After confirmation by radiographic contrast, corticosteroid with or
without local anaesthetic is injected around the nerve root.
Possible indications and evidence: For lumbar procedures, there is limited high-quality evidence that
transforaminal epidural corticosteroid is effective for treatment of lumbar radicular pain (radiating leg pain,
‘sciatica’) in the short-term (1 month). It can yield significant improvements in function and disability, and
reductions in use of other health care. Some patients maintain relief beyond 12 months.
Transforaminal injections of corticosteroid at cervical levels cannot be recommended unless further research
demonstrates benefit and elucidates mechanisms of serious adverse events.
Risks and adverse effects: see Invasive techniques for chronic pain: adverse effects. Although adverse
effects reported in prospective series are minor and infrequent, there are case reports of rare, potentially
catastrophic neurological sequelae. Paraplegia following lumbar transforaminal corticosteroid injection, and
brain and spinal cord infarction following cervical transforaminal corticosteroid injection, are thought to be
due to intravascular uptake of particulate steroids. The overall incidence is unclear but might be reduced, and
potentially eliminated, by using nonparticulate corticosteroids, testing for intra-arterial injection with digital
subtraction angiography, and giving a preliminary injection of local anaesthetic.
Epidural injection sites (Figure 1.6A)
Line drawing of posterior view L4 to coccyx. Needles are shown positioned for a) caudal, b) interlaminar and
c) transforaminal epidural injections.
Axial view showing epidural and intrathecal injection sites (Figure 1.6B)
Line drawing of an axial view of L4 vertebra showing nerve roots forming spinal nerves as they exit through
the intervertebral foramina. Nerve roots are surrounded by CSF in the intrathecal space (inside the dural sac).
The dura is surrounded by epidural fat and vessels within the bony central canal and intervertebral foramina.
Intrathecal block
The intrathecal space lies deep to the epidural space, between the outer and inner layers of the dura, and
contains the CSF, spinal cord and roots. Drugs administered into this CSF space have very short distances to
diffuse so much smaller doses are needed compared with the epidural route (see Figure 1.6B).
Drugs used include preservative-free local anaesthetics, opioids and clonidine for diagnostic or prognostic
blocks, and neurolytic agents (alcohol) for selective chemical ablation. The latter procedure has been
superseded by improved technology that allows intrathecal infusion of reversible drugs (see Intrathecal
infusion below). However, it may still have a role in selected patients with cancer pain.
Intrathecal infusion
Description: Intrathecal infusion is achieved by inserting a special catheter into the CSF space. The other
end of the catheter can be externalised, tunnelled to a subcutaneous portal, or connected to a fully implanted
pump. Drugs infused include opioids, local anaesthetics, clonidine and baclofen. The system used depends on
patient life expectancy, mobility and nursing care. The implanted pumps are expensive, have a failure rate of
10% per year, and a limited lifespan of up to 7 years.
Possible indications and evidence: This therapy is used mainly for cancer pain when patients have
inadequate relief or dose-limiting adverse effects from other analgesic routes. Analgesia can be achieved with
much lower doses than with other routes of administration, thus reducing adverse effects and allowing
relative dose escalation. Patients with pathological fractures, movement-related pains, plexus involvement,
and hepatic capsule pain may benefit.
Risks and adverse effects: see Invasive techniques for chronic pain: adverse effects. There are also potential
problems associated with the catheter (kinking, migration, granuloma formation, blockage) and the pump
(failure). Severe oedema can occur.
Electrical stimulation for chronic pain management
Introduction
Electrical stimulation of neural tissues emerged in the 1960s as a clinical application of the gate-control
theory of pain. Although its mechanism for analgesia remains largely unexplained, there is growing evidence
that electrical stimulation can induce neuromodulation in nociceptive pathways.
Stimulating electrodes designed for use in different locations are implanted surgically or inserted
percutaneously. The leads of the electrodes can be externalised for trial purposes or connected to fully
implanted programmable devices for long-term management. The devices and associated equipment are
expensive.
Electrical stimulation should be considered as part of a multidisciplinary assessment and treatment plan.
Appropriate patient selection is essential. Factors such as patient expectations, psychosocial aspects of the
pain, and baseline physical parameters should be examined. The goal of electrical stimulation therapy is to
reduce pain (rather than eliminate it) and, thereby, to reduce the use of pharmacological analgesics and
improve functioning.
Spinal cord stimulation

Description: Spinal cord stimulation (SCS), also known as dorsal column stimulation, is performed by
trained specialists. An electrode is implanted into the epidural space adjacent to a targeted spinal cord area
presumed to be transmitting the pain.
Possible indications and evidence: There is limited evidence of efficacy for SCS in failed back surgery
syndrome and complex regional pain syndrome. There is conflicting evidence regarding efficacy for pain
associated with peripheral vascular disease and refractory angina. Studies addressing long-term outcome and
safety have been underpowered.
Risks and adverse effects: see Invasive techniques for chronic pain: adverse effects. Compression of
neuraxial structures by epidural haematoma or abscess, and delayed complications of lead migration, lead
fracture, system malfunction, leak of cerebrospinal fluid and meningitis are serious complications of SCS.
Adverse effects are observed in all patients, and complications in 34%. Other considerations include limited
battery life and possible risk with diathermy, cardiac pacemakers and magnetic resonance imaging.
Cerebral stimulation
Electrical stimulation of deep brain centres involved in the modulation of pain (deep brain stimulation) and
motor cortex stimulation have been reported. However, evidence for these interventions remains very weak,
being drawn from case series alone.
Neurosurgical procedures for chronic pain management

Introduction
Neurosurgical procedures for pain do not address the underlying pathology, but rather aim to interrupt neural
pathways involved in nociceptive transmission.
Except for percutaneous radiofrequency neurotomy, the use of these procedures has declined in recent
decades. This is due to the limited duration of benefit, and to advances in pharmacological management of
refractory pain. The limited duration of analgesia restricts utility to refractory pain in patients with similarly
limited life expectancy.
Percutaneous radiofrequency neurotomy

Description: A prerequisite for percutaneous radiofrequency neurotomy is to identify the peripheral nerve(s)
that transmit the pain using controlled diagnostic local anaesthetic blocks (see Medial branch blocks). It is
performed by trained specialists under local anaesthesia and imaging guidance, and involves insertion of a
needle-electrode to lie adjacent to the target nerve. Radiofrequency current is applied to generate small
thermal lesions (80 ºC). Analgesia may last several months to years. Limited data suggest the procedure can
be repeated when pain returns.
Possible indications: Although percutaneous radiofrequency neurotomy has been attempted for other targets
in the past, established applications include:
trigeminal ganglion or peripheral branches (for trigeminal neuralgia)

medial branches of the cervical dorsal rami (for chronic neck pain, or cervicogenic headache due to
cervical zygapophyseal joint pain)
medial branches of the lumbar dorsal rami (for chronic low back pain due to lumbar zygapophyseal
joint pain).
Radiofrequency lesions may also be generated in central neural pathways after open neurosurgical exposure
of the target tissue (see specific surgical procedures below).
Adverse effects: see Invasive techniques for chronic pain: adverse effects. Other effects are specific to each
procedure. Specialist proceduralist consultation is recommended to evaluate risk and discuss adverse effects
with individual patients.
Dorsal root entry zone lesions
Description: The procedure is performed under general anaesthesia by specialist neurosurgeons, often using
computer-assisted guidance. The spinal cord is exposed surgically and lesions are made in the dorsal root
entry zone (DREZ) of the spinal cord using radiofrequency current or laser. This is repeated at short intervals
along the spinal cord in areas related to the patient’s pain. The mechanism of action is largely unexplained.
Possible indications and evidence: DREZ lesions may be considered for adults with refractory central
segmental neuropathic pain due to traumatic spinal cord injury or deafferentation pain due to brachial plexus
avulsion. Evidence for other indications is lacking.
Adverse effects: see Invasive techniques for chronic pain: adverse effects. Other effects are specific to the
level and number of spinal segments being lesioned. Neurosurgical consultation is recommended to evaluate
risk and discuss adverse effects with individual patients.
Cordotomy
Description: Cordotomy is performed by specialist neurosurgeons, under local anaesthesia and fluoroscopic
or computerised-tomographic (CT) guidance. A needle-electrode is inserted at the C1–C2 level to target the
anterolateral funiculus (anterior spinothalamic tract) contralateral to the patient’s pain. This interrupts the
afferent nociceptive pathway.
Possible indications and evidence: Cordotomy may be considered for adults with refractory unilateral
cancer pain (localised in the upper limb and thorax or the lower limb and pelvis) or refractory bilateral cancer
pain (localised in the lower body and lower limbs).
Adverse effects: see Invasive techniques for chronic pain: adverse effects. The descending respiratory
pathway can be damaged by lesions for upper limb and body pain. Unilateral destruction of this pathway
results in little functional respiratory loss, but bilateral lesioning may cause Ondine’s curse (sleep-induced
apnoea).
Intradiscal electrothermal therapy

Description: In intradiscal electrothermal therapy (IDET), a catheter electrode is inserted through a needle
into a putatively painful disc by trained specialists. Current is used to generate thermal lesions in the
posterolateral annulus. The mechanism of analgesia is unclear but may be due to ablation of nociceptors and
some physical effects on collagen.
Possible indications and evidence: IDET is considered when a diagnosis of chronic low back pain due to
internal disc disruption has been made with disc stimulation and CT discography (see also Symptomatic
lumbar disc herniation). However, there is conflicting evidence about its effectiveness.
Adverse effects: see Invasive techniques for chronic pain: adverse effects. Adverse effects are reported
infrequently but include radiculopathy, discitis, bladder dysfunction, vertebral osteonecrosis and cauda equina
syndrome.
Invasive techniques for chronic pain: further reading

The Faculty of Pain Medicine, Australian and New Zealand College of Anaesthetists has links to relevant
established guidelines including the following:
PM3: Lumbar epidural administration of corticosteroids—2010. [URL]

PM4: Guidelines for patient assessment and implantation of intrathecal catheters, ports and pumps for
intrathecal therapy—2005. [URL]
PM6: Guidelines for longterm intrathecal infusions (analgesics / adjuvants / antispasmodics)—2007.
[URL]
PM9: Neuromodulation (spinal cord stimulation) in the management of patients with chronic pain—
2011. [URL]
PS3: Guidelines for the management of major regional analgesia—2011. [URL]
PS9: Guidelines on sedation and/or analgesia for diagnostic and interventional medical, dental or
surgical procedures—2010. [URL]
Accident Compensation Corporation, New Zealand provides evidence-based guidance on interventional pain
management that can be searched either by body region or procedure type. [URL]
Bogduk N, editor. Practice guidelines for spinal diagnostic and treatment procedures. San Francisco:
International Spine Intervention Society; 2004. ISBN 0-9744402-0-5
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Pain in children
Overview
Infants and children have the capacity to perceive pain. Experiences expected to be painful for adults will also be
painful for infants and children. The pain can be:
transient (eg scrapes and bruises that do not require medical management)
acute (eg due to illness, trauma or medical procedures such as immunisation, blood tests and surgery)
recurrent (eg abdominal pain, headaches, limb pain and chest or back pain, which are experienced
occasionally to frequently by up to 30% of children)
chronic (eg juvenile arthritis, migraine, inflammatory bowel disease, cancer, malaria, HIV/AIDS, sickle cell
disease, neuropathic pain from peripheral nerve or spinal cord injury).
Children, like adults, have a fundamental human right to access pain management without discrimination. This
includes the right to have their pain acknowledged, assessed and treated, and to be involved in decision-making as
developmentally capable.
National and international pain management standards and guidelines that are relevant to infants and children are
listed in Further reading. These documents should guide clinical decision-making beyond the decision to prescribe
analgesics for children.
Children’s development and pain

Even very premature neonates are born with pain pathways and respond to noxious stimuli. Severe or repeated
pain early in life may have adverse long-term consequences due to its impact on the developing nervous system.
Throughout childhood, pain continues to have adverse physiological and psychological effects, which can be
ameliorated by pain management.
Pain interrupts attention and disrupts function during all phases of development. If severe, repeated or persistent:
pain in infants may disrupt sleep, feeding, motor development, attachment and early social development
pain in children may interfere with preschool or school attendance, interrupt concentration and learning, and
disrupt emerging physical, emotional and social skills
pain in adolescents may interfere with the normal tasks of transitioning to adulthood—becoming
independent from parents and family, identifying with peers, gaining self-confidence and stable identity,
exploring educational, vocational and relationship aspirations.
Children’s ability to communicate their pain experience changes throughout these developmental stages, so a
variety of approaches to pain assessment are needed (see Pain assessment in children).
Children’s ability to process the meaning and implications of their pain also changes with development. Children
less than 7 years old are usually unable to logically connect causal agents with pain, or to comprehend the
benevolent motives of clinicians (or parents) who expose them to painful procedures. These young children do not
understand constructs such as tolerating ‘short-term pain for long-term gain’. Consequently, they experience more
anxiety, pain-related distress and, occasionally, post-traumatic stress as a result of painful medical and dental
procedures. Pay special attention to nonpharmacological and pharmacological analgesia for procedure-related pain
in this age group.
Pain assessment in children

Introduction
Good pain assessment is the foundation for rational analgesic prescribing. The goals of assessment are to:
establish a diagnosis or mechanism for the child’s pain

determine the urgency for intervention
inform the most appropriate management.
Always assess the child’s pain in context—consider age and developmental level; family, social and cultural
factors; general health; and previous pain experience.
Comprehensive pain assessment in children
A comprehensive pain assessment includes:
clinical interview with the child and parent or guardian to ascertain a pain history (ie course, location,
quality) and to explore the context of the pain experience (other stressors, past pain experiences, coping
style)
physical examination including vital signs, and a focused assessment of the painful condition and associated
physical limitations (eg ability to breathe, move, play, sleep)
an age- and context-appropriate pain intensity scale
investigations as indicated by above.
A comprehensive evaluation is not required every time the child’s pain is assessed, but should be performed at the
initial presentation and whenever there are significant or unexpected changes in pain.
Review for analgesic toxicity at least every 24 hours. If the child’s physical status (eg dehydration, fasting, liver or
kidney dysfunction) or the drugs or dosing pose an increased risk of toxicity, a medical officer should evaluate the
child for symptoms and signs of adverse effects and arrange further testing and consultation as indicated.
Pain intensity scales used in children

Intensity is just one dimension of pain. Although it is not sufficient to describe pain only in terms of intensity, this
does guide prescribing decisions to a considerable extent (see Translating pain assessment into prescribing
decisions). Reliable, quick and clinically valid pain intensity scales are available for children of all ages and
cognitive abilities, in a variety of clinical contexts.
Use Table 1.16 to:
determine whether the child is developmentally old enough to self-report pain intensity
select an appropriate scale
follow links to commonly used scales.
Document the pain intensity scale selected for a given child so that it can be used consistently by all staff caring
for the child. Parents often appreciate instruction in how to use the scales to help them more confidently evaluate
their child’s pain experience.
If the child is in hospital, perform pain intensity scores and record regularly like other vital signs (eg temperature,
respiratory rate, heart rate, blood pressure)—pain is the ‘fifth vital sign’. Record pain intensity scores at intervals
appropriate to the child’s clinical condition:
on initial assessment/admission, and then daily as long as pain is not a feature

four-hourly while pain is controlled by oral analgesics
whenever a child appears distressed or complains of pain and again after analgesic intervention to assess for
adequate relief
more often if an opioid infusion, patient-controlled analgesia, epidural or continuous regional analgesia is
used—refer to local guidelines and procedures.
Pain intensity scales used in children (Table 1.16)
Reliability of pain intensity

Developmental age Pain intensity scales
self-report
use observer estimate tool relevant to clinical context:
cognitively impaired acute procedural pain—NCCPC-R, PPP

none or marginal
children acute postoperative pain—NCCPC-PV, PPP,
FLACC-R
acute procedural pain—PIPP, CRIES, NFCS

neonates none
acute postoperative pain—PIPP, CRIES
neonatal intensive care unit—PIPP, COMFORT
acute procedural pain—FLACC, CHEOPS

infants less than 3 acute postoperative pain—FLACC
marginal
years acute pain at home—PPPM
paediatric intensive care unit—COMFORT
use observer estimate tools as above
OR if the parent thinks their child can respond in a valid

3 to 4 years emerging
way:
Pieces of Hurt (poker chip) tool

better with pictures and
5 to 6 years Faces Pain Scale—Revised (FPS-R)
visual scales than numbers
Faces Pain Scale—Revised (FPS-R)
good, but still better with
7 years OR
visual scales
0 to 100 mm visual analogue scale (VAS)
8 years or more good 0 to 10 numerical rating scale (NRS)
CHEOPS = Children’s Hospital of Eastern Ontario Pain Scale
COMFORT = COMFORT Behaviour Scale
CRIES = Crying, Requires oxygen, Increased vital signs, Expression, Sleep Scale
FLACC = Faces, Legs, Activity, Cry, Consolability Observational Tool (see Appendix 1.1)
FLACC-R = Faces, Legs, Activity, Cry, Consolability-Revised Observational Tool
NCCPC-PV = Non-communicating Children’s Pain Checklist-Postoperative Version [URL]
NCCPC-R = Non-communicating Children’s Pain Checklist-Revised [URL]
NFCS = Neonatal Facial Coding Scale
PIPP = Premature Infant Pain Profile
PPP = Paediatric Pain Profile [URL]
PPPM = Parents’ Postoperative Pain Measure
Information about some of these scales can be found at the website of the Centre for Pediatric Pain Research, University of Dalhousie [URL]
Translating pain assessment into prescribing decisions
Pain assessment has utility when it facilitates clinical and prescribing decisions that yield good patient outcomes.
Algorithms such as Figure 1.2 and Figure 1.4 can help to translate acute pain assessment into prescribing
decisions. These algorithms may not be appropriate to guide prescribing in children with complex health problems
or chronic pain (see Pain in children with chronic medical conditions and Other chronic pain syndromes in
children).
Nonpharmacological management of pain in children

Nonpharmacological pain management interventions are generally divided into three categories—environmental,
physical and psychological (see Table 1.17 for examples of each of these interventions). The evidence of efficacy
for the interventions varies in quantity, quality and in the size of the clinical benefit demonstrated.
Nonpharmacological interventions may be used alone for mild pain and distress, or in combination with
pharmacotherapy for moderate to severe pain and painful procedures. Their use may avert drug–drug interactions
that may be seen with supplemental analgesics or sedatives.
Tailor the intervention(s) to the individual child, family and clinical context. This necessitates a good clinical
assessment (see Pain assessment in children), knowledge of available strategies (see Table 1.17), and timely access
to the necessary resources.
In addition to symptom management, children often enjoy these interventions, and gain an enhanced sense of
empowerment and control.
Nonpharmacological pain management interventions are generally considered safe. To reduce the risk of cross-
infection, play materials should be designated as single-patient use, or cleaned appropriately.
Simple, age-appropriate, nonpharmacological pain management strategies (Table 1.17)
Environmental Physical interventions Distraction techniques

Developmental stage
interventions [NB1] [NB2]
non-nutritive sucking (eg
dummy/pacifier)
breastfeeding
warm crib parental eye contact, voice,
swaddling
singing
neonate quiet atmosphere
kangaroo care
parental eye contact nursing/holding/rhythmic
movements
gentle music
using mobiles over the cot

non-nutritive sucking (eg
dummy/pacifier)
parental eye contact, voice
warm room sitting up if possible noise makers (eg rattles,

shakers)
calm atmosphere hugging
infant or toddler bubble blowing
parental presence patting
puppet play
familiar toys stroking
music and singing
storytelling
cause and effect toys

cuddles/stroking/patting
bubble blowing
sound books
warm room ‘find it’ books

sitting up if possible
calm atmosphere drawing
preschool child hugging
parental presence music and singing
stroking
familiar toys puppet play
talking about familiar

things
some basic electronic

games
talking and questioning
counting
music
stress balls
sitting up if possible
warm room
‘find it’ books
hugging
privacy
drawing
application of heat or cold
school-age or adolescent calm atmosphere
or vibration device guided imagery (ie
parental presence imagining a favourite
menthol or heat cream rubs
place)
familiar items or music
warm soak
TV/videos/electronic games
deep breathing
humour
magic
NB1: These are simple physical interventions. Physical interventions that require more training include massage, splinting and physiotherapy.
NB2: Distraction is a simple psychological strategy. Psychological techniques that require more training and resources include medical play, cognitive
behavioural therapy, hypnosis and virtual reality immersion.
Pharmacological management of pain in children

Analgesic pharmacology in children
During the first year of life there are many changes that affect the pharmacokinetic profile of analgesic drugs.
These include changes in body water and fat composition, plasma protein binding, and liver and kidney function.
In addition, changes in nociceptive processing may affect the pharmacodynamic response to analgesics in infancy
and childhood.
These factors result in significant maturation- and size-related changes in dose requirements for many analgesics
and other drugs during infancy and childhood. Particularly in premature neonates, gestational age (rather than
postnatal age) is used as an approximation of maturity. Guidance for drugs used commonly in neonates will be
based on both gestational age and actual body weight.
Unless otherwise specified, prescribing advice in this guideline is given as the dose per kilogram based on the
least of: actual body weight or ideal body weight or 50 kg maximum. Ideal body weight can be estimated as the
50th centile on an appropriate weight-for-age percentile chart (see weight-for-age percentile charts available at
[URL]).
Analgesic dosing in children

Exercise caution when determining all drug doses in children. The most common error is to get the decimal point
wrong and be out by a factor of 10. Be particularly cautious when prescribing for infants and children who are
dehydrated, malnourished, obese, have liver or kidney dysfunction, sepsis or other critical illness.
Exercise caution when determining drug doses in children.
The dosages of analgesics commonly used in children are given in Table 1.18, Table 1.19, Table 1.20, Table 1.21,
Table 1.22, Table 1.23 and Table 1.24. These tables are a guide only. Prescribers should consult drug information
resources and full product information to check indications, contraindications, drug interactions and adverse
effects. The off-label use of any medication should be discussed with parents or guardians and their informed
consent obtained.
Sucrose
Sucrose is used to modify responses to minor procedural pain in infants from 32 weeks gestational age up to 4
months of age. Sucrose reduces crying, grimacing and heart rate, but reduces pain scores by only 1 to 2 points on a
10-point scale. The sweet taste is thought to evoke a fast-onset analgesic effect mediated by endogenous opioids.
This effect peaks at 2 minutes and lasts 5 to 10 minutes.
Administer sucrose directly onto the tongue or buccal mucosa (inside of the cheek) via a pacifier (dummy) or oral
syringe 2 minutes before the procedure (see Table 1.18 for dose).
Combine sucrose with nonpharmacological comfort measures (eg non-nutritive sucking, positioning and
swaddling). Breastfeeding and the use of expressed breast milk are alternatives to sucrose. Also consider the need
for other analgesics as appropriate for the child, procedure and anticipated pain level.
Maximum recommended dose of sucrose for neonates and infants (Table 1.18) [NB1]
Age Maximum dose (mL) of 25% sucrose [NB2]

32 to 36 weeks gestational age [NB3] 1 mL
37 weeks gestational age [NB3] to 4 months
2 mL
[NB4]
NB1: Do not use sucrose in babies weighing less than 1000 g. In babies weighing 1000 g or more, dosing is based on age as indicated above.
NB2: Although more concentrated sucrose solutions are sometimes used, there is no evidence that they are more efficacious. At the time of writing, there
are no published data on maximum dose per day of sucrose. Consensus guidelines recommend a maximum of 4 doses in 24 hours. If additional doses are
considered necessary above this limit, contact the medical officer to authorise additional doses and/or consider alternative management.
NB3: Gestational age is taken from the first day of the last menstrual period before conception.
NB4: Research in older infants is limited and suggests that sucrose efficacy dwindles between 4 and 6 months of age. If used for older infants, monitor
effectiveness and consider additional analgesics.
Paracetamol
Paracetamol is one of the commonest analgesics used in children. Oral bioavailability is approximately 90%, with
onset of analgesia within 30 minutes. It is available in a range of oral preparations including drops, suspensions of
various concentrations and tablets. It is also present in many nonprescription combination preparations for colds
and pain relief. Combination analgesics may reduce medication costs for parents in the community, but also reduce
the scope for effective titration of individual components.
Paracetamol rectal suppositories have variable bioavailability (50% to 100%), are slowly absorbed and peak blood
concentration may not be reached for up to 90 minutes. Intravenous paracetamol (10 mg/mL), available for
hospital use in Australia, has 100% bioavailability and onset of analgesic effect within 5 to 10 minutes of
commencing an IV infusion. These formulations may be useful when oral administration is not possible, but oral
paracetamol should be substituted at the earliest opportunity.
Dosing of paracetamol-containing medications is given in Table 1.19. Paracetamol can be used with appropriate
doses of nonsteroidal anti-inflammatory drugs (NSAIDs) (see Table 1.20) or opioids (see Table 1.21 and Table
1.22) for greater analgesia. Use of paracetamol after surgery can reduce opioid requirements by 15% to 20%.
In neonates and small infants, metabolic pathways are still maturing and paracetamol clearance is slower.
Paracetamol is not contraindicated in this age group but specialist involvement in prescribing is recommended.
Take care to avoid administration errors.
Risk of liver toxicity is increased in children with pre-existing liver disease, prolonged fasting, chronic under-
nutrition, vomiting, dehydration, febrile illness, severe kidney dysfunction, morbid obesity, systemic sepsis and
prior paracetamol intake over several days. The presence of risk factors does not contraindicate treatment with
paracetamol but dosing and management need to be carefully considered. The risk of paracetamol toxicity is
increased by the concurrent use of multiple formulations that contain paracetamol or use of adult formulations for
children.
Take care to avoid paracetamol overdosage.
Dosing of paracetamol-containing medications for analgesia in children 1 month to 12 years

(Table 1.19) [NB1]
Route Paracetamol dose [NB2] Maximum total daily (24-hour) dose

1 to 6 months: 60 mg/kg/day
6 months or more: 90 mg/kg/day for up to 2

days in children treated in hospital then
reduce to 60 mg/kg/day
OR
oral 15 mg/kg orally, 4-hourly
60 mg/kg/day for children treated in a
paracetamol [NB3] Never exceed 1 g/dose.
community setting and children with fever or
risk factors for hepatotoxicity
Never exceed 4 g in 24 hours.
Review dosing at 48 hours and consider

reducing dose.
As for oral (see above).
rectal 20 mg/kg rectally, 6-hourly
Substitute oral paracetamol at the earliest
paracetamol [NB4] Never exceed 1 g/dose.
opportunity.
less than 6 months and/or less than 5 kg:
only use with specialist review
10 kg or less: 7.5 mg/kg by IV infusion, 6-
10 kg or less: 30 mg/kg/day
hourly
more than 10 kg up to 33 kg: 15 mg/kg by more than 10 kg up to 33 kg: 60 mg/kg/day,
IV infusion, 6-hourly not exceeding 2 g/24 hours
intravenous
more than 33 kg up to 50 kg: 15 mg/kg by
more than 33 kg up to 50 kg: 60 mg/kg/day,
paracetamol [NB5] IV infusion, 4- to 6-hourly (up to 4 doses per
not exceeding 3 g/24 hours
day)
Review dosing at 24 hours and consider
reducing dose.
Never exceed 1 g/dose.
Substitute oral paracetamol at the earliest
opportunity.
NB1: Although children aged more than 12 years are generally considered adults for the purposes of paracetamol dosing, adolescents who are below
ideal body weight for their age should continue to have their paracetamol dose calculation based on their actual body weight.
NB2: In obese children, the dosage should be based on ideal body weight, which can be estimated as the 50th centile on an appropriate weight-for-age
percentile chart (see weight-for-age percentile charts available at [URL]).
NB3: Some specialist centres have protocols for administration of preoperative/preprocedural loading doses of oral paracetamol (up to 30 mg/kg). Use of
loading doses outside the specialist setting is not recommended. The loading dose must be included in the total 24-hour calculation.
NB4: Do not use the rectal route in immunocompromised children or those with coagulopathy. Only use when oral dosing is not possible and intravenous
dosing is not indicated. Obtain parental consent. Do not cut suppositories—calculate dose to nearest suppository strength.
NB5: Only use the intravenous route when oral dosing is not possible. Do not use if paracetamol was administered by another route in preceding 6 hours.
Do not give further paracetamol by any other route until at least 6 hours after an intravenous dose (this may be reduced to at least 4 hours if the child is
more than 33 kg and has no hepatic or renal impairment). Give intravenous paracetamol by IV infusion over 15 minutes.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are very effective for mild to moderate pain in older children.
Several nonselective NSAIDs have been studied and approved for use in children (see Table 1.20). Selective
cyclo-oxygenase-2 (COX-2) inhibitors (or coxibs), including intravenous parecoxib, have only been used off-label
in children. Evidence supporting the use of COX-2 inhibitors in children remains limited.
Clinical studies suggest NSAIDs and paracetamol have similar analgesic efficacy. When paracetamol analgesia is
inadequate, adding an NSAID has been shown to improve analgesia. As a component of multimodal analgesia,
NSAIDs decrease opioid consumption.
After major surgery, oral NSAIDs are usually only started once the child is eating and drinking adequately, and
they are prescribed for a set time period (eg 3 days).
Short-term use of ibuprofen appears to be safe in most children, with risk of serious adverse events being similar to
that following paracetamol.
Contraindications to the use of NSAIDs in children include:
known hypersensitivity to aspirin or NSAIDs

active peptic ulcer disease
bleeding diatheses, or thrombocytopenia
severe asthma, especially if aspirin-sensitive, corticosteroid-dependent or with nasal polyposis
concurrent kidney dysfunction, hypovolaemia and diuretic therapy
planned major surgery.
Use NSAIDs with caution in cardiac, hepatic and renal impairment. In patients with renal impairment, kidney
function should be monitored as it may deteriorate with NSAID use. The safety of long-term NSAID use (for more
than 3 to 7 days) in children is uncertain.
Aspirin should be avoided in children under the age of 16 years due to its rare association with Reye syndrome. It
may occasionally be used in juvenile arthritis.
Dosing of nonsteroidal anti-inflammatory drugs (NSAIDs) used in children (Table 1.20) [NB1]
[NB2]
Drug Dose [NB3] [NB4] Licensed age range Formulations available

1 mg/kg orally or rectally, 2 or 3 suppositories: 12 months suppositories
times daily with food and over
diclofenac tablets and powder for oral
maximum of 3 mg/kg/day up to tablets and oral solution: 14 solution are available but not
150 mg/day years and over licensed for use in children
multiple presentations including
5 to 10 mg/kg orally, 3 or 4 times
flavoured oral suspensions,
daily with food
ibuprofen 3 months and over drops, tablets, capsules
maximum of 30 mg/kg/day up to
also in various combination
1200 mg/day
analgesics
5 mg/kg orally, twice daily with
naproxen food 2 years and over tablets, oral suspension
maximum 1000 mg/day
NB1: Although children aged more than 12 years are generally considered adults for the purposes of prescribing, adolescents who are below ideal body
weight for their age should continue to have their NSAID dose calculation based on their actual body weight.
NB2: Nonselective NSAIDs and COX-2 inhibitors not licensed for use in children are omitted. Consult specialist services and research literature for
dosing advice and precautions.
NB3: In obese children, the dosage should be based on ideal body weight, which can be estimated as the 50th centile on an appropriate weight-for-age
percentile chart (see weight-for-age percentile charts available at [URL]).
NB4: Higher doses may be used for juvenile idiopathic arthritis (see Juvenile idiopathic arthritis: oligoarthritis) under specialist care.
Opioids
Opioid analgesics are primarily used for moderate to severe acute pain or cancer pain in children. They also have a
role in the treatment of disabling pain associated with chronic disease. All full opioid agonists used short-term in
appropriate doses produce similar analgesic effects and therapeutic index. Different opioids have different
pharmacokinetic properties that determine their onset and duration of effect.
In the neonatal period and infancy, there are significant developmental changes in the pharmacokinetic handling
and pharmacodynamic response to opioids. For neonates, select the lower limit of the loading dose range and
administer in increments. If maintenance opioid is required, consult specialist paediatric or pain services as soon as
feasible for advice.
Opioid kinetics also vary considerably between individuals (2- to 3-fold), so loading doses are simply a safe
starting point. Dosing should then be titrated to the individual child’s response. Genetic variation in analgesic
metabolism is particularly important for codeine, tramadol and oxycodone. These drugs are metabolised by the
hepatic enzyme cytochrome P450 2D6—ultrarapid metabolisers may have higher peak levels of active metabolites
with associated increased adverse effects; poor metabolisers may have inadequate analgesia.
Many children’s hospitals internationally have removed codeine from their formularies due to its risk in ultrarapid
metabolisers. Codeine should not be used in patients known to be ultrarapid metabolisers, in children younger than
12 years, and in children 12 to 18 years who have recently had a tonsillectomy and/or adenoidectomy for
obstructive sleep apnoea. For more information, see the TGA Medicines Safety Update.
Recommendations for oral and intravenous opioid dosing in children are given in Table 1.21 and Table 1.22.
During loading and titration, regularly assess pain severity, the analgesic response, and the incidence of adverse
effects (particularly sedation, nausea and vomiting). See Monitoring and managing adverse effects of opioids in
children for detailed monitoring advice.
Monitor for sedation, which is the earliest sign of opioid-induced respiratory depression.
If children require maintenance opioid dosing via the intravenous route, consider contacting an inpatient pain
service, where available, for advice or assistance in monitoring and management.
Do not use modified-release opioid tablets, transdermal patches or oral transmucosal fentanyl citrate lozenges for
initial management of acute pain in opioid-naive children. These formulations may have a role in children with
persisting pain and predictable background opioid requirements, but specialist involvement in prescribing is
recommended.
Providing information and education for parents can help them understand that the risks of serious adverse events,
tolerance or addiction with opioid use in children are very low. Explain how the medication is administered,
monitored and how risks are anticipated and managed.
Addiction in children receiving parenteral opioids for acute pain is extremely rare.
Opioid-induced adverse effects are similar in children and adults (see Table 1.3 for adverse effects with short-term
use of opioids and Table 1.15 for adverse effects with long-term use of opioids). If opioids are to be administered
regularly for more than 24 hours, implement a bowel management plan to prevent constipation (see Constipation
in children). There is insufficient evidence in children to recommend the use of novel naloxone-containing oral
opioids to reduce opioid-induced constipation.
Dosing of immediate-release oral opioids used in children (Table 1.21) [NB1]
Drug Dose Formulations available

0.5 to 1 mg/kg orally, 4- to 6-
hourly linctus, tablets
codeine [NB2]
maximum 3 mg/kg/day up to also a component in many combination analgesics [NB3]
240 mg/day
0.2 to 0.4 mg/kg orally, 4-
morphine oral solution, tablets
hourly
0.1 to 0.2 mg/kg orally, 4-
oxycodone oral solution, tablets, capsules
hourly
1 to 2 mg/kg orally, 4-hourly
tramadol [NB4] oral drops, tablets
maximum 6 mg/kg/day up to
400 mg/day
NB1: Children weighing more than 50 kg are considered adults for the purposes of prescribing.
NB2: Codeine efficacy in children is variable, particularly in poor metabolisers (neonates and 10 to 46% of children may have low cytochrome P450 2D6
activity). If ineffective, consider alternatives. Ultrarapid metabolisers may experience morphine-related adverse effects; codeine should not be used in
patients known to be ultrarapid metabolisers, in children younger than 12 years, and in children 12 to 18 years who have recently had a tonsillectomy
and/or adenoidectomy for obstructive sleep apnoea. For more information, see the TGA Medicines Safety Update.
NB3: Calculate the dose of paracetamol+codeine combination analgesics based on the paracetamol dose appropriate for the child’s weight—see Table
1.19.
NB4: Tramadol is licensed to treat moderate to severe pain in children aged 12 years and older.
Dosing of intravenous opioids commonly used in children (Table 1.22) [NB1]
Dosing Fentanyl Morphine [NB2]

1 to 1.5 micrograms/kg, in increments
loading dose [NB3] (if IV access is delayed, use 1.5 100 micrograms/kg, in increments
micrograms/kg intraNASAL and repeat
in 15 minutes if required)
intermittent bolus [NB4] 0.3 to 0.5 microgram/kg, 1- to 3-hourly 30 to 50 micrograms/kg, 1- to 3-hourly
add fentanyl 20 micrograms/kg to add morphine 1 mg/kg to 0.9% sodium
typical solutions for PCA, NCA 0.9% sodium chloride to make total chloride to make total volume of 50
or infusion volume of 50 mL mL
= 0.4 microgram/kg/mL = 20 micrograms/kg/mL

bolus: 0.4 microgram/kg bolus: 20 micrograms/kg
typical PCA starting settings lockout: 5 minutes lockout: 5 minutes

[NB5]
background (optional): 0.1 background (optional): 5
microgram/kg/hour micrograms/kg/hour
bolus: 0.4 microgram/kg bolus: 20 micrograms/kg
lockout: 15 minutes [NB7] lockout: 15 minutes [NB7]

typical NCA starting settings background: start neonates at 0.2 background: start neonates at 10
[NB6] microgram/kg/hour, and infants and micrograms/kg/hour, and infants and
children at 0.4 microgram/kg/hour; children at 20 micrograms/kg/hour;
then titrate in range 0.2 to 0.8 then titrate in range 10 to 40
microgram/kg/hour micrograms/kg/hour
infusion: start neonates at 0.2 infusion: start neonates at 10
microgram/kg/hour, and infants and micrograms/kg/hour, and infants and
children at 0.4 microgram/kg/hour; children at 20 micrograms/kg/hour;
typical infusion starting then titrate in range 0.2 to 0.8 then titrate in range 10 to 40
settings microgram/kg/hour micrograms/kg/hour
bolus: 0.4 microgram/kg, at 30-minute bolus: 20 micrograms/kg, at 30-minute

intervals if needed intervals if needed
NCA = nurse-controlled analgesia; PCA = patient-controlled analgesia
NB1: Children weighing more than 50 kg are considered adults for the purposes of prescribing.
NB2: Avoid morphine in children with significant renal impairment. Use fentanyl instead.
NB3: The speed of administration of an IV loading dose should be adjusted according to clinical urgency, level of monitoring and skill level of the staff
present. In the emergency department it might be appropriate to give the full loading dose immediately, but in most clinical settings safety is enhanced if
half the loading dose or less is given followed by observation of effect and further increments at 5-minute intervals as required.
NB4: Intermittent bolus dosing is generally reserved for pain during assessment. Repeated boluses are labour-intensive and patients may experience
inadequate analgesia during the dosing interval.
NB5: PCA using a programmable bolus/infusion device is usually suitable for school-aged children (see Patient-controlled analgesia in Postoperative
phase).
NB6: NCA using a programmable bolus/infusion device is useful for preschool children and those who are otherwise unable to understand or physically
press the button (see Nurse-controlled analgesia in Postoperative phase).
NB7: The NCA lockout interval is usually longer than for PCA, so that the peak effect of a bolus is achieved (at least 15 minutes following morphine
bolus) before pain reassessment and further bolus administration. Shorter intervals may be appropriate in tertiary paediatric hospitals if specific protocols
and staff credentialing exist.
Antineuropathic analgesics
Neuropathic pain in children may respond to simple analgesics and opioids, but relief is often inadequate. Tricyclic
antidepressants (eg amitriptyline, nortriptyline), antiepileptic drugs (eg carbamazepine, gabapentin) and ketamine
have all been studied and have a long history of off-label use for treating neuropathic pain in children. Specialist
involvement in assessment and prescribing is strongly advised.
Inhalational agents
Nitrous oxide
Nitrous oxide is a useful anxiolytic and modest analgesic for procedural pain in children. Concentrations ranging
from 50% to 70% nitrous oxide in oxygen have been used. The higher concentrations have not been shown to
provide superior analgesia but are associated with a higher risk of adverse effects. The administrator should be
experienced with the equipment, only look after the administration of nitrous oxide, monitor the child’s level of
pain and sedation, airway, breathing and pulse oximetry, and should maintain verbal contact with the child
throughout.
Care should be taken in children aged less than 2 years old, those with a difficult airway, illness or taking other
sedating medications. Contraindications include conditions in which gas is trapped within a body cavity (eg
pneumothorax, obstruction of middle ear, sinus or bowel) as nitrous oxide may expand or increase pressure within
such spaces.
At the conclusion of administration of nitrous oxide it is standard practice to administer supplemental oxygen
(more than 50% oxygen; usually 15 L/min via a Hudson mask) for 3 to 5 minutes to prevent an abrupt decrease in
oxygen saturation of arterial blood (termed ‘diffusion hypoxaemia’). Recent evidence suggests this may not be
essential when 50% nitrous oxide (or less) is used in healthy patients who have not received other sedatives.
Patients requiring frequent administration of nitrous oxide (eg 3 times per week for 2 weeks or more) may require
vitamin B12 and folate supplementation. Consult your local hospital pharmacist for available oral formulations and
dosing.
Methoxyflurane
Methoxyflurane (see Stepwise approach to acute pain management: methoxyflurane) use and efficacy in children
over 5 years of age has been reported, but a high incidence of deep sedation was observed in those less than 5
years. Methoxyflurane should only be used where appropriate resuscitation facilities are available.
Local anaesthetics
Introduction
Local anaesthetics can provide excellent pain relief when used to block nerves that are transmitting nociceptive
signals. They are an important component of multimodal analgesia, and can significantly decrease opioid
requirements.
Topical local anaesthetics
The dose of topical local anaesthetic varies depending on the surface area of anaesthesia required, but should never
exceed the maximum recommended dose for age and weight (see Table 1.23). Cover the topical local anaesthetic
with an occlusive dressing and remove after the prescribed application time.
Maximum recommended doses of topical local anaesthetics commonly used in children (Table
1.23) [NB1]
Drug Maximum dose by age (application time)

neonates: seek specialist advice
amethocaine 4% (Local AnGel) [NB2] 1 month to 12 years: up to 0.5 g (for at least 30 minutes for
venipuncture; 45 to 60 minutes for venous cannulation; maximum
60 minutes)
EMLA cream
premature neonates: seek specialist advice
0 to 3 months: up to 1 g (for 1 hour)
3 to 12 months: up to 2 g (for 1 to 4 hours)
1 to 6 years: up to 10 g (for 1 to 4 hours)

eutectic mixture of local anaesthetics 5%— 6 to 12 years: up to 20 g (for 1 to 4 hours)
lidocaine and prilocaine (EMLA) [NB3]
EMLA 5% patch—apply at least 1 hour before procedure
premature neonates: seek specialist advice

0 to 3 months: not more than 1 patch at a time (for 1 hour)
3 to 12 months: not more than 2 patches at a time (for 1 to 4 hours)
1 to 12 years: not more than 5 patches at a time (for 1 to 4 hours)

neonates: seek specialist advice
1 to 3 months: up to 1 g (for 30 to 60 minutes)

liposomal lidocaine 4% (LMX4) [NB4]
3 to 12 months: up to 1 g (for 30 minutes to 4 hours)
1 to 12 years: up to 2.5 g (for 30 minutes to 5 hours)

1 year and older: 0.1 mL/kg or 1 mL per cm of laceration,
whichever is the smaller volume (for 20 to 30 minutes, maximum
amethocaine 0.5% + lidocaine 4% +
60 minutes)
adrenaline 0.1% (ALA or Laceraine) [NB5]
maximum dose: 5 mL
NB1: Children older than 12 years or weighing more than 50 kg are considered adults for the purposes of prescribing.
NB2: 1 g of AnGel contains amethocaine 40 mg. A 0.5 g dose of AnGel is achieved by squeezing a circular blob of gel the size of a small coin ($2). Do
not spread or rub in. Anaesthesia lasts 4 to 6 hours after removal. If the procedure is not performed immediately after gel removal, it is helpful to circle
the application zone so that the proceduralist can later identify and target the anaesthetised area.
NB3: 1 g of EMLA cream or one EMLA 5% patch contains lidocaine 25 mg and prilocaine 25 mg. A 1 g dose of EMLA cream is achieved by squeezing
a circular blob of cream the size of a small coin ($2), or by squeezing a length of approximately 3.5 cm from the tube. Anaesthesia lasts 2 hours after
removal.
NB4: 1 g of LMX4 cream contains lidocaine 40 mg. A 1 g dose of LMX4 is achieved by squeezing a blob of cream to cover a 2.5 × 2.5 cm (6.25 cm2)
skin area, or a length of 5 cm from the tube. Do not clean skin surface with alcohol or acetone before application—the cream has to mix with surface oils
to be absorbed. Anaesthesia lasts 1 to 2 hours after removal.
NB5: This combination product is available in some hospitals under TGA Schedule 5A–subregulation 12(1A) for topical application to superficial
wounds and lacerations less than 7 cm. Cotton balls are soaked in the solution then held in place over the laceration with a dressing.
Other routes
Dosage of local anaesthetic required via any other route (transmucosal, infiltration, epidural) varies and depends on
the:
area to be anaesthetised
vascularity of the tissues
number of neuronal segments to be blocked
depth of anaesthesia and degree of muscle relaxation required
individual’s tolerance
technique of concurrent systemic sedation or anaesthesia
physical condition of the patient.
Use the lowest dose that results in effective anaesthesia, but do not exceed the maximum recommended doses
given in Table 1.24. Appropriate resuscitation equipment and personnel should be available for the management of
local anaesthetic toxicity.
Maximum recommended doses of local anaesthetic in children (Table 1.24) [NB1]
Maximum bolus dose of plain Maximum bolus dose of solution

Drug
solution [NB2] containing adrenaline [NB3]
bupivacaine 2 mg/kg 2 mg/kg
levobupivacaine more than 6 months of age: 2 mg/kg not applicable
lidocaine 3 mg/kg 7 mg/kg
ropivacaine 2 mg/kg not applicable
NB1: Children older than 12 years or weighing more than 50 kg are considered adults for the purposes of prescribing.
NB2: Bolus dose should not be repeated within 4 hours.
NB3: Adrenaline concentration should not exceed 5 micrograms/mL and adrenaline-containing solutions should not be used in parts of the body with
compromised blood supply or supplied by end arteries (eg fingers, toes, nose, ears, penis).
Local infiltration
Infiltration of local anaesthetic should be used routinely in children for surgery and for procedures such as lumbar
puncture. If the child is awake, the pain of injection can be reduced by:
warming the solution to body temperature

using the smallest needle possible (eg 27 gauge)
injecting slowly
buffering lidocaine (eg add 1 mL of 8.4% sodium bicarbonate to 9 mL of lidocaine 1%; calculate volume to
be injected based on lidocaine dose). Buffering reduces injection pain and speeds onset but may result in
precipitation.
Do not use adrenaline-containing solutions in end-artery regions (eg fingers, toes, nose, ears, penis).
Do not use local anaesthetics with adrenaline in end-artery regions.
Regional blocks
Femoral nerve and axillary brachial plexus blocks are examples of regional blocks. Use of these blocks requires
a detailed knowledge of the relevant anatomy. An intravenous cannula should be inserted before the block, in case
there is an adverse reaction.
Many peripheral nerve blocks are performed under general anaesthesia for postoperative pain control in children.
Care should be taken with dressings, pressure areas and positioning, and mobilisation because that part of the body
will have reduced sensation.
Central neuraxial blocks involve the intrathecal (spinal) or epidural administration of local anaesthetic, clonidine
and opioids. They should only be performed by experienced practitioners (eg paediatric anaesthetists) and only in
institutions where there are guidelines and expertise to care for these children. These blocks are usually inserted
under general anaesthesia and can provide excellent analgesia after major surgery.
Acute pain in children

Introduction
Acute pain in children can occur due to:
acute medical conditions such as headache, ear ache, dental caries, musculoskeletal pain (see Acute pain:
general approach)
trauma (minor and major) and burns
surgery
procedures and investigations.
Acute pain management principles may also be appropriate for the treatment of new-onset or intermittent pain in
children with cancer, chronic medical conditions such as inflammatory bowel disease, juvenile arthritis, sickle cell
disease or HIV/AIDS, and those with developmental disabilities.
Perioperative pain
Preoperative phase
Plans for intraoperative and postoperative analgesia should be discussed with the child and parents preoperatively.
If postoperative intravenous opioid analgesia is anticipated, assess the child’s cognitive and physical ability to use
patient-controlled analgesia (PCA). Familiarisation with PCA equipment before surgery improves efficacy of use
(see below).
Simple analgesics can be given orally, especially for short and day-stay procedures. The usual dose is:
paracetamol 15 mg/kg orally, 30 minutes before surgery.
Specialist centres may have protocols for administration of higher preoperative or preprocedural loading doses of
paracetamol (typically 30 mg/kg orally, 30 to 60 minutes before surgery). The child’s prehospital paracetamol
intake must be checked and paracetamol given according to protocol. Use of loading doses outside the specialist
setting is not recommended. If used, the loading dose must be included in the total 24-hour dosing calculation.
In children, especially where high levels of anxiety exist, it can be helpful to use:
midazolam 0.5 mg/kg up to 20 mg mixed with paracetamol elixir (dose as above) or a few
mL of apple juice orally, 20 to 30 minutes before the procedure [Note 1] [Note 2].
Note 1: Midazolam solution for injection (hydrochloride salt) may be given orally. A buccal formulation of
midazolam maleate (= 10 mg/mL midazolam base) is available through the Special Access Scheme. Telephone
(02) 6232 8111 [URL]. The buccal formulation must not be given intravenously.
Note 2: Use the lowest of actual body weight, ideal body weight or 50 kg to calculate the midazolam dose.
Intraoperative phase
Although intraoperative analgesia will be determined by the surgeon and anaesthetist, it is important to be aware of
the techniques used and their implications for postoperative management. Analgesic techniques that are to be used
postoperatively are usually commenced intraoperatively. A combination of analgesic approaches are often used (ie
multimodal analgesia).
Combination techniques consist of:
local anaesthetic infiltration of the wound, specific peripheral nerve blocks, or epidural analgesia
nonopioid analgesics (eg paracetamol and/or NSAIDs) given orally, rectally or parenterally
intraoperative parenteral loading with opioid to achieve adequate postoperative analgesia if indicated.
Postoperative phase
Postoperative analgesia is an important part of recovery. The child should be respected as an authority about their
own pain. Continue to assess pain using appropriate approaches and tools (see Pain assessment in children).
For mild pain, if the child is tolerating oral fluids, use:
1 paracetamol orally, see Table 1.19 for dosage. Review dosing after 48 hours
AND/OR
1 an NSAID orally, if there are no contraindications and there is no potential for ongoing
blood loss. See Table 1.20 for dosage.
If the child is not tolerating oral fluids, analgesics can be given intravenously or rectally:
1 paracetamol IV slowly over 15 minutes, see Table 1.19 for dosage. Review dosing after
24 hours [Note 3]
AND/OR
1 an NSAID rectally, if there are no contraindications and there is no potential for ongoing
blood loss. See Table 1.20 for dosage [Note 4].
For moderate to severe pain, treat with paracetamol and/or an NSAID (as above), and add an opioid. After
adequate intraoperative opioid loading, if tolerating oral intake, use:
1 morphine orally, see Table 1.21 for dosage. Titrate to changing clinical needs
OR
1 oxycodone orally, see Table 1.21 for dosage. Titrate to changing clinical needs.
If the child is not tolerating oral intake, use:
morphine via IV patient-controlled analgesia (see below) unless patient is too young or
unable to operate it, or equipment, protocols and trained staff are not available. Use
fentanyl if patient has kidney dysfunction or prior morphine intolerance. See Table 1.22
for dosage.
In children under 7 years of age, consider using morphine (or fentanyl) via IV nurse-controlled analgesia (NCA) if
equipment, protocols and trained staff are available (see Table 1.22 for dosage).
If neither PCA nor NCA is available, morphine (or fentanyl) may be given via an intravenous infusion (see Table
1.22 for dosage) or subcutaneous infusion, with intermittent boluses if needed.
Pethidine is not recommended for the maintenance of analgesia in children.
Patient-controlled analgesia (PCA) is a valuable means of providing postoperative analgesia. The following
points are relevant to use of PCA in children:
Most children over 7 years can understand and use PCA. This cognitive capacity is evolving between 5 and
7 years of age. Assess the individual child’s cognitive and physical capacity.
PCA efficacy is enhanced by preoperative explanation, but its use is not excluded after emergency surgery in
children.
PCA should be supervised by the pain service or teams with comparable expertise, and managed using
agreed protocols, including monitoring and managing adverse effects of opioids in children.
The bolus dose button should only be activated by the child. However, in certain circumstances, nurse-
controlled analgesia (see below) may be appropriate if specific protocols and staff credentialing exist.
Parents should not activate boluses for their children.
There is a lockout period, usually 5 minutes, when further boluses will not be delivered.
The addition of a low-dose background infusion can be particularly effective for the first 1 to 3 days after
major surgery in children, without significant increase in adverse events.
Typical starting doses for PCA in children are shown in Table 1.22. See also Patient-controlled analgesia
(PCA) for general information about PCA and Figure 1.4 for how to titrate analgesia.
Nurse-controlled analgesia (NCA) refers to an opioid infusion with potential for boluses to be given by
credentialed nursing staff using the same programmable device as is used for PCA. This removes some of the
logistic obstacles (and potential errors) associated with administering boluses and titrating infusion rates using
standard infusion pumps. Once the syringe preparation and NCA programming are double-checked by two staff,
only the bedside nurse is required to administer each bolus using the press of a button. See Table 1.22 for typical
starting dosage.
Note 3: If IV paracetamol is not appropriate, rectal paracetamol (see Table 1.19 for dosage) can be used but see
Pharmacological management of pain in children: paracetamol for limitations of the rectal route. Review dosing
after 48 hours.
Note 4: Intravenous NSAIDs (eg ketorolac, parecoxib) are not licensed for use in children and adolescents.
However, specialists in tertiary paediatric hospitals sometimes use these drugs off-label in infants, children and
adolescents.
Monitoring and managing adverse effects of opioids in children
Observations that should be recorded for children receiving intravenous opioids include:
sedation score hourly (see Table 1.25)—an increase is often the earliest indicator of respiratory depression
respiratory rate hourly (see Table 1.26)
pain score hourly while awake (see Pain assessment in children)
other adverse effect monitoring (eg pruritus, nausea and vomiting, constipation, urinary retention)
pulse oximetry—check whenever a child has sedation, respiratory distress, tachypnoea or bradypnoea,
pallor, cyanosis, hypotension, confusion, agitation or whenever staff are concerned. Use continuous
oximetry for infants aged less than 6 months or in the presence of lung disease, obstructive sleep disorder,
myopathy, neurological disease including seizure disorders, upper airway pathology, upper airway surgery,
or coadministered sedatives (eg diazepam), or whenever a ‘spot’ check reveals saturation below 94% SpO2.
Appropriate protocols for escalating care, resuscitation, oxygenation and contacting appropriate personnel should
be immediately available when children are receiving parenteral opioids. These should include details for the
reversal of opioid-induced respiratory depression using naloxone.
For moderate sedation with early respiratory depression, consider:
naloxone (child less than 12 years) 1 microgram/kg IV, initially and titrate with further 1
microgram/kg increments every 2 minutes until the effects of excessive sedation or
respiratory depression are reversed.
If the child is unrousable or apnoeic, or in the event of absolute opioid overdose due to medication error, use:
naloxone (child less than 12 years) 5 to 10 micrograms/kg IV, every 2 minutes until the
effects of excessive sedation or respiratory depression are reversed. If no response after
several doses, review diagnosis and escalate care.
If naloxone is required, move the child to a high dependency or intensive care area.
An example of a sedation score classification (Table 1.25) [NB1]
Sedation score State of consciousness

0 awake, alert
1 mild sedation, easy to rouse
2 moderate sedation, easy to rouse, unable to remain awake
3 difficult to rouse
NB1: Classifications may vary between Australian states.
Approximate normal respiratory rates in children (Table 1.26)
Age Breaths/minute
less than 3 months 30 to 60
3 months up to 1 year 30 to 50
1 year up to 5 years 20 to 40
5 years up to 12 years 20 to 30
12 years and older 10 to 25
Procedure-related pain
Introduction
Acute pain caused by diagnostic and treatment procedures is an enormous issue for children, particularly those
who are younger (see Children’s development and pain) and those needing repeated procedures. Poor analgesia
during an initial procedure can increase anticipation of pain and distress during subsequent medical care.
As in adults, the key to managing procedure-related pain in children is anticipating the child’s needs (see
Procedure-related pain in adults: preparing for the procedure). Use the least intrusive and least sedating analgesia
that will meet the child’s needs (see Figure 1.5).
Nonpharmacological techniques for procedure-related pain
Whenever possible, conduct procedures in a ‘child-friendly’ environment with a parent or close carer present.
Avoid performing procedures in the child’s bed or room.
Prepare parents and children for what to expect [Note 5]. Familiarising the child with the environment and
allowing them to play with medical equipment before the procedure may help some children.
Offer suggestions for age-appropriate distraction techniques (see Nonpharmacological management of pain in
children). Involve a music, art or play therapist if available. Try to keep procedural talk calm and to a minimum,
with one person speaking at a time, so that the child can remain engaged in the therapeutic distraction.
Note 5: The following fact sheets prepared by The Children’s Hospital at Westmead, Sydney Children’s
Hospital, Randwick and Kaleidoscope Hunter Children’s Health Network provide information for parents about
how they can help:
—Children's painful procedures and operations: how can parents help? 2010 [URL]
—Procedural sedation, 2011 [URL]
—Nitrous oxide, 2009 [URL].
Analgesics for procedure-related pain
Give analgesics pre-emptively to manage procedure-related pain in children. Anticipate the severity and time-
course of procedural (and postprocedural) pain and match the analgesic plan to the child’s anticipated needs (see
Figure 1.5).
See relevant sections for guidance on the use of sucrose, paracetamol, NSAIDs, local anaesthetics and opioids in
children.
In addition, nitrous oxide, methoxyflurane or ketamine may be appropriate for short-term management of
procedure-related pain in some children and contexts. Ketamine should only be prescribed by those trained and
experienced in its use, and where local protocols, staff, monitoring and resuscitation facilities support its use.
If sedation is needed to manage non–pain-related distress and control motion, see Sedation for procedures in
children.
Monitor the child during the procedure and recovery period to assess adequacy of analgesia and any adverse
effects (see Monitoring and managing adverse effects of opioids in children and Monitoring and managing
sedation-related adverse events in children).
Sedation for procedures in children
Medication-induced sedation may be necessary when:
pain remains distressing despite optimal analgesia

non–pain-related distress is significant
motion control is critical to safe or timely completion of the procedure.
Assessment before sedation should include the child’s general health and developmental level. Also assess anxiety,
fasting status and airway, and look for the presence of other risk factors (see Procedure-related pain in adults:
procedures with sedation).
Use the least intrusive route and lightest sedation necessary. Sedation level achieved depends on the medication
and dose, but also on where the child is in their natural sleep–wake cycle and the amount of external stimulation
(conversation, handling, pain). Sedation is a continuum (see Table 1.9), and it is easy to inadvertently proceed
from one level to another, especially if using potent or intravenous medication.
Before prescribing and administering procedural sedation, check that necessary personnel, monitoring and
resuscitation equipment, and recovery care are prepared (see Monitoring and managing sedation-related adverse
events in children and Table 1.10).
Sedative medications most commonly used to induce minimal to moderate sedation in children are nitrous oxide
and midazolam. Midazolam is a benzodiazepine that provides anxiolysis and some amnesia, and can be
administered by different routes. In children, the oral or buccal route may be preferable. For all routes, use the
lowest of actual body weight, ideal body weight or 50 kg to calculate the dose. Use:
1 midazolam 0.5 mg/kg up to 15 mg orally, 20 to 30 minutes before the procedure [Note 6]
OR
1 midazolam 0.2 to 0.3 mg/kg up to 10 mg intranasally or buccally, 10 to 15 minutes before

the procedure [Note 6]
OR
1 midazolam 0.02 to 0.05 mg/kg IV, 5 minutes before the procedure; supplement with 0.02
to 0.05 mg/kg at 3- to 5-minute intervals until desired effect is achieved or up to a
maximum total dose of 0.15 mg/kg or 5 mg, whichever is lower.
Midazolam has a bitter taste and is more palatable orally if administered with apple juice. Midazolam stings when
given by the intranasal route—avoid this route for repeated procedures.
Midazolam can cause ataxia, and the child should stay in bed or sit on the parent’s lap. Begin monitoring (see also
Table 1.10) as soon as the child is sufficiently compliant.
Note 6: Midazolam solution for injection (hydrochloride salt) may be given orally, buccally or intranasally. A
buccal formulation of midazolam maleate (= 10 mg/mL midazolam base) is available through the Special Access
Scheme. Telephone (02) 6232 8111 [URL]. The buccal formulation must not be given intravenously.
Monitoring and managing sedation-related adverse events in children
The majority of adverse events with sedation relate to loss of airway control and respiratory compromise. Children
develop hypoxaemia much faster than adults, because of higher oxygen consumption and decreased oxygen
reserves.
Adverse events in children are more likely with deeper levels of sedation, if three or more sedative drugs are used,
and if the sedative drug effects outlast the stimulating procedure. Adverse events are also more common in
children less than 5 years, and are more difficult to manage in children less than 2 years.
An appropriately trained person must be assigned to exclusively monitor the child throughout sedation until
recovered. Staff must be able to assess sedation level, manage sedation at least one level deeper than intended, and
have resuscitation skills relevant to the child’s age and condition (see Table 1.10).
Monitor according to the depth of sedation actually achieved (see Table 1.10). If sedation deepens during
monitoring, escalate care accordingly. If the child is to remain undisturbed (sedation level not being evaluated),
staff and monitor as for deep sedation.
If oversedation occurs, escalate monitoring and manage as for a deteriorating patient. For benzodiazepine
sedation reversal (child less than 50 kg), use:
flumazenil 5 micrograms/kg up to 200 micrograms IV. Repeat every 1 to 2 minutes until

desired effect is achieved or up to a maximum total dose of 40 micrograms/kg or 1 mg,
whichever is lower.
If flumazenil is used to reverse long-acting benzodiazepines (eg diazepam), doses may need to be repeated or an
infusion commenced.
After the procedure
Provision should be made to adequately observe the child after the procedure, and ensure that the child fulfils
appropriate discharge criteria (eg normal observations including pulse oximetry, tolerating fluids, ambulating,
voiding, and leaving with a responsible adult). A contact phone number or referral should be available for
problems that occur after-hours.
For more detailed information, see the guidelines on procedural sedation and management of procedure-related
pain listed in Pain in children: further reading.
Specific procedures in neonates and children
Suggested strategies for management of specific procedures in neonates and children are given in Table 1.27.
Suggested strategies for managing specific procedures in neonates and children (Table 1.27)
Suggested strategies in addition to age-

appropriate nonpharmacological techniques
Procedure [NB1] Comments
Neonates and infants Older infants and
up to 4 months of age children
venipuncture is preferred method
for blood sampling as heel
lancing is more painful even
topical local anaesthetic, topical local anaesthetic, when automated devices are used
blood sampling,
plus either breastfeed or with or without nitrous try to limit the number of
cannulation
sucrose oxide attempts by having the most
experienced person perform the
procedure
dislocations and
see Acute pain: minor trauma
fractures
ear canal
lidocaine 2% topically by dripping the solution

examination and removal of a
for injection into the external ear canal, 5 to 10
foreign body from a child’s ear or
minutes before procedure (see Table 1.24 for
nose can be painful and
maximum lidocaine dose for weight)
distressing
foreign body
nose consider the type of foreign body
removal
and its location and select the
lidocaine 5% + phenylephrine 0.5% nasal spray least painful method of removal
(child 2 to 4 years: 1 spray/nostril; 4 to 8 years: 2 first
sprays/nostril; 8 to 12 years: 3 sprays/nostril;
more than 12 years: up to 5 sprays/nostril)
topically, 5 to 10 minutes before procedure
topical local anaesthesia may
consider procedure reduce immunisation pain, but
modifications such as there is insufficient evidence to
immunisation,
vaccine formulation, recommend routine use
intramuscular breastfeed or sucrose
needle size, depth of paracetamol may be used for
injection
injection (25 mm, 25 postprocedural pain but is not
gauge needle) recommended pre-emptively
in young children and those who

are likely to need the procedure
repeated, consider general
lumbar puncture topical local anaesthetic, topical local anaesthetic, anaesthesia, or sedation with
plus either breast milk followed by local nitrous oxide or midazolam (see
or sucrose anaesthetic infiltration Sedation for procedures in
children for dosage)
lidocaine 5% +
phenylephrine 0.5%
nasal spray (see foreign nasogastric tube insertion is
nasogastric tube painful and distressing for
sucrose body removal, above,
insertion children
for dosage) topically, 5
to 10 minutes before
procedure
if sepsis is suspected, do not delay
antibiotic administration while
waiting for topical anaesthesia to
work
topical local anaesthetic for very young or anxious
suprapubic
plus either breast milk topical local anaesthetic children consider the benefits and
aspiration
or sucrose risks of sedation with either
nitrous oxide or midazolam (see
Sedation for procedures in
children for dosage)
lidocaine 2% gel up to 0.3 mL/kg (= 6 mg/kg

also consider use of nitrous oxide
urethral lidocaine maximum) topically to the meatus and
or midazolam (see Sedation for
urethra, 10 minutes before procedure
catheterisation procedures in children for dosage)
plus sucrose in infants up to 4 months old
wounds and
see Acute pain: minor trauma
lacerations
NB1: For age-appropriate nonpharmacological techniques, see Nonpharmacological management of pain in children.
Pain in children with developmental disabilities

Children with developmental disabilities have a disproportionately high burden of pain. Those with intellectual
impairment and communication problems may require more procedural interventions, yet may receive less
analgesia than cognitively intact children. Pay special attention to pain assessment and management in these
children.
Pain assessment can be challenging for clinicians, parents and carers. An awareness of the spectrum of potential
presentations (see Table 1.28) is important so that diagnosis of the cause of pain is not overlooked or definitive
management delayed.
Although the principles of analgesic prescribing for children with developmental disabilities are the same as for
other children and young people, the following additional considerations are important:
Assessment should include input from the parent or carer and a scale validated for use in noncommunicating
children (see Pain assessment in children).
Many children with developmental disabilities are not ideal weight for age—many are underweight due to
feeding problems but some are obese. Take care with dose calculations.
They may be on concurrent medications such as antiepileptic drugs and benzodiazepines that interact with
analgesics.
Comorbidities may include limited respiratory function and reserve due to scoliosis, reflux and recurrent
aspiration with frequent pulmonary infection; chronic constipation; lowered seizure threshold; impaired
nutritional status.
Follow general principles of analgesic prescribing outlined in the relevant sections of this guideline. Avoid
NSAIDs or limit to short-term use. Avoid constipating analgesics when possible, and escalate bowel care when
needed (see Constipation in children). Exercise caution when prescribing starting doses of opioids and consider
specialist involvement in ongoing prescribing.
At the time of writing, it is not possible to make evidence-based recommendations for the use of benzodiazepines
or baclofen in the management of pain in children with muscle spasm and spasticity. Specialist involvement in
prescribing these medications is recommended.
When comorbidities are likely to be life-limiting, consider involving a paediatric palliative care team (see
Principles of paediatric palliative care).
For general information about children with developmental disability, see Management Guidelines: Developmental
Disability [PDF, 7MB].
Potential mechanisms of pain in children with developmental disabilities (Table 1.28)
Mechanism Comments
due to communication difficulties, children may present with more
childhood illness advanced illness and consequently with more pain and
complications
spasticity, intermittent muscle spasm, contractures, joint immobility,
musculoskeletal disorders hip dislocation, and positioning problems may be associated with
background and/or incident pain
oesophageal reflux, gastritis, feeding tube problems, constipation
gastrointestinal disorders
can cause intermittent pain
dental caries, periodontal disease, temporomandibular joint disorder
oral health
can cause intermittent pain
orthotics, splints and wheelchairs can cause rubbing or pressure
pressure from positioning or assistive
areas, particularly if the child is growing rapidly or scoliosis is
devices
progressing
scoliosis surgery, femoral osteotomies, tendon releases and transfers
surgery are major surgeries associated with significant postoperative
analgesic requirements and risk of persistent postoperative pain
Pain in children with cancer

The spectrum of cancer in children is different from that in adults, with fewer solid tumours and more
haematological malignancies. Over 75% of children with cancer will experience severe pain at some stage of their
disease.
Tumour-related pain can be due to:
tumour invasion of bone and marrow with solid tumours (eg Ewing’s sarcoma), or marrow invasion with
leukaemia
headache with brain tumours and raised intracranial pressure
invasion of major nerves, plexus or spinal canal in advanced solid tumours
obstruction of hollow viscus.
The initial approach to assessing and managing new pain in children with cancer does not differ from other
children. However, it is important to consider the following:
Pain (and opioid analgesia) may be perceived by patients and/or their families as a signal of treatment failure
or disease progression. Be mindful of context when assessing pain.
Many children undergoing cancer treatment are below their ideal body weight. Take care with dose
calculation.
Neutropenia due to bone marrow invasion or chemotherapy render children more prone to infection. Avoid
the rectal route of drug administration.
Abnormal immune, nutritional and coagulation status may render these children more vulnerable to the
multiple adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Use NSAIDs with caution and
in consultation with the child’s oncologist.
Opioid analgesia may need to be continued for weeks or months in the acute phase so opioid tolerance often
develops and necessitates dose titration. Full opioid agonists (morphine, oxycodone or fentanyl) should be
used in preference to codeine or tramadol. Modified-release preparations provide good background
analgesia. Dose-limiting adverse effects can often be resolved by switching from one opioid to another.
Children experience a range of other physical symptoms and emotional, social and spiritual challenges.
Consider involvement of a paediatric palliative care team (see Principles of paediatric palliative care).
A significant proportion of children experience pain related to cancer therapy and its complications.
Therapy-related pain in children can be from:
investigative procedures (eg lumbar puncture, bone marrow aspiration)

complications of chemotherapy (eg mucositis, neutropenic colitis)
surgery
infection associated with immunosuppression (eg herpes zoster)
radiotherapy-induced dermatitis and mucositis
neuropathic pain occurring secondary to
–
surgery (eg amputation for osteosarcoma)
–
direct nerve involvement by tumour
–
drug therapy (eg vincristine).
Because these children undergo repeated procedures over months to years, it is important to provide good
nonpharmacological support and procedural analgesia from the outset.
Many childhood cancers are curable. Some cancer survivors experience persistent pain following neurotoxic drugs,
surgery/amputation or radiotherapy. Apply the principles of managing chronic pain in children, young people and
adults as appropriate.
Pain in children with chronic medical conditions

Chronic diseases that produce acute, recurrent and persisting pain in children include HIV/AIDS, sickle cell
disease, rheumatic diseases and some rarer diseases of childhood. Persisting pain can also follow trauma, burns
and amputations.
The general principles of pain assessment in children apply. When assessing effectiveness of analgesia and to
make appropriate modifications to the analgesic plan, carefully distinguish between pain episodes that occur
toward the end of a dosing interval (breakthrough pain), episodic pain related to movement or procedure (incident
pain), and unpredictable episodic pain.
When planning pain management, always consider optimising disease-specific management as well. Regular
analgesics, both nonopioid and opioid, may be required. The oral route is preferred. For moderate to severe pain,
full opioid agonists (morphine, oxycodone or fentanyl) should be used in preference to codeine or tramadol (see
the WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses, 2012
for detail on the ‘2-step’ analgesic ladder).
For children with persisting pain who require regular opioids, modified-release preparations provide good
background analgesia. An appropriate strategy for managing breakthrough pain (eg immediate-release oral opioid)
is also necessary. Dose-limiting adverse effects can often be resolved by switching from one opioid to another.
At the time of writing, it is not possible to make evidence-based recommendations for the use of tricyclic
antidepressants, selective serotonin reuptake inhibitors (SSRIs), antiepileptic drugs, ketamine or systemic use of
local anaesthetics in the treatment of persisting neuropathic pain in children. These medications are used off-label
and specialist involvement in prescribing is recommended.
Other chronic pain syndromes in children

Chronic pain that is not associated with specific diseases in childhood has a different spectrum from that in adults.
Headache, abdominal pain and recurrent musculoskeletal pain are most prevalent. Limb pain due to complex
regional pain syndrome may be under-recognised in children. Although reported in younger children, chronic pain
is more prevalent in early to mid adolescence and in girls. A proportion (10% to 30%) of children with chronic
pain develop significant pain-related disability. Children’s chronic pain can impact on family dynamics and have
significant economic costs.
Follow general principles for initial pain assessment in children, with particular emphasis on exploring the child’s
family and social context and psychological experiences. Always consider self-reported pain scores in context.
Assess the impact of pain on sleep, independent self-care, mobility, school attendance, recreation, family and
social relationships. Plan appropriate investigations and referrals, but prepare the child and family for the
possibility that a definitive diagnosis may not be found.
Do not use analgesics in isolation. A multidisciplinary, multimodal rehabilitation approach is required, similar to
that in adults, but with staff who have paediatric expertise. When such skills are not available locally, therapy may
need to be delivered in a major paediatric centre. Family involvement and school liaison are important.
Using pain scores to guide analgesic prescribing is insufficient. Consider the context and child’s function. It may
be reasonable to prescribe analgesics when pain interferes with sleep, independent self-care or dignity, or when
they enable school attendance and learning. Start with paracetamol, consider short-term use of an NSAID and
adjust in a stepwise manner (see Stepwise approach to acute pain management).
At the time of writing, it is not possible to make evidence-based recommendations for the use of opioids or
antineuropathic analgesics in chronic pain that is not associated with serious childhood disease. Specialist
involvement in prescribing is recommended. In this context, assess individual patient risks, obtain informed
consent, and prescribe for a trial period with specified goals before considering time-limited prescribing.
Ensure regular review of goals and aim to replace pharmacological management with nonpharmacological
strategies at the earliest opportunity. Opioids may exacerbate abdominal pain and headache.
Regularly review goals and aim to replace pharmacological management with nonpharmacological strategies at the earliest
opportunity.
Pain in children: further reading

World Health Organization:
World Health Organization. WHO guidelines on the pharmacological treatment of persisting pain in children with
medical illnesses. Geneva: WHO Press; 2012. [URL]
Australia and New Zealand:

The paediatric patient (chapter 10). In: Macintyre PE, Scott DA, Schug SA, Visser EJ, Walker SM, editors. Acute
pain management: scientific evidence. 3rd ed. Melbourne: Australian and New Zealand College of Anaesthetists
and Faculty of Pain Medicine; 2010.
The Royal Australasian College of Physicians, Paediatrics & Child Health Division. Guideline Statement:
management of procedure related pain in neonates. Sydney: Royal Australasian College of Physicians; 2005.
[URL]
The Royal Australasian College of Physicians, Paediatrics & Child Health Division. Guideline Statement:
management of procedure related pain in children and adolescents. Sydney: Royal Australasian College of
Physicians; 2005. [URL]
The Royal Australasian College of Physicians, Paediatrics & Child Health Division. Position statement:
circumcision of infant males. Sydney: Royal Australasian College of Physicians; 2010. [URL]
Australian and New Zealand College of Anaesthetists. Policy documents on sedation for diagnostic, surgical,
dental and endoscopy procedures (PS9, 2010), including preoperative assessment (PS07, 2008), consent (PS26,
2005) and minimum safe facilities (PS55, 2012). Available at: [URL]
United Kingdom:
Royal College of Nursing. The recognition and assessment of acute pain in children. London: Royal College of
Nursing; 2009. [URL]
Association of Paediatric Anaesthetists of Great Britain and Ireland. Good practice in postoperative and
procedural pain, 2nd ed. Paediatr Anaesth 2012;22(Suppl 1):1-79.
National Institute for Health and Clinical Excellence (NICE). Sedation for diagnostic and therapeutic procedures
in children and young people. London; 2010. [URL]
United States of America:

American Academy of Pediatrics, American Pain Society. The assessment and management of acute pain in
infants, children, and adolescents. Pediatrics 2001;108(3):793-7. [URL]
American Academy of Pediatrics, American Academy of Pediatric Dentistry, Cote CJ, Wilson S. Guidelines for
monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic
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young children. Pediatr Nurs 1997;23(3):293–7. [ ]
von Baeyer CL. Children's self-report of pain intensity: what we know, where we are headed. Pain Res Manag
2009;14(1):39–45. [ ]
von Baeyer CL, Spagrud LJ. Systematic review of observational (behavioral) measures of pain for children and
adolescents aged 3 to 18 years. Pain 2007;127(1-2):140–50. [ ]
Nonpharmacological management of pain in children
Chambers CT, Taddio A, Uman LS, McMurtry CM. Psychological interventions for reducing pain and distress during
routine childhood immunizations: a systematic review. Clin Ther 2009;(31 Suppl 2):S77–S103 .
Liossi C. Psychological interventions for acute and chronic pain in children. Pain Clinical Updates 2006;14(4):1–4. [108
KB].
Pillai Riddell RR, Racine NM, Turcotte K, Uman LS, Horton RE, Din Osmun L, et al. Non-pharmacological
management of infant and young child procedural pain. Cochrane Database Syst Rev 2011;(10):CD006275. [
]
Sinha M, Christopher NC, Fenn R, Reeves L. Evaluation of nonpharmacologic methods of pain and anxiety
management for laceration repair in the pediatric emergency department. Pediatrics 2006;117(4):1162–8. [ ]
Uman LS, Chambers CT, McGrath PJ, Kisely S. Psychological interventions for needle-related procedural pain and
distress in children and adolescents. Cochrane Database Syst Rev 2006;(4):CD005179. [ ]
Pain in children with developmental disabilities
Malviya S, Voepel-Lewis T, Tait AR, Merkel S, Lauer A, Munro H, et al. Pain management in children with and without
cognitive impairment following spine fusion surgery. Paediatr Anaesth 2001;11(4):453–8. [ ]
Oberlander TF, Symons FJ. Pain in children and adults with developmental disabilities. Baltimore: Paul H. Brookes
Pub.; 2006.
Stevens B, McGrath P, Gibbins S, Beyene J, Breau L, Camfield C, et al. Determining behavioural and physiological
responses to pain in infants at risk for neurological impairment. Pain 2007;127(1-2):94–102. [ ]
Pain in children with cancer
Pain in children with chronic medical conditions
Other chronic pain syndromes in children
Kashikar-Zuck S. Treatment of children with unexplained chronic pain [letter]. Lancet 2006;367(9508):380–2. [
]
Keogh E, Eccleston C. Sex differences in adolescent chronic pain and pain-related coping. Pain 2006;123(3):275–84. [
]
Kozlowska K, Rose D, Khan R, Kram S, Lane L, Collins J. A conceptual model and practice framework for managing
chronic pain in children and adolescents. Harv Rev Psychiatry 2008;16(2):136–50. [ ]
Perquin CW, Hazebroek-Kampschreur AA, Hunfeld JA, Bohnen AM, van Suijlekom-Smit LW, Passchier J, et al. Pain in
children and adolescents: a common experience. Pain 2000;87(1):51–8. [ ]
Pain assessment tools (Appendix 1.1)
Pain rating scales
Introduction
A number of scales are available to assess pain severity. Although the intensity of the pain is only one aspect
of assessment, the pain score can be used to guide prescribing decisions (see Figure 1.2). It can also be used to
monitor the efficacy of analgesia and adjust therapy accordingly (see Figure 1.4).
Select a scale that is appropriate for the age and clinical context of the patient. For appropriate scales in
children, see Table 1.16.
Word descriptor scales have a higher completion rate by older individuals, particularly those with cognitive
impairment, than numerical pain scales and visual analogue scales.
Categorical or verbal descriptor pain scale
Categorical or verbal descriptor scales use words to describe the severity of pain (see Figure 1.7 for an
example). They may be useful when patients are unable to use a numerical rating scale (eg visually impaired
patients, older patients and those with mild to moderate cognitive impairment). Ask the patient which
descriptor best fits their pain experience.
Categorical scale (Figure 1.7)
Numerical pain scale

A 0 to 10 numerical rating scale (see Figure 1.8) is commonly used for pain assessment. Explain to the patient
that 0 represents no pain and 10 is the worst pain imaginable. Ask the patient to select the number that
corresponds best to their level of pain.
Numerical pain scale (0 to 10) (Figure 1.8)
Visual analogue pain scale

The visual analogue scale (see Figure 1.9) uses a 10 cm horizontal line with word anchors at each end. Ask
the patient to mark the line at the point that best represents their level of pain. Convert to a numerical score by
measuring (in cm) from the left-hand side of the scale to the mark.
Visual analogue pain scale (Figure 1.9)
Faces Pain Scale
The Faces Pain Scale (see Figure 1.10) was developed for use in children. It shows a close linear relationship
with visual analogue pain scales across the age range of 4 to 16 years, but is particularly recommended for
children aged about 5 to 6 years. The Faces Pain Scale may also be used to assess pain in older people with
mild to moderate cognitive impairment.
Faces Pain Scale—Revised (FPS-R) (Figure 1.10)

Print-friendly PDF
In the following instructions, say ‘hurt’ or ‘pain’, whichever seems right for a particular child:
These faces show how much something can hurt. This face [point to left-most face] shows no pain. The
faces show more and more pain [point to each from left to right] up to this one [point to right-most face] –
it shows very much pain. Point to the face that shows how much you hurt [right now].
Score the chosen face 0, 2, 4, 6, 8, or 10, counting left to right, so ‘0’ = ‘no pain’ and ‘10’ = ‘very much pain.’
Do not use words like ‘happy’ and ‘sad.’ This scale is intended to measure how children feel inside, not how
their face looks.
Click here to download a print-friendly version of the Faces Pain Scale—Revised (FPS-R).
The FACES Visual Pain Scale has been reproduced with permission of the International Association for the
Study of Pain (IASP). The Scale may not be reproduced for any other purpose without permission.
It is available (with instructions in numerous languages) from the IASP website at [URL].
Source: Hicks CL, von Baeyer CL, Spafford PA, von Korlaar I, Goodenough B. The Faces Pain Scale -
Revised: toward a common metric in pediatric pain measurement. Pain 2001;93:173—83.
FLACC behavioural scale
The FLACC behavioural scale (see Table 1.29) is an observational tool that incorporates five categories—
facial expression, leg movement, activity, crying and consolability. It is used to assess acute postoperative and
acute postprocedural pain in young children who are unable to provide a reliable self-report (see Table 1.16).
A revised version is available for children with cognitive impairment.
FLACC behavioural scale (Table 1.29)
Scoring
Categories
0 1 2
occasional grimace or frequent to constant
no particular expression or
Face frown, withdrawn, frown, clenched jaw,
smile
disinterested quivering chin
Legs normal position or relaxed uneasy, restless, tense kicking, or legs drawn up
lying quietly, normal squirming, shifting back
Activity arched, rigid or jerking
position, moves easily and forth, tense
moans or whimpers; crying steadily, screams or
Cry no cry (awake or asleep)
occasional complaint sobs, frequent complaints
reassured by occasional
touching, hugging or difficult to console or
Consolability content, relaxed
being talked to, comfort
distractable
Each of the five categories (F) Face; (L) Legs; (A) Activity; (C) Cry; (C) Consolability is scored from 0 to 2, which results in a total score between
zero and 10.
Reproduced with permission from: Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative
pain in young children. Pediatr Nurs 1997;23(3):293-7. © 2002, The Regents of the University of Michigan. [URL]
The Abbey Pain Scale
The Abbey Pain Scale (see Box 1.12) is an Australian-designed observational tool for assessing pain in people
unable to give a subjective pain report because of dementia.
The Abbey Pain Scale (Box 1.12)

For measurement of pain in people with dementia who cannot verbalise
How to use scale: While observing the resident, score questions 1 to 6.
Name of resident:
.......................................................................................................................................................
Name and designation of person completing the scale:

.............................................................................................
Date: ............................................................................. Time:

...................................................................................
Latest pain relief given was ...................................................................................................................... at

.......hrs.
1.
Vocalisation
eg Absent 0 Mild 1 Moderate 2 Severe 3 Q1

whimpering,
groaning,
crying
2. Facial
expression
eg looking
tense, Absent 0 Mild 1 Moderate 2 Severe 3 Q2
frightened,
frowning,
grimacing
3. Change in
body
language
eg fidgeting, Absent 0 Mild 1 Moderate 2 Severe 3 Q3

rocking,
guarding
body part,
withdrawn
4.
Behavioural
change
eg increased
confusion, Absent 0 Mild 1 Moderate 2 Severe 3 Q4
refusing to
eat, alteration
in usual
patterns
5.
Physiological
change
eg
temperature,
pulse or
blood Absent 0 Mild 1 Moderate 2 Severe 3 Q5
pressure
outside
normal limits,
perspiring,
flushing or
pallor
6. Physical
changes
eg skin tears,
pressure
areas, Absent 0 Mild 1 Moderate 2 Severe 3 Q6
arthritis,
contractures,
previous
injuries
Add scores for questions 1 to 6 and record here TOTAL PAIN SCORE
Now tick the
box that
0 to 2 No 3 to 7 8 to 13 14+
matches the
pain Mild Moderate Severe
Total Pain
Score
Finally, tick the box which
Acute on
matches the resident's type of Chronic Acute
chronic
pain
Abbey J, De Bellis A, Piller N, Esterman A, Giles L, Parker D, Lowcay B. Funded by the JH & JD Gunn Medical Research Foundation 1998–
2002.
This document may be reproduced with this reference retained.
Key references
Faces Pain Scale
Bieri D, Reeve RA, Champion GD, Addicoat L, Ziegler JB. The Faces Pain Scale for the self-assessment of the
severity of pain experienced by children: development, initial validation, and preliminary investigation for ratio
scale properties. Pain 1990;41(2):139–50. [ ]
Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain Scale-Revised: toward a
common metric in pediatric pain measurement. Pain 2001;93(2):173–83. [ ]
FLACC behavioural scale
Malviya S, Voepel-Lewis T, Burke C, Merkel S, Tait AR. The revised FLACC observational pain tool: improved
reliability and validity for pain assessment in children with cognitive impairment. Paediatr Anaesth
2006;16(3):258–65. [ ]
Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative
pain in young children. Pediatr Nurs 1997;23(3):293–7. [ ]
Analgesic drug use in pregnancy
General information on drug use in pregnancy: analgesic drugs
Paracetamol is the analgesic of choice in pregnancy. Aspirin and other nonsteroidal anti-inflammatory drugs
(NSAIDs) should be avoided in late pregnancy. Aspirin will affect maternal platelet function and is
associated with increased risk of prepartum and postpartum haemorrhage. Other NSAIDs could be expected
to demonstrate these same effects. NSAIDs may also cause premature closure of the fetal ductus arteriosus
and delay labour and birth. Women taking opioids chronically who become pregnant should let their
obstetrician and their neonatologist know about the opioid use. They should probably be delivered in an
appropriate tertiary hospital, where development in the neonate of a withdrawal syndrome will be prevented
if possible, looked for, and managed as necessary. See also NSAIDS and reproductive health in women with
musculoskeletal conditions.
Bartonella infections
Bartonella infections
Bartonella species that cause disease in humans include B. bacilliformis, B. quintana, and B. henselae.
In immunocompetent patients, B. henselae infection (cat-scratch disease) presents as regional lymph node
enlargement, with or without associated systemic disease. It is usually self-limiting, so most cases do not require
antimicrobial therapy. Treatment is recommended in immunocompetent patients with: unresolved
lymphadenopathy (lasting more than 1 month); lymphadenopathy associated with significant morbidity; systemic
disease with organ involvement (eg liver, eye, neurological); or endocarditis. Diagnosis is usually based on
serology or nucleic acid amplification testing (eg polymerase chain reaction [PCR]).
For unresolved lymphadenopathy, lymphadenopathy associated with significant morbidity, and systemic disease,
use:
azithromycin 500 mg (child: 10 mg/kg up to 500 mg) orally on the first day, then 250 mg
(child: 5 mg/kg up to 250 mg) orally, daily for a further 4 days.
For endocarditis in adults and children 8 years or older, use:
doxycycline orally, 12-hourly for 6 weeks

adult: 100 mg
child 8 years or older and less than 26 kg: 50 mg
child 8 years or older and 26 to 35 kg: 75 mg
child 8 years or older and more than 35 kg: 100 mg
PLUS EITHER
1 gentamicin (adult and child) 1 mg/kg intravenously, 8-hourly for 2 weeks. Monitor
plasma concentration from the first dose—see Principles of aminoglycoside use for
dosage adjustment and principles of use [Note 1]
OR
2 rifampicin 300 mg (child: 7.5 mg/kg up to 300 mg) orally, 12-hourly for 2 weeks.
For treatment of endocarditis in children younger than 8 years, seek expert advice.
In severely immunocompromised patients, including those with advanced HIV infection, B. henselae and other
Bartonella species cause skin disease (bacillary angiomatosis) and internal organ disease (bacillary peliosis). Such
infection occurs rarely in immunocompetent patients. Treatment is essential—seek expert advice.
Treatment of infections caused by B. quintana (trench fever) and B. bacilliformis (Carrion disease or Oroya fever)
is complex—seek expert advice.
Note 1: If the patient is obese (for adults, body mass index 30 kg/m2 or more), use adjusted body weight (see Box 2.46) to calculate the dose.
Key references
Edouard S, Nabet C, Lepidi H, Fournier PE, Raoult D. Bartonella, a common cause of endocarditis: a report on 106
cases and review. J Clin Microbiol 2015;53(3):824–9.
Lindeboom JA. Pediatric cervicofacial lymphadenitis caused by Bartonella henselae. Oral Surg Oral Med Oral Pathol
Oral Radiol 2015;120(4):469–73.
Mendoza-Mujica G, Flores-Leon D. [Antimicrobial resistance of Bartonella bacilliformis strains from regions endemic to
bartonellosis in Peru]. Rev Peru Med Exp Salud Publica 2015;32(4):659–66.
Okaro U, Addisu A, Casanas B, Anderson B. Bartonella species, an emerging cause of blood-culture-negative

endocarditis. Clin Microbiol Rev 2017;30(3):709–46.
Published April 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Osteomyelitis
Classification of osteomyelitis
In these guidelines, osteomyelitis is classified by its anatomical location (long bone or vertebral) and time course
(acute or chronic).
Long-bone osteomyelitis most commonly occurs in children, with haematogenous seeding of bacteria to the well-
vascularised metaphyseal bone adjacent to the physis (growth plate).
Vertebral osteomyelitis (also referred to as discitis and spondylodiscitis) primarily occurs in older adults, with
haematogenous seeding of the vertebral end-plate, invasion of the avascular disc, and subsequent destruction of the
adjacent vertebral bodies. Secondary spinal and paraspinal collections often develop. Spinal epidural abscess can
also occur in the absence of vertebral osteomyelitis.
Acute osteomyelitis refers clinically to a newly recognised bone infection, and is characterised pathologically by
the absence of bone necrosis and sequestra (fragments of necrotic bone). Symptoms present for fewer than 14 days
correlate with acute osteomyelitis histopathologically.
Chronic osteomyelitis refers clinically to a relapsed or longstanding bone infection that may involve a sinus or a
compromised soft tissue envelope. It is characterised pathologically by low-grade inflammation, and the presence
of sequestra or involucra (new bone formation adjacent to sequestra).
Aetiology of osteomyelitis in adults

In adults, Staphylococcus aureus is the most common cause of osteomyelitis; risk factors for infection with
methicillin-resistant strains should be considered (see Box 2.31).
Around half of vertebral osteomyelitis cases and at least one-third of long-bone osteomyelitis cases are due to
infection with other organisms, particularly in patients with the following risk factors:
history of injecting drugs

postoperative infection
current or recent confirmed urinary tract, hepatobiliary or gastrointestinal infection
healthcare-associated infection.
In vertebral osteomyelitis, pathogens other than S. aureus include coagulase-negative staphylococci, beta-
haemolytic streptococci, enterococci and Cutibacterium acnes (formerly Propionibacterium acnes); approximately
20% of cases are caused by Gram-negative organisms, including Enterobacteriaceae (such as Escherichia coli and
Klebsiella pneumoniae) and Pseudomonas species. Rare pathogens include Mycobacterium tuberculosis,
Brucella species and fungi including Candida.
In adults with diabetes or vascular insufficiency, acute osteomyelitis contiguous with a foot or leg ulcer is usually
caused by S. aureus or streptococci. Chronic infections are often polymicrobial, involving Gram-positive and
Gram-negative aerobic and anaerobic bacteria.
Aetiology of osteomyelitis in children

In children, osteomyelitis is almost always caused by Staphylococcus aureus; risk factors for infection with
methicillin-resistant strains should be considered (see Box 2.31).
Haemophilus influenzae type b (Hib) can cause acute osteomyelitis in children younger than 5 years who are not
fully vaccinated against H. influenzae type b. Kingella kingae is an increasingly recognised cause of osteomyelitis,
primarily in infants and children younger than 4 years.
Approach to managing osteomyelitis

Pursue a microbiological diagnosis in patients with osteomyelitis to facilitate tailored antibiotic therapy—see
Investigations for osteomyelitis. Aetiology of osteomyelitis in adults and children outlines potential pathogens.
Take appropriate samples. Start empirical treatment while awaiting the results of culture and susceptibility testing,
except in adults with vertebral osteomyelitis not associated with sepsis who have a normal neurological
examination. In these patients, withhold antibiotic therapy until a microbiological diagnosis is made.
For adults, empirical regimens are included in these guidelines for:
osteomyelitis complicated by sepsis or septic shock—see Sepsis or septic shock associated with a bone or
joint source
osteomyelitis contiguous with a leg or foot ulcer—see Diabetic foot infection
long-bone osteomyelitis—the choice of empirical regimen depends on the patient’s risk of methicillin-
resistant Staphylococcus aureus (MRSA) infection (see Box 2.31). Separate recommendations are included
for patients:
at increased risk of MRSA infection
at low risk of MRSA infection
vertebral osteomyelitis—the choice of empirical regimen depends on the patient’s neurological status.
Separate recommendations are included for:
patients in whom infection is associated with epidural abscess or progressive neurological
compromise
patients who have a normal neurological examination. Although empirical therapy is usually not
indicated for these patients, empirical regimens are included for use when a microbiological diagnosis
cannot be achieved. In these circumstances, antibiotic choice depends on whether the patient is at low
risk or increased risk of infection with MRSA or a Gram-negative organism.
For children, empirical therapy is the same for both long-bone and vertebral osteomyelitis—see here.
For adults or children with osteomyelitis associated with prosthetic material, seek expert advice.
Modify therapy according to the results of culture and susceptibility testing. See Directed therapy for native bone
and joint infection for suggested regimens. For patients with S. aureus bacteraemia associated with osteomyelitis,
consider both the recommendations in this topic and the recommendations in Staphylococcus aureus bacteraemia.
Prolonged antibiotic therapy is required to cure osteomyelitis. The duration of therapy depends on the patient’s
age, whether the infection is acute or chronic, the pathogen and the patient’s clinical response. Intravenous
antibiotic therapy is almost always required initially, but oral antibiotic therapy is usually preferred to complete the
treatment course.
Treatment of vertebral osteomyelitis can be difficult and surgical intervention is often required for successful
management—seek expert advice. Surgery should be considered for patients with spinal or paraspinal collections,
and is critical for patients with neurological compromise.
To cure chronic osteomyelitis, surgical debridement of necrotic bone and sequestra is essential.
Investigations for osteomyelitis

A microbiological diagnosis should be pursued in all patients with osteomyelitis, but is particularly important in
adults with vertebral osteomyelitis because of the large number of potential pathogens. Take samples for culture
before administering antibiotics if possible. However, take samples even if antibiotics have been started, because
culture results often remain positive.
Collect blood samples for culture because more than 50% of patients with vertebral or acute long-bone
osteomyelitis have bacteraemia. To increase blood culture yield, adults should have two sets of samples (ie four
bottles) collected. If blood culture results are positive, bone biopsy is generally unnecessary. However, if no
organism, or an organism of questionable significance (eg a commensal organism such as a coagulase-negative
staphylococcus), is identified, it is critical to collect suitable samples of bone or pus for culture and histopathology.
These samples should be collected by radiologically guided percutaneous or open biopsy. In children, bone biopsy
is not required if there is a good response to empirical antibiotic therapy, even if blood culture results are negative.
Negative bone-biopsy culture results are most often due to sampling error, though antibiotic administration in the
days before sampling can also reduce culture yield. If suspicion of osteomyelitis remains high, bone biopsy should
be repeated; in vertebral osteomyelitis, open surgical biopsy is more likely to result in a diagnosis than needle
biopsy. If culture results are still negative and alternative pathology (eg malignancy, tuberculosis) is excluded,
empirical therapy is often indicated.
Duration of therapy for osteomyelitis

There is a lack of high-level clinical evidence to inform the optimal duration of antibiotic therapy for
osteomyelitis, or the timing of switch to oral therapy. The durations of therapy suggested in Table 2.1 are widely
accepted and commonly used in practice, but should be modified according to clinical response and, in some
circumstances, the pathogen and the antibiotic(s) used—seek expert advice.
For adults who are clinically improving, emerging evidence [Note 1] supports an earlier switch to oral therapy
than suggested in Table 2.1. Expert advice is recommended to select an appropriate oral antimicrobial regimen that
is as effective as intravenous therapy (eg ciprofloxacin, clindamycin; see also Box 2.34) and to monitor treatment
progress. However, an earlier switch is not always appropriate, and some adults need a longer duration of
intravenous therapy than recommended in Table 2.1. Adults with Staphylococcus aureus bacteraemia associated
with osteomyelitis usually require a minimum of 4 weeks of intravenous therapy (see Duration of therapy for
Staphylococcus aureus bacteraemia in adults).
A total of 6 weeks of antibiotic therapy (intravenous + oral) is likely to successfully treat vertebral osteomyelitis
in adults, as long as there is an early clinical response and any collections have been drained. Longer therapy may
be required when infection is caused by methicillin-resistant S. aureus (MRSA), or a Gram-negative organism not
treated with ciprofloxacin—seek expert advice. Ongoing pain can be expected for months after treatment is
completed, and does not necessarily indicate that infection is unresolved; it may be a symptom of vertebral
instability. Magnetic resonance imaging (MRI) changes lag behind clinical response by months. Therefore, repeat
MRI scans are not useful for monitoring infection resolution, but are recommended if there are new or changing
neurological signs.
For long-bone osteomyelitis in adults, an improvement in symptoms is expected over days to weeks, with
minimal symptoms by the end of treatment.
Children usually require a shorter duration of therapy than adults because their bones have an excellent blood
supply. Intravenous therapy should generally be continued until blood culture results are negative, the child is
afebrile and has clinically improved, and C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) is
decreasing. Some children need a longer duration of intravenous therapy than recommended in Table 2.1. For
additional detail on duration of therapy and the timing of switch to oral therapy, see the Australian and New
Zealand Paediatric Infectious Diseases Group–Australasian Stewardship of Antimicrobials in Paediatrics
guidelines [Note 2].
Symptoms of long-bone osteomyelitis improve more rapidly in children than in adults.
In adults and children who are stable but require prolonged intravenous therapy, community-based parenteral
antimicrobial therapy may be appropriate.
Suggested duration of antibiotic therapy for long-bone or vertebral osteomyelitis (Table 2.1)
Patient age Suggested duration of antibiotic therapy [NB1]

Intravenous Total (intravenous + oral)
neonate 4 weeks 4 weeks (all intravenous)
3 days or until blood culture
results are negative, the child is
Acute osteomyelitis child afebrile and has clinically minimum 3 weeks
improved, and CRP or ESR is
decreasing
adult 4 weeks minimum 6 weeks
Chronic child may not be necessary minimum 6 weeks
osteomyelitis adult 2 weeks many months
CRP = C-reactive protein; ESR = erythrocyte sedimentation rate
NB1: The durations of therapy suggested in this table are a guide only—modify according to clinical response. See Duration of therapy for
osteomyelitis for further discussion.
Note 1: Li HK, Rombach I, Zambellas R, Walker AS, McNally MA, Atkins BL, et al. Oral versus Intravenous
Antibiotics for Bone and Joint Infection. N Engl J Med 2019;380(5):425-36. [URL]
Note 2: McMullan BJ, Andresen D, Blyth CC, Avent ML, Bowen AC, Britton PN, et al. Antibiotic duration and
timing of the switch from intravenous to oral route for bacterial infections in children: systematic review and
guidelines. Lancet Infect Dis 2016;16(8):e139-52. [URL]
Approach to empirical therapy for osteomyelitis in adults

For long-bone osteomyelitis in adults without sepsis or septic shock, empirical therapy usually targets
Staphylococcus aureus, because S. aureus remains the most likely pathogen even in patients with risk factors for
infection with other pathogens. See adults at low risk of methicillin-resistant S. aureus (MRSA) infection or adults
at increased risk of MRSA infection.
For vertebral osteomyelitis in adults without sepsis or septic shock, urgent empirical therapy is only indicated for
patients with epidural abscess or progressive neurological compromise. For patients with vertebral osteomyelitis
who have a normal neurological examination, withhold antibiotic therapy until a definitive microbiological
diagnosis is made.
For patients with spinal epidural abscess in the absence of vertebral osteomyelitis, see here.
For patients with osteomyelitis complicated by sepsis or septic shock, see here.
Empirical therapy for adults with osteomyelitis contiguous with leg or

foot ulcers
For adults with diabetes or vascular insufficiency who have osteomyelitis contiguous with a leg or foot ulcer, see
Diabetic foot infection.
Empirical therapy for adults with long-bone osteomyelitis who are at

low risk of MRSA infection
The regimens below are recommended for both acute and chronic long-bone osteomyelitis until a microbiological
diagnosis is made. Obtain diagnostic samples before antibiotic therapy is started (see Investigations for
osteomyelitis). Once a microbiological diagnosis is made, modify therapy accordingly (see Directed therapy for
native bone and joint infection).
For empirical therapy for adults with long-bone osteomyelitis who are at low risk of methicillin-resistant
Staphylococcus aureus (MRSA) infection (see Box 2.31), use:
flucloxacillin 2 g intravenously, 6-hourly.
For adults with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use:
cefazolin 2 g intravenously, 8-hourly.
For adults with immediate severe or delayed severe hypersensitivity to penicillins, use:
vancomycin intravenously; see Principles of vancomycin use for dosage and principles of
use.
Empirical therapy for adults with long-bone osteomyelitis who are at

increased risk of MRSA infection
The regimen below is recommended for both acute and chronic long-bone osteomyelitis until a microbiological
diagnosis is made. Obtain diagnostic samples before antibiotic therapy is started (see Investigations for
osteomyelitis). Once a microbiological diagnosis is made, modify therapy accordingly (see Directed therapy for
native bone and joint infection).
For empirical therapy for adults with long-bone osteomyelitis who are at increased risk of methicillin-resistant
Staphylococcus aureus (MRSA) infection (see Box 2.31), use:
use.
Empirical therapy for adults with vertebral osteomyelitis who have a

normal neurological examination
In adults with vertebral osteomyelitis who have a normal neurological examination and do not have sepsis or
septic shock, withhold antibiotic therapy until a definitive microbiological diagnosis is made. Once the pathogen is
identified, see Directed therapy for native bone and joint infection for suggested antibiotic regimens.
Withhold antibiotic therapy until a microbiological diagnosis is made in adults who have a normal neurological examination.
If a microbiological diagnosis cannot be achieved, treatment choice depends on the risk of infection with
methicillin-resistant Staphylococcus aureus (MRSA) or a Gram-negative organism.
For adults at low risk of infection caused by MRSA or a Gram-negative organism (see Aetiology of
osteomyelitis in adults), narrower-spectrum therapy targeting methicillin-susceptible S. aureus (MSSA) and beta-
haemolytic streptococci is appropriate. Use:
use.
For timing of switch to oral therapy, see Duration of therapy. Seek expert advice for oral antibiotic choice.
For adults at increased risk of infection caused by MRSA or Gram-negative organisms (see Aetiology of
osteomyelitis in adults), broader-spectrum therapy is needed—seek expert advice to optimise invasive and
noninvasive investigations, and to guide selection of an appropriate antibiotic regimen.
Empirical therapy for adults with vertebral osteomyelitis associated

with epidural abscess or progressive neurological compromise
Urgent empirical therapy is indicated for adults with vertebral osteomyelitis who have progressive neurological
compromise and are awaiting surgical intervention, including patients with secondary spinal epidural abscess. The
regimens below are recommended until a microbiological diagnosis is made. Obtain blood samples for culture
before antibiotic therapy is started (see Investigations for osteomyelitis for details). Once a microbiological
diagnosis is made, modify therapy accordingly (see Directed therapy for native bone and joint infection).
For urgent empirical therapy of vertebral osteomyelitis in adults, as a three-drug regimen, use initially:
flucloxacillin 2 g intravenously, 6-hourly
PLUS
use
PLUS EITHER
1 ceftriaxone 2 g intravenously, 12-hourly
OR
1 cefotaxime 2 g intravenously, 6-hourly.
Prioritise administration of flucloxacillin and either ceftriaxone or cefotaxime, because vancomycin requires slow
infusion.
For adults with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, as a two-drug
regimen, use initially:
OR
1 cefotaxime 2 g intravenously, 6-hourly
PLUS (with either of the above regimens)
use.
For adults with immediate severe or delayed severe hypersensitivity to penicillins, use initially:
ciprofloxacin 400 mg intravenously, 8-hourly
PLUS
use.
Empirical therapy for osteomyelitis in children

Empirical regimens for neonates with osteomyelitis are not included in these guidelines—seek expert advice.
For children with osteomyelitis associated with sepsis or septic shock, treat as for sepsis or septic shock with an
unknown source—see Empirical therapy for sepsis or septic shock in infants 1 month to younger than 2 months or
Empirical therapy for sepsis or septic shock in children 2 months or older.
Empirical therapy for both long-bone and vertebral osteomyelitis in children without sepsis or septic shock targets
Staphylococcus aureus. Therapy is adjusted if the child is at increased risk of methicillin-resistant S. aureus
(MRSA) infection (see Box 2.31) or if infection with Kingella kingae is suspected (especially in children younger
than 4 years who fail to improve rapidly with antistaphylococcal therapy [eg flucloxacillin] or if there is
microbiological evidence of K. kingae).
The regimens below are recommended for both acute and chronic osteomyelitis until a microbiological diagnosis
is made. Obtain diagnostic samples before antibiotic therapy is started (see Investigations for osteomyelitis). Once
a microbiological diagnosis is made, modify therapy accordingly (see Directed therapy for native bone and joint
infection).
For empirical therapy for children without sepsis or septic shock with long-bone or vertebral osteomyelitis, use:
flucloxacillin 50 mg/kg up to 2 g intravenously, 6-hourly.
For children with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use:
cefazolin 50 mg/kg up to 2 g intravenously, 8-hourly.
For children at increased risk of MRSA infection (see Box 2.31) or with immediate severe or delayed severe
hypersensitivity to penicillins, use:
use.
In some regions, based on local susceptibility data, clindamycin or lincomycin is a suitable alternative to
vancomycin:
1 clindamycin 15 mg/kg up to 600 mg intravenously, 8-hourly
OR
2 lincomycin 15 mg/kg up to 600 mg intravenously, 8-hourly.
If infection with K. kingae is suspected (see above), add cefotaxime or ceftriaxone to the above regimens. Use:
1 cefotaxime 50 mg/kg up to 2 g intravenously, 8-hourly
OR
1 ceftriaxone 50 mg/kg up to 2 g intravenously, daily.
Cefotaxime and ceftriaxone are suitable for children with immediate nonsevere or delayed nonsevere
hypersensitivity to penicillins in whom K. kingae infection is suspected.
For children with immediate severe or delayed severe hypersensitivity to penicillins in whom K. kingae infection
is suspected, the choice of empirical regimen is complex—seek expert advice.
Key references
Classification of osteomyelitis
D'Agostino C, Scorzolini L, Massetti AP, Carnevalini M, d'Ettorre G, Venditti M, et al. A seven-year prospective study
on spondylodiscitis: epidemiological and microbiological features. Infection 2010;38(2):102–107 .
Murillo O, Grau I, Lora-Tamayo J, Gomez-Junyent J, Ribera A, Tubau F, et al. The changing epidemiology of
bacteraemic osteoarticular infections in the early 21st century. Clin Microbiol Infect 2015;21(3):254.e1–254.e8
.
Aetiology of osteomyelitis in adults
D'Agostino C, Scorzolini L, Massetti AP, Carnevalini M, d'Ettorre G, Venditti M, et al. A seven-year prospective study on
spondylodiscitis: epidemiological and microbiological features. Infection 2010;38(2):102–107 .
Murillo O, Grau I, Lora-Tamayo J, Gomez-Junyent J, Ribera A, Tubau F, et al. The changing epidemiology of
bacteraemic osteoarticular infections in the early 21st century. Clin Microbiol Infect 2015;21(3):254.e1–254.e8
.
Park KH, Cho OH, Jung M, Suk KS, Lee JH, Park JS, et al. Clinical characteristics and outcomes of hematogenous
vertebral osteomyelitis caused by gram-negative bacteria. J Infect 2014;69(1):42–50 .
Park KH, Chong YP, Kim SH, Lee SO, Choi SH, Lee MS, et al. Clinical characteristics and therapeutic outcomes of
hematogenous vertebral osteomyelitis caused by methicillin-resistant Staphylococcus aureus. J Infect
2013;67(6):556–564 .
Aetiology of osteomyelitis in children
Khatami A, Rivers BR, Outhred AC, Kesson AM. Low prevalence of Kingella kingae carriage in children aged 6-48
months in Sydney, Australia. J Paediatr Child Health 2017;53(2):170–172 .
Williams N, Cooper C, Cundy P. Kingella kingae septic arthritis in children: recognising an elusive pathogen. J Child
Orthop 2014;8(1):91–95 .
Investigations for osteomyelitis
Nickerson EK, Sinha R. Vertebral osteomyelitis in adults: an update. Br Med Bull 2016;117(1):121–138 .
Pääkkönen M, Kallio MJ, Peltola H, Kallio PE. Antibiotic treatment and surgery for acute hematogenous calcaneal
osteomyelitis of childhood. J Foot Ankle Surg 2015;54(5):840–843 .
Duration of therapy for osteomyelitis
Bernard L, Dinh A, Ghout I, SimoIssartelZeller DBV, et al. Antibiotic treatment for 6 weeks versus 12 weeks in patients
with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial. Lancet
2015;385(9971):875–882 .
Li HK, Rombach I, Zambellas R, Walker AS, McNally MA, Atkins BL, et al. Oral versus intravenous antibiotics for bone
and joint infection. N Engl J Med 2019;380(5):425–436 .
McMullan BJ, Andresen D, Blyth CC, Avent ML, Bowen AC, Britton PN, et al. Antibiotic duration and timing of the
switch from intravenous to oral route for bacterial infections in children: systematic review and guidelines. Lancet Infect
Dis 2016;16(8):e139–e152 .
2013;67(6):556–564 .
Seyman D, Berk H, Sepın-Ozen N, Kızılates F, Turk CC, Buyuktuna SA, et al. Successful use of tigecycline for
treatment of culture-negative pyogenic vertebral osteomyelitis. Infect Dis (Lond) 2015;47(11):783–788 .
Empirical therapy for adults with vertebral osteomyelitis associated with epidural abscess or
progressive neurological compromise
Babouee Flury B, Elzi L, Kolbe M, Frei R, Weisser M, Schären S, et al. Is switching to an oral antibiotic regimen safe
after 2 weeks of intravenous treatment for primary bacterial vertebral osteomyelitis?. BMC Infect Dis 2014;14:226.
.
Berbari EF, Kanj SS, Kowalski TJ, Darouiche RO, Widmer AF, Schmitt SK, et al. 2015 Infectious Diseases Society of
America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults.
Clin Infect Dis 2015;61(6):e26–e46 .
2013;67(6):556–564 .
Empirical therapy for osteomyelitis in children
Khatami A, Rivers BR, Outhred AC, Kesson AM. Low prevalence of Kingella kingae carriage in children aged 6-48
months in Sydney, Australia. J Paediatr Child Health 2017;53(2):170–172 .
Vardakas KZ, Kontopidis I, Gkegkes ID, Rafailidis PI, Falagas ME. Incidence, characteristics, and outcomes of patients
with bone and joint infections due to community-associated methicillin-resistant Staphylococcus aureus: a systematic
review. Eur J Clin Microbiol Infect Dis 2013;32(6):711–721 .
Williams N, Cooper C, Cundy P. Kingella kingae septic arthritis in children: recognising an elusive pathogen. J Child
Orthop 2014;8(1):91–95 .
Septic arthritis
Aetiology of septic arthritis
Septic arthritis usually presents as a monoarticular arthritis, either spontaneously or following penetrating trauma.
Infection is most commonly caused by Gram-positive organisms—predominantly Staphylococcus aureus, but also
Streptococcus species. Risk factors for infection with methicillin-resistant S. aureus (MRSA) should be considered
(see Box 2.31).
Neisseria gonorrhoeae is a common cause of native joint septic arthritis in sexually active adults.
Consider a broader range of pathogens, as well as polymicrobial infection, in patients with septic arthritis
contiguous with ulceration, particularly in patients with infection of joints of the lower limbs and vascular
insufficiency or diabetes. See Diabetic foot infection for management, including antibiotic choice.
Diagnosis of septic arthritis

Take diagnostic samples before starting antibiotic therapy to exclude alternative or coexisting diagnoses (such as
an acute crystal arthropathy) and enable antibiotic therapy to be directed. Appropriate diagnostic samples include
blood for culture, and a joint aspirate for Gram stain, culture and microscopy.
Joint aspiration should be performed by experienced clinicians, using an aseptic technique. When performing
diagnostic aspiration, aspirating the bulk of the effusion can offer therapeutic benefits. Aspiration should be as
complete as possible without compromising patient comfort or causing damage to the joint. See also Joint
aspiration in adults.
Acute rheumatic fever may present as an acute monoarthritis and should be excluded, particularly in Aboriginal
and Torres Strait Islander people living in rural or remote settings, and other populations who may be at high risk
(eg Aboriginal and Torres Strait Islander people living in urban settings, Maori and Pacific Islander people).
Approach to managing septic arthritis

Suspected septic arthritis requires urgent hospital referral. In children, septic arthritis of the hip is an emergency,
and urgent operative drainage is required to prevent necrosis of the femoral head.
Early surgical intervention is essential for source control of septic arthritis. Drainage of pus with joint irrigation
and synovectomy reduces pathogen load, facilitates diffusion of antibiotic into the joint, and protects the articular
surface. Drainage and irrigation may need to be repeated several times to control the infection.
Urgent empirical therapy is indicated for patients with septic arthritis complicated by sepsis or septic shock, while
awaiting the results of Gram stain—see Sepsis or septic shock associated with a bone or joint source for regimens.
For patients without sepsis or septic shock, empirical therapy of septic arthritis should be directed by Gram stain of
a joint aspirate.
If Gram-positive cocci in clusters are identified, suspect Staphylococcus species—see Empirical therapy for
suspected staphylococcal septic arthritis for treatment.
If Gram-positive cocci in chains are identified, suspect Streptococcus species—see Empirical therapy for
suspected streptococcal or Gram-negative septic arthritis for treatment.
If a Gram-negative organism is identified, see Empirical therapy for suspected streptococcal or Gram-
negative septic arthritis for treatment.
If Gram stain is not available or morphology (clusters or chains) is not reported, start empirical treatment
targeting the most common pathogen, Staphylococcus aureus—see Empirical therapy for suspected
staphylococcal septic arthritis for treatment.
Modify therapy according to the results of culture and susceptibility testing. See Directed therapy for native bone
or joint infection for suggested regimens. For patients with S. aureus bacteraemia associated with septic arthritis,
consider both the recommendations in this topic and the recommendations in Staphylococcus aureus bacteraemia.
If tuberculous arthritis is suspected or confirmed, see Tuberculosis for general advice on managing tuberculous
infections.
For directed therapy of septic arthritis caused by other organisms, seek expert advice.
For the suggested duration of therapy for septic arthritis, see Table 2.2. Adults with S. aureus bacteraemia
associated with septic arthritis usually require a minimum of 4 weeks of intravenous therapy (see Duration of
therapy for Staphylococcus aureus bacteraemia in adults).
Community-based parenteral antimicrobial therapy may be appropriate in carefully selected patients.
Suggested duration of antibiotic therapy for septic arthritis (Table 2.2)
Patient age Suggested duration of antibiotic therapy [NB1] [NB2]

Intravenous (minimum) Total (intravenous + oral)
neonate 3 weeks 3 weeks (all intravenously)
child 3 days 3 weeks
adult 2 weeks [NB3] 4 weeks
NB1: The durations of therapy suggested in this table should be modified according to clinical response.
NB2: These treatment durations do not apply to gonococcal arthritis, which should be treated for a total of 7 days.
NB3: If the patient is clinically improving, an earlier switch to oral therapy may be possible, as long as there is an appropriate oral antimicrobial
available that is as effective as intravenous therapy (eg ciprofloxacin, clindamycin; see also Box 2.34). Conversely, some patients need a longer duration
of intravenous therapy than recommended in this table. Seek expert advice.
Empirical therapy for suspected staphylococcal septic arthritis

The regimens below are recommended for septic arthritis when Gram stain of a joint aspirate identifies Gram-
positive cocci in clusters (consistent with Staphylococcus species), or if Gram stain is not available or
morphology is not reported.
For patients at low risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31), use:
flucloxacillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly.
If the patient is at increased risk of MRSA infection (see Box 2.31), use:
use.
In some regions, based on local MRSA susceptibility patterns, clindamycin or lincomycin is a suitable alternative
to vancomycin:
1 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly
OR
2 lincomycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins who are at low risk
of MRSA infection, use:
cefazolin 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, use vancomycin as
monotherapy (as above).
Empirical therapy for suspected streptococcal or Gram-negative septic

arthritis
For empirical therapy for septic arthritis when Gram stain of a joint aspirate identifies Gram-positive cocci in
chains (consistent with Streptococcus species) or a Gram-negative organism, use:
1 ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously, daily
OR
1 cefotaxime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, seek expert advice.
Septic arthritis contiguous with a foot or leg ulcer

In adult patients with diabetes or vascular insufficiency who have septic arthritis contiguous with a foot or leg
ulcer, see Diabetic foot infection for management, including antibiotic choice.
Postoperative infections of the shoulder

Cutibacterium acnes (formerly Propionibacterium acnes) can cause postoperative infections of both native and
prosthetic shoulder joints. Prolonged incubation of cultures and/or 16S ribosomal RNA sequencing are
recommended for diagnosis.
The optimal antibiotic regimen for postoperative infections of the shoulder has not been established, but an
antibiotic with activity against C. acnes is recommended for empirical treatment. C. acnes is typically susceptible
to beta-lactam antibiotics (including benzylpenicillin), clindamycin and vancomycin, but is resistant to
metronidazole. For culture-proven C. acnes infection, adding rifampicin to the treatment regimen is unlikely to
provide benefit.
For native shoulder joints, seek expert advice on the choice of empirical therapy and see Table 2.2 for the
suggested duration of therapy.
Management of postoperative infection of prosthetic shoulder joints is complex—seek expert advice. For the
general approach to managing prosthetic joint infection, see Arthroplasty device infections.
Key references
Jacobs AM, Van Hooff ML, Meis JF, Vos F, Goosen JH. Treatment of prosthetic joint infections due to
Propionibacterium. Similar results in 60 patients treated with and without rifampicin. Acta Orthop 2016;87(1):60–6.
Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM, et al. Diagnosis and management of
prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis
2013;56(1):e1–e25.
Septic bursitis
Aetiology and diagnosis of septic bursitis
Bursitis is most commonly noninfective. Septic bursitis is usually caused by Staphylococcus aureus and often
follows local trauma. The usual sites of infection are the prepatellar and olecranon bursae. When there are signs of
infection, confirm the diagnosis by microscopic examination and culture of a bursal aspirate. If the joint is
involved, see Septic arthritis.
Septic bursitis without systemic symptoms

For patients with septic bursitis without systemic symptoms, use:
1 dicloxacillin 1 g (child: 25 mg/kg up to 1 g) orally, 6-hourly
OR
1 flucloxacillin 1 g (child: 25 mg/kg up to 1 g) orally, 6-hourly.
Cefalexin is often preferred to dicloxacillin or flucloxacillin in children because the liquid formulation is better
tolerated. In most cases, it can also be used for patients with delayed nonsevere hypersensitivity to penicillins
[Note 1]. Use:
cefalexin 1 g (child: 25 mg/kg up to 1 g) orally, 6-hourly.
For patients with immediate (nonsevere or severe) or delayed severe hypersensitivity to penicillins, use:
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly.
If the patient is at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31),
use:
1 doxycycline orally, 12-hourly
adult: 100 mg
OR
1 trimethoprim+sulfamethoxazole 320+1600 mg (child 1 month or older: 8+40 mg/kg up to

320+1600 mg) orally, 12-hourly.
In some regions, based on local MRSA susceptibility data, clindamycin (as above) is a suitable alternative to
doxycycline or trimethoprim+sulfamethoxazole.
Continue treatment until infection has clinically resolved (usually 2 weeks). If infection is not improving after 48
hours of oral therapy, start intravenous therapy as for septic bursitis with systemic symptoms, and consider
repeated aspiration or catheter drainage.
Note 1: It is safe to use cefalexin in patients who had a delayed nonsevere reaction to a penicillin in the distant past. It is also safe to use cefalexin in
patients who have had a delayed nonsevere reaction recently, unless the reaction involved amoxicillin or ampicillin, because cross-reactivity between
these drugs is possible. For patients who have had a recent delayed nonsevere reaction to amoxicillin or ampicillin, use the drug recommended for
patients with immediate (nonsevere or severe) or delayed severe hypersensitivity.
Septic bursitis with systemic symptoms
For patients with septic bursitis associated with systemic symptoms or who are not improving after 48 hours of
oral therapy, start intravenous therapy. Use initially:
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use initially:
For patients with immediate severe or delayed severe hypersensitivity to penicillins, use initially:
1 vancomycin intravenously; see Principles of vancomycin use for dosage and principles of
use
OR
OR
If the patient is at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31),
use vancomycin (as above).
In some regions, based on local MRSA susceptibility data, clindamycin or lincomycin (as above) is a suitable
alternative to vancomycin.
Community-based parenteral antimicrobial therapy may be considered in carefully selected patients.
If clinical improvement is delayed, repeated aspiration, catheter drainage or surgical excision may be required.
When the patient is clinically improving (usually 3 to 7 days), switch to oral therapy as for septic bursitis without
systemic symptoms and continue until the resolution of symptoms (usually 2 weeks).
Sepsis or septic shock associated with a bone or joint
source
Approach to managing sepsis or septic shock associated with a bone or
joint source
Patients with sepsis or septic shock (see here for definitions in adults and here for definitions in children)
associated with a bone or joint source require broad-spectrum therapy because the risk of mortality is high.
Empirical regimens target Staphylococcus aureus as well as other potential pathogens (eg beta-haemolytic
streptococci, Enterobacteriaceae, Pseudomonas aeruginosa).
For the management of patients with sepsis or septic shock associated with an open fracture, see here.
Give antibiotics within 1 hour of the patient presenting to medical care or, for a ward-based patient, developing
sepsis or septic shock; antibiotics should be given immediately after appropriate samples are taken for culture.
Blood samples should always be taken before antibiotic administration. Other relevant samples (eg joint aspirate,
pus aspirate, bone biopsy) should be collected as soon as possible but should not delay antibiotic administration.
For nonantibiotic management of sepsis or septic shock, see Early intervention for sepsis or septic shock.
Children with sepsis or septic shock associated with a bone or joint

source
For children with sepsis or septic shock associated with a bone or joint source, treat as for sepsis or septic shock
with an unknown source—see Empirical therapy for sepsis or septic shock in infants 1 month to younger than 2
months or Empirical therapy for sepsis or septic shock in children 2 months or older.
Adults with sepsis or septic shock associated with a bone or joint source
For adults, the regimens below are recommended for initial therapy (up to 48 hours) of sepsis or septic shock
associated with a bone or joint source. Modify therapy as soon as additional information is available (eg results of
Gram stain, culture and susceptibility testing). If the results of culture or susceptibility testing are not available by
72 hours, and intravenous therapy is still required, stop the gentamicin-containing regimen and seek expert advice.
Evaluate appropriateness of antibiotic therapy daily, with consideration given to the patient’s clinical status and the
principles of antimicrobial stewardship.
For empirical therapy for adults with sepsis or septic shock associated with a bone or joint source, use:
gentamicin intravenously over 3 to 5 minutes; see Principles of aminoglycoside use for

principles of use [Note 1]
adults with septic shock or requiring intensive care support, but without known or likely
pre-existing kidney impairment: 7 mg/kg, for the first dose. See Principles of
aminoglycoside use for subsequent dosing [Note 2] [Note 3]
adults with septic shock or requiring intensive care support, and with known or likely
pre-existing kidney impairment: 4 to 5 mg/kg, for the first dose. See Principles of
adults without septic shock and not requiring intensive care support: 4 to 5 mg/kg, for the
first dose. See Principles of aminoglycoside use for subsequent dosing [Note 2] [Note 3]
PLUS
PLUS
vancomycin 25 to 30 mg/kg intravenously, as a loading dose; see Principles of

vancomycin use for further dosing and principles of use.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use:

PLUS
cefazolin 2 g intravenously, 6-hourly
PLUS

For patients with immediate severe or delayed severe hypersensitivity to penicillins, use:

PLUS

Note 1: Consider monitoring from the first dose.
Note 2: If the patient is obese (body mass index 30 kg/m2 or more), use adjusted body weight (see Box 2.46) to
calculate the dose.
Note 3: Prompt antibiotic initiation is essential, so do not delay gentamicin administration to ascertain kidney
function.
Directed therapy for native bone or joint infection
Methicillin-susceptible Staphylococcus aureus (MSSA) native bone or
joint infection
The regimens below are recommended for osteomyelitis of native bone, or septic arthritis of a native joint, when
infection is caused by methicillin-susceptible Staphylococcus aureus (MSSA). For the suggested duration of
antibiotic therapy and timing of oral switch for osteomyelitis of native bone, see here. For the suggested duration
of antibiotic therapy and timing of oral switch for septic arthritis of a native joint, see here.
To treat methicillin-susceptible Staphylococcus aureus osteomyelitis or septic arthritis, use initially:
When it is appropriate to switch to oral therapy, use:
1 dicloxacillin 1 g (child: 25 mg/kg up to 1 g) orally, 6-hourly
OR
1 flucloxacillin 1 g (child: 25 mg/kg up to 1 g) orally, 6-hourly.
Cefalexin (see dosage below) is often preferred to oral dicloxacillin or flucloxacillin in children because the liquid
formulation is better tolerated.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use initially:
When it is appropriate to switch to oral therapy for patients with immediate nonsevere or delayed nonsevere
hypersensitivity to penicillins, antibiotic choice depends on the patient’s history of penicillin hypersensitivity. For
patients who had a delayed nonsevere reaction to a penicillin in the distant past, it is safe to use cefalexin.
Cefalexin is also safe for patients who have had a recent delayed nonsevere reaction to a penicillin, unless the
reaction involved amoxicillin or ampicillin [Note 1]. If cefalexin is indicated, use:
cefalexin 1 g (child: 25 mg/kg up to 1 g) orally, 6-hourly.
For oral continuation therapy in patients who have had a recent delayed nonsevere reaction to amoxicillin or
ampicillin, or who have immediate nonsevere hypersensitivity to penicillins, use clindamycin (see dosage below).
For children and nonbacteraemic adults with immediate severe or delayed severe hypersensitivity to penicillins
whose infection is caused by confirmed lincosamide-susceptible MSSA, use:
OR
When it is appropriate to switch to oral therapy, use:
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly.
Avoid clindamycin or lincomycin monotherapy in adults with S. aureus bacteraemia; use vancomycin (as below)
instead.
For patients with immediate severe or delayed severe hypersensitivity to penicillins whose infection is caused by
lincosamide-resistant MSSA, use:
use.
For patients initially treated with vancomycin, seek expert advice on choice of oral therapy and timing of switch.
Note 1: In patients who have had a recent delayed nonsevere reaction to amoxicillin or ampicillin, avoid cefalexin because these drugs have similar R1
side-chains, so cross-reactivity is possible.
Methicillin-resistant Staphylococcus aureus (MRSA) native bone or

joint infection
The regimens below are recommended for osteomyelitis of native bone, or septic arthritis of a native joint, when
infection is caused by methicillin-resistant Staphylococcus aureus (MRSA). For the suggested duration of
antibiotic therapy and timing of oral switch for osteomyelitis of native bone, see here. For the suggested duration
of antibiotic therapy and timing of oral switch for septic arthritis of a native joint, see here.
To treat methicillin-resistant Staphylococcus aureus osteomyelitis or septic arthritis, use:
use.
If susceptibility is confirmed, clindamycin or lincomycin is a suitable alternative to vancomycin; however, avoid

intravenous clindamycin or lincomycin monotherapy in adults with S. aureus bacteraemia. Use:
OR
When it is appropriate to switch to oral therapy, according to the results of susceptibility testing, use:
1 clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly
OR
1 doxycycline orally, 12-hourly
adult: 100 mg
OR

If resistance to all of the oral drugs above is confirmed, and susceptibility to rifampicin and either fusidate sodium
or ciprofloxacin has been demonstrated, use a combination of:
rifampicin 300 mg (child: 7.5 mg/kg up to 300 mg) orally, 12-hourly
PLUS EITHER
1 ciprofloxacin 750 mg (child: 20 mg/kg up to 750 mg) orally, 12-hourly [Note 2] [Note 3]
OR
1 fusidate sodium 500 mg (child: 12 mg/kg up to 500 mg) orally, 8-hourly. If this dosage is
not tolerated, 500 mg 12-hourly can be used.
Do not use monotherapy with rifampicin, fusidate sodium or ciprofloxacin.
Rifampicin and fusidate sodium interact significantly with many commonly used medicines; ciprofloxacin also has
significant drug interactions. For comprehensive information on drug interactions, consult an appropriate drug
information resource.
Note 2: An oral liquid formulation of ciprofloxacin is not commercially available; for formulation options for children or people with swallowing
difficulties, see the Don’t Rush to Crush Handbook, published by the Society of Hospital Pharmacists of Australia [URL].
Note 3: Ciprofloxacin is not licensed for use in children on the basis of animal studies that showed an adverse effect on cartilage development with
quinolone use; however, there are few data from human trials to support this finding. Ciprofloxacin can be used in children when it is the drug of
choice.
Directed therapy for native bone or joint infection caused by other

pathogens
For pathogens other than Staphylococcus aureus, modify therapy based on the results of culture and susceptibility
testing. While awaiting the results of culture and susceptibility testing, seek expert advice for the choice of
intravenous therapy.
For the suggested duration of antibiotic therapy and timing of oral switch for osteomyelitis of native bone, see
here. For the suggested duration of antibiotic therapy and timing of oral switch for septic arthritis of a native joint,
see here.
When it is appropriate to switch to oral therapy, ciprofloxacin is the drug of choice for susceptible
Enterobacteriaceae and Pseudomonas species. Use:
ciprofloxacin 750 mg (child: 20 mg/kg up to 750 mg) orally, 12-hourly [Note 4] [Note 5].
For directed therapy for tuberculous native bone and joint infection, see Tuberculosis for general advice on
managing tuberculous infections.
For directed therapy for native bone and joint infection caused by Brucella species, see Brucellosis.
For directed therapy for native bone and joint infection caused by Candida species or other fungi, seek expert
advice.
Septic arthritis is the most common presentation of disseminated gonococcal infection and is usually preceded by
asymptomatic mucosal infection. Gonococcal arthritis may not require joint washouts. For antibiotic therapy for
gonococcal septic arthritis, use:
1 ceftriaxone 2 g (child: 50 mg/kg up to 2 g) intravenously, daily
OR
For patients with gonococcal arthritis, continue intravenous therapy until the patient has been afebrile for 48 hours,
then switch to oral therapy according to the results of culture and susceptibility testing. Total treatment duration is
7 days. See here for advice on further testing and contact tracing.
choice.
Key references
hematogenous vertebral osteomyelitis caused by methicillin-resistant Staphylococcus aureus. J Infect 2013;67(6):556–
64.
Arthroplasty device infections
Aetiology of arthroplasty device infections
Arthroplasty device infections (prosthetic joint infections) can be classified as early postoperative (occurring
within 30 days of joint implantation), late chronic (indolent presentation), or late acute haematogenous
(sudden onset in a previously well-functioning joint). Early postoperative and late acute haematogenous
infections are usually caused by virulent organisms, primarily Staphylococcus aureus, but also beta-
haemolytic streptococci and aerobic Gram-negative organisms. Chronic infections are likely to be caused by
less virulent organisms, including coagulase-negative staphylococci, Enterococcus species and Cutibacterium
(formerly Propionibacterium) species. Infections of prosthetic shoulder joints more frequently involve
Cutibacterium acnes; see Postoperative infections of the shoulder.
Approach to managing arthroplasty device infections

Extensive debridement, with or without removal of the prosthesis, is generally required to cure arthroplasty
device infections. Multidisciplinary management, involving a surgeon experienced in arthroplasty and an
infectious diseases physician, is recommended.
The choice of orthopaedic management should be individualised for each patient’s circumstances, with
antibiotic therapy tailored to the management strategy chosen. The most commonly employed orthopaedic
strategies are exchange arthroplasty and debridement and implant retention (DAIR), both of which have
curative intent. Patients who are not fit for surgery may be considered for treatment without curative
intent using long-term suppressive antibiotic therapy.
The choice of orthopaedic management should be individualised for each patient’s circumstances, with antibiotic therapy
tailored to the management strategy chosen.
Exchange arthroplasty is usually necessary for infected prosthetic shoulder joints, because these infections
(especially those caused by Cutibacterium acnes) are usually chronic. See Postoperative infections of the
shoulder for management.
Investigations for arthroplasty device infections

Three to six joint tissue biopsies and a sample of synovial fluid should be collected intraoperatively.
Microscopy, culture and histological examination of these samples is required to detect infection with optimal
sensitivity and specificity. Sonication of a removed prosthesis, to release organisms from a biofilm, may
increase diagnostic sensitivity and may be particularly useful when antibiotics have been received before the
operation. It is common practice to delay surgical antibiotic prophylaxis until after the collection of samples;
however, data suggest that microbiological yield is not affected by giving prophylaxis before samples are
collected (see Surgical prophylaxis for orthopaedic surgery).
Newer diagnostic tests (eg alpha-defensin) are reported to have high sensitivity; however, at the time of
writing they have not been validated in large cohort studies and cannot be recommended.
Exchange arthroplasty
Overview of exchange arthroplasty
The first stage of a two-stage exchange arthroplasty involves debridement of compromised soft tissue and
bone, and removal of implanted materials (including the prosthesis, bone cement and, if present, ancillary
screws, plates and wires). A spacer, which is usually antibiotic-impregnated, is inserted. At the second
operation, the spacer is replaced by a new definitive prosthesis. Two-stage exchange arthroplasty has the
highest reported cure rate (85 to 95%) of the orthopaedic strategies for arthroplasty device infection.
However, it requires multiple operations and may involve prolonged impaired mobility.
A one-stage exchange arthroplasty (in which the prosthesis is resected, soft tissue and bone are debrided
and a new prosthesis is implanted during a single surgery) has a similar success rate to a two-stage exchange
arthroplasty when performed in experienced centres. A microbiological diagnosis is usually made
preoperatively to direct postoperative antibiotic choice.
Antibiotic choice for two-stage exchange arthroplasty
After removal of the prosthesis at the first operation, 6 weeks of antibiotic therapy is indicated. Antibiotic
treatment is often stopped 7 to 14 days before the second operation; however, evidence to support this
practice is lacking.
Tailor antibiotic treatment between the two stages to the susceptibility of the pathogen isolated from
aspiration or biopsy samples. For empirical therapy while awaiting the results of culture and susceptibility
testing, or if culture results are negative, use:
vancomycin intravenously; see Principles of vancomycin use for dosage and

principles of use.
For patients managed in a unit with a high incidence of Gram-negative infections, consider adding treatment
for Gram-negative infection.
In carefully selected patients whose condition is stable, community-based parenteral antimicrobial therapy
may be appropriate.
At the second operation, samples for culture should be taken intraoperatively. If culture results are positive,
give a further 6 weeks of antibiotics, guided by the results of susceptibility testing.
Debridement and implant retention (DAIR)

Overview of DAIR
Debridement and implant retention (DAIR) has curative intent. The procedure involves extensive surgical
debridement and replacement of exchangeable components, and the prosthesis is retained. DAIR offers some
advantages over two-stage exchange arthroplasty (reduced costs and morbidity, and a shorter stay in hospital)
but has a lower rate of cure after 2 years of follow-up (compared to cure rates of 85 to 95% with two-stage
arthroplasty, cure is achieved in approximately 70% of patients with early postoperative infection treated with
DAIR and 50 to 60% of patients with late acute haematogenous infection treated with DAIR).
Appropriate patient selection and thorough surgical debridement are crucial to clinical success with DAIR;
the choice of antibiotic regimen is less important. Surgical debridement may need to be repeated to control
the infection.
Patient selection for DAIR
Success with DAIR is highly dependent on patient selection and surgical technique. DAIR may be
appropriate to treat early postoperative infection or late haematogenous infection with a short duration of
symptoms (less than 3 weeks).
It is recommended that DAIR only be considered if the following criteria are met:
a stable, well-fixed prosthesis (without periprosthetic lytic areas identified by radiological

investigation)
good condition of the surrounding skin and soft tissue (without evidence of a sinus)
no associated sepsis or septic shock (see here for definitions).
The following are relative contraindications to DAIR because lower success rates are reported:
polymicrobial infection
infection with an organism(s) resistant to oral antibiotics suitable for treating prosthetic joint infection
(ie antibiotics with good oral bioavailability and biofilm activity)
the presence of multiple comorbidities or immune compromise (including rheumatoid arthritis,
immunosuppressive therapy or active malignancy).
Antibiotic choice for DAIR
There is a lack of high-quality randomised controlled trial evidence on which to base antibiotic regimens for
patients treated with DAIR. Choosing an appropriate antibiotic regimen is complex—seek advice from an
infectious diseases physician or clinical microbiologist.
Choosing an appropriate antibiotic regimen for DAIR is complex—seek advice from an infectious diseases physician or
clinical microbiologist.
Emerging evidence supports initial intravenous therapy with an early switch to oral antimicrobials [Note 1].
Early switch regimens usually involve 1 to 2 weeks of therapy with an intravenous beta lactam or
vancomycin, followed by 6 weeks to 6 months of oral therapy. For staphylococcal infections, oral rifampicin
is used with a companion drug (either oral fusidate sodium or an oral quinolone, depending on
susceptibilities). For Gram-negative infections, an oral quinolone is used alone. Expert advice is
recommended to determine an appropriate regimen with good oral bioavailability, to consider inclusion of a
biofilm active agent, and to monitor treatment progress.
Alternative antibiotic regimens have been described in retrospective observational studies; in these regimens
an intravenous beta lactam (usually flucloxacillin) or vancomycin is administered for 6 weeks, with or
without a subsequent 6 weeks of oral antibiotic therapy. For susceptible Staphylococcus species, rifampicin
may be added to the intravenous regimen once bacteraemia is cleared. Limited evidence from cohort studies
supports the addition of rifampicin to intravenous regimens for streptococcal infection.
Ciprofloxacin-containing regimens have the highest success rates for arthroplasty device infections caused by
susceptible Gram-negative organisms.
For initial empirical postoperative antibiotic therapy, while awaiting culture and susceptibility results, use:

principles of use.
For initial antibiotic therapy for confirmed infection with methicillin-susceptible staphylococci, while
awaiting infectious diseases or clinical microbiology advice, use:
For initial antibiotic therapy for patients with immediate nonsevere or delayed nonsevere hypersensitivity
to penicillins, while awaiting infectious diseases or clinical microbiology advice, use:
For initial antibiotic therapy for patients with immediate severe or delayed severe hypersensitivity to
penicillins, while awaiting infectious diseases or clinical microbiology advice, use:

principles of use.
For initial antibiotic therapy for confirmed infection with methicillin-resistant staphylococci, while awaiting
infectious diseases or clinical microbiology advice, use vancomycin (as above).
Rifampicin and fusidate sodium interact significantly with many commonly used medicines; ciprofloxacin
also has significant drug interactions. For comprehensive information on drug interactions, consult an
appropriate drug information resource.
Note 1: Li HK, Rombach I, Zambellas R, Walker AS, McNally MA, Atkins BL, et al. Oral versus
Intravenous Antibiotics for Bone and Joint Infection. N Engl J Med 2019;380(5):425-36. [URL]
Implant retention without curative intent
Patients who are not fit for surgery may be considered for treatment without curative intent using long-term
suppressive antibiotic therapy—seek expert advice.
Intravenous therapy is required only until the patient is clinically improving because the goal of treatment is
suppression of infection rather than cure. Oral continuation therapy is required indefinitely. Unlike antibiotic
choice for implant retention with curative intent, antibiotics used for long-term suppression do not need good
biofilm penetration and activity; well-tolerated antibiotics are often preferred.
Key references
Haasper C, Buttaro M, Hozack W, Aboltins CA, Borens O, Callaghan JJ, et al. Irrigation and debridement. J
Arthroplasty 2014;29(2 Suppl):100–3.
Hansen E, Belden K, Silibovsky R, Vogt M, Arnold WV, Bicanic G, et al. Perioperative antibiotics. J Arthroplasty
2014;29(2 Suppl):29–48 .
Li HK, Rombach I, Zambellas R, Walker AS, McNally MA, Atkins BL, et al. Oral versus intravenous antibiotics for
bone and joint infection. N Engl J Med 2019;380(5):425–436 .
Lora-Tamayo J, Murillo O, Iribarren JA, Soriano A, Sanchez-Somolinos M, Baraia-Etxaburu JM, et al. A large
multicenter study of methicillin-susceptible and methicillin-resistant Staphylococcus aureus prosthetic joint
infections managed with implant retention. Clin Infect Dis 2013;56(2):182–94.
Lora-Tamayo J, Senneville E, Ribera A, Bernard L, Dupon M, Zeller V, et al. The not-so-good prognosis of
streptococcal periprosthetic joint infection managed by implant retention: The results of a large multicenter study.
Clin Infect Dis 2017;64(12):1742–52 .
Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM, et al. Diagnosis and management of
prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis
2013;56(1):e1–e25.
Peel TN, Spelman T, Dylla BL, Hughes JG, Greenwood-Quaintance KE, Cheng AC, et al. Optimal periprosthetic
tissue specimen number for diagnosis of prosthetic joint infection. J Clin Microbiol 2017;55(1):234–243
.
Pérez-Prieto D, Portillo ME, Puig-Verdié L, Alier A, Gamba C, Guirro P, et al. Preoperative antibiotic prophylaxis in
prosthetic joint infections: not a concern for intraoperative cultures. Diagn Microbiol Infect Dis 2016;86(4):442–
445 .
Tetreault MW, Wetters NG, Aggarwal V, Mont M, Parvizi J, Della Valle CJ. The Chitranjan Ranawat Award: Should
prophylactic antibiotics be withheld before revision surgery to obtain appropriate cultures?. Clin Orthop Relat Res
2014;472(1):52–56 .
Tornero E, Morata L, Martinez-Pastor JC, Angulo S, Combalia A, Bori G, et al. Importance of selection and
duration of antibiotic regimen in prosthetic joint infections treated with debridement and implant retention. J
Antimicrob Chemother 2016;71(5):1395–401.
Zmistowski B, Della Valle C, Bauer TW, Malizos KN, Alavi A, Bedair H, et al. Diagnosis of periprosthetic joint
infection. J Arthroplasty 2014;29(2 Suppl):77–83 .
Published April 2019. Amended June 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Infection of fracture fixation devices
Approach to managing infection of fracture fixation devices
Similar principles to those that apply to infections involving arthroplasty devices also apply to the management of
infections involving fracture fixation devices (intramedullary nails, and pins, plates and screws).
After thorough debridement of infected and compromised soft tissue and bone, it is essential that the infected
fracture is mechanically stabilised to aid infection control, as well as progression to bony union.
Antibiotic choice depends on the susceptibility of the pathogen identified in aspirates or biopsy samples. Continue
antibiotics until fracture union (usually 3 to 6 months). Once fracture union is achieved, consider elective removal
of internal or definitive ring fixation. If infection recurs after antibiotic therapy is stopped, remaining internal
fixation should be removed and an additional 6 weeks of antibiotics given.
Pin-site infection
Improved pin-site care may be sufficient to treat mild inflammation (eg slight erythema, minimal exudate) at the
site of orthopaedic pins and wires. Treat superficial infection (eg increased erythema, warmth, exudate or pain at
the pin site) with a short course of antibiotics targeting Staphylococcus aureus, and seek expert orthopaedic advice
for consideration of pin removal. Swab exudate for culture. While awaiting the results of culture and susceptibility
testing, use:
1 dicloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 days
OR
1 flucloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 days.
Cefalexin is often preferred to dicloxacillin and flucloxacillin in children because the liquid formulation is better
[Note 1]. Use:
cefalexin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 days.
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly for 7 days.
Modify therapy according to the results of culture and susceptibility testing.
If there are systemic symptoms or pin loosening, or if signs of infection fail to respond to a short course of oral
antibiotic therapy, seek expert orthopaedic advice.
Brucellosis
Brucellosis
Brucellosis is a zoonosis that usually presents as a prolonged febrile illness; it is uncommon in Australia. Brucella
suis infection can occur in hunters of feral pigs; it has spread from Queensland into New South Wales and possibly
the Northern Territory. Brucella abortus or Brucella melitensis infection occurs occasionally in recent migrants
and travellers from endemic areas (eg Middle East, southern Europe). Laboratory workers who handle samples
from patients with unrecognised brucellosis are also at risk. For postexposure prophylaxis of brucellosis, seek
expert advice.
Doxycycline is the mainstay of treatment. Adjunctive gentamicin or rifampicin reduces the rate of treatment failure
and relapse.
For adults and children 8 years or older, use:
doxycycline orally, 12-hourly for 6 weeks

adult: 100 mg
PLUS
gentamicin 5 mg/kg (child 8 years to younger than 10 years: 7.5 mg/kg up to 320 mg;
child 10 years and older: 6 mg/kg up to 560 mg) intravenously, daily for 7 days. Monitor
plasma concentration from the first dose—see Principles of aminoglycoside use for dosage
adjustment and principles of use [Note 1].
For children 1 month to 8 years, use:
trimethoprim+sulfamethoxazole 5+25 mg/kg orally, 12-hourly for 6 weeks
PLUS
gentamicin 7.5 mg/kg up to 320 mg intravenously, daily for 7 days. Monitor plasma
concentration from the first dose—see Principles of aminoglycoside use for dosage
adjustment and principles of use [Note 2].
If gentamicin is contraindicated (see Box 2.42), replace gentamicin in the above regimens with:
rifampicin 600 mg (child: 15 mg/kg up to 600 mg) orally, daily for 6 weeks.
Clinical relapse occurs in up to 10% of cases after a 6-week treatment course. Patients with relapsed infection,
osteoarticular disease, neurobrucellosis or endocarditis need a longer duration of therapy and may require
alternative combination regimens—seek expert advice.
Note 1: If the patient is obese (for adults, body mass index 30 kg/m2 or more), use adjusted body weight (see Box 2.46) to calculate the dose.
Note 2: If the child is obese, use adjusted body weight (see Box 2.46) to calculate the dose.
Key references
Hasanain A, Mahdy R, Mohamed A, Ali M. A randomized, comparative study of dual therapy (doxycycline-rifampin)
versus triple therapy (doxycycline-rifampin-levofloxacin) for treating acute/subacute brucellosis. Braz J Infect Dis
2016;20(3):250–4.
Sofian M, Velayati AA, Aghakhani A, McFarland W, Farazi AA, Banifazl M, et al. Comparison of two durations of triple-
drug therapy in patients with uncomplicated brucellosis: A randomized controlled trial. Scand J Infect Dis
2014;46(8):573–7.
Vrioni G, Bourdakis A, Pappas G, Pitiriga V, Mavrouli M, Pournaras S, et al. Administration of a triple versus a
standard double antimicrobial regimen for human brucellosis more efficiently eliminates bacterial DNA load. Antimicrob
Agents Chemother 2014;58(12):7541–4.
Principles of managing infective endocarditis
Assessment of infective endocarditis
The diagnosis of infective endocarditis should be made using the modified Duke diagnostic criteria [Note 1].
Take three sets of blood for culture (from separate venepuncture sites) in patients with suspected infective
endocarditis before starting antibiotic therapy. This should be possible even in sepsis and septic shock, when
prompt empirical use of antimicrobials is essential. When three sets of blood samples are taken for culture
before antibiotic administration, the pathogen is identified in about 90% of cases.
Perform an echocardiogram for patients with suspected infective endocarditis. Transoesophageal

echocardiogram (TOE) is significantly more sensitive in the diagnosis of infective endocarditis than
transthoracic echocardiogram (TTE), particularly for prosthetic valve and cardiac implantable electronic
device–associated endocarditis, due to poor visualisation of heart valves and device leads by transthoracic
echocardiogram.
The spread of infection to other organs and the progression of cardiac infection are common, and should be
particularly considered in patients who fail to improve or deteriorate on antibiotic therapy.
Note 1: Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis
2000;30:633-8. [URL]
Approach to managing infective endocarditis

Management of infective endocarditis requires a collaborative, multidisciplinary approach.
Ideally, infective endocarditis should be managed by a dedicated endocarditis team; an endocarditis team
dramatically reduces infective endocarditis mortality.
At a minimum, this team should include the following members with expertise in infective endocarditis
management:
an infectious diseases physician or clinical microbiologist

a cardiologist
a cardiac surgeon.
Involvement of other specialities including neurology, neurosurgery and radiology may be required,
depending on the individual case.
If an endocarditis team is not available, consult with a cardiologist and an infectious diseases physician or
clinical microbiologist as soon as infective endocarditis is suspected. Determining if early surgical
intervention is required is critical to the management of infective endocarditis; early consultation with a
cardiac surgeon is advised. However, patients with the following features should be discussed with an
endocarditis team to determine whether early patient transfer to a centre with an endocarditis team is required:
prosthetic valves or cardiac implantable electronic devices

severe valvular regurgitation
symptoms or signs of heart failure
mobile vegetations larger than 10 mm
recurrent embolism
extravalvular complications (eg abscess, fistulas, heart block)
acute kidney injury
septic shock
requirement for intensive care support
neurological complications (including stroke)
endocarditis caused by organisms that are virulent or difficult to manage (eg staphylococcal
endocarditis, endocarditis caused by other organisms and culture-negative endocarditis)
persistent infection (positive blood culture results or fever for longer than 7 days).
Patients who have had an episode of infective endocarditis are at risk of further episodes; see Prevention of
infective endocarditis for further advice.
Principles of antimicrobial therapy for infective endocarditis

General approach
Antimicrobials for infective endocarditis must be given intravenously to ensure adequate drug concentrations,
except in rare cases (eg infective endocarditis caused by Coxiella burnetii).
Beta lactams frequently form the basis of treatment for infective endocarditis. When beta-lactam antibiotics
are recommended as first-line therapy, using vancomycin instead is often less effective and associated with the
selection of antimicrobial resistance and an increased risk of toxicity. If hypersensitivity to penicillins is
reported, assess whether the patient has immune-mediated hypersensitivity (see Types of antimicrobial
hypersensitivity). For patients with immediate hypersensitivity to penicillins, strongly consider
desensitisation to enable the use of beta lactams.
Avoid clindamycin or lincomycin because rates of treatment failure with these drugs are unacceptably high for
all types of infective endocarditis.
Particular attention should be given to therapeutic drug monitoring in endocarditis. Recommended dosages
are for initial treatment only and may need to be modified according to the plasma concentrations attained (see
Monitoring antimicrobial blood concentrations).
Treatment of infective endocarditis usually involves 4 to 6 weeks of intravenous therapy. The duration of
therapy may be altered by valve surgery (see Duration of therapy after valve surgery for endocarditis). Once
medically stable (usually after at least 2 weeks of inpatient treatment), some patients are suitable for
Community-based parenteral antimicrobial therapy for endocarditis. Following initial intravenous therapy, a
switch to combination oral antibiotic therapy may be appropriate for patients that are carefully selected and
managed by an endocarditis team who have expertise in antimicrobial pharmacokinetics.
Gentamicin for the treatment of infective endocarditis

Gentamicin given once daily is recommended as part of the empirical therapy regimen for native valve,
prosthetic valve and cardiac implantable electronic device–associated endocarditis to cover the possibility of
Gram-negative sepsis. This is an initial regimen pending the results of blood culture.
For confirmed streptococcal or enterococcal endocarditis, gentamicin is often continued for several weeks for
synergistic therapy. For these types of endocarditis, these guidelines continue to recommend multiple-daily
dosing of gentamicin.
Some international consensus-based guidelines recommend once-daily dosing of gentamicin for streptococcal
and enterococcal endocarditis because of ease of administration and lower rates of nephrotoxicity compared
with multiple-daily dosing. This recommendation is based on animal studies and small observational studies.
It is the consensus view of the Antibiotic Expert Groups that there is insufficient evidence to support routine
once-daily dosing of gentamicin for the treatment of streptococcal or enterococcal endocarditis. However,
once-daily gentamicin dosing (3 mg/kg) may have a role for patients receiving community-based parenteral
antimicrobial therapy, particularly for patients with streptococcal endocarditis.
Monitor the gentamicin plasma concentration and regularly assess for nephrotoxicity as well as vestibular and
auditory toxicity if gentamicin therapy is planned for longer than 48 hours—see Principles of aminoglycoside
use.
The combination of gentamicin with vancomycin is recommended for synergistic therapy for various types of
infective endocarditis. Combining an aminoglycoside with vancomycin increases the risk of nephrotoxicity
compared to using either drug alone; this risk must be considered on a case-by-case basis. For patients with
immediate hypersensitivity to penicillins, desensitisation is recommended rather than using a prolonged
course of vancomycin.
Duration of therapy after valve surgery for infective endocarditis

A sample of valve tissue should be taken for culture at the time of valve surgery for endocarditis.
If the results of valve culture are negative, give postoperative antibiotics to complete the recommended
duration of therapy for the type of endocarditis, or for at least a further 2 weeks, whichever is longer.
If the results of valve culture are positive, give postoperative antibiotic treatment for 4 to 6 weeks.
A longer treatment course is required if there is evidence of extracardiac infection—seek expert advice.
Community-based parenteral antimicrobial therapy for infective endocarditis

After initial inpatient therapy (usually for at least 1 to 2 weeks or until the patient is medically stable), transfer
to an established community-based parenteral antimicrobial therapy program is appropriate for selected
patients with endocarditis who meet all of the following criteria:
medically stable and responding to therapy

no medical contraindications for community-based parenteral antimicrobial therapy
afebrile for at least 72 hours with negative blood culture results
no evidence of heart failure, or if heart failure present, it is stable and controlled with medical therapy
small vegetations (eg less than 10 mm) and no intracardiac abscess or paravalvular extension on
transoesophageal echocardiography (TOE)
no new cardiac conduction abnormalities
no neurological findings that could result from cerebral embolism or infected (mycotic) aneurysm
no uncontrolled extracardiac infection
continued supervision by a cardiologist and an infectious diseases physician or clinical microbiologist.
Particular care must be taken in patients with a form of endocarditis that often requires cardiac surgery (eg
prosthetic valve endocarditis) or infection caused by virulent organisms such as Staphylococcus aureus, which
has a high rate of complications and mortality.
Warn patients to seek medical attention if they develop symptoms of heart failure. Patients should be reviewed
regularly (at least weekly) by an experienced clinician for symptoms and signs of heart failure.
For further information, see Community-based parenteral antimicrobial therapy.
Key references
Assessment of infective endocarditis
Hoen B, Duval X. Clinical practice. Infective endocarditis. N Engl J Med 2013;368(15):1425–33.
Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective
endocarditis. Clin Infect Dis 2000;30:633–8.
Wang A, Gaca JG, Chu VH. Management considerations in infective endocarditis: a Review. JAMA
2018;320(1):72–83.
Approach to managing infective endocarditis
Baddour LM, Wilson WR, Bayer AS, Fowler VG, Jr., Tleyjeh IM, Rybak MJ, et al. Infective endocarditis in adults:
diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare
professionals from the American Heart Association. Circulation 2015;132(15):1435–86.
Bannay A, Hoen B, Duval X, Obadia JF, Selton-Suty C, Le Moing V, Tattevin P, Iung B, Delahaye F, Alla F, et al.
The impact of valve surgery on short- and long-term mortality in left-sided infective endocarditis: do differences in
methodological approaches explain previous conflicting results?. Eur Heart J 2011;32(16):2003–2015 .
Botelho-Nevers E, Thuny F, Casalta JP, Richet H, Gouriet F, Collart F, et al. Dramatic reduction in infective
endocarditis-related mortality with a management-based approach. Arch Intern Med 2009;169(14):1290–8.
Cahill TJ, Baddour LM, Habib G, Hoen B, Salaun E, Pettersson GB, et al. Challenges in infective endocarditis. J
Am Coll Cardiol 2017;69(3):325–44.
Carrasco-Chinchilla F, Sánchez-Espín G, Ruiz-Morales J, Rodríguez-Bailón I, Melero-Tejedor JM, Ivanova-

Georgieva R, et al. Influence of a multidisciplinary alert strategy on mortality due to left-sided infective
endocarditis. Revista Española de Cardiología (English Edition) 2014;67(05):380–6.
http://www.revespcardiol.org/en/influencia-una-estrategia-alerta-multidisciplinaria/articulo/90302497/
Chambers J, Sandoe J, Ray S, Prendergast B, Taggart D, Westaby S, et al. The infective endocarditis team:
recommendations from an international working group. Heart 2014;100(7):524–7.
Chirillo F, Scotton P, Rocco F, Rigoli R, Borsatto F, Pedrocco A, et al. Impact of a multidisciplinary management
strategy on the outcome of patients with native valve infective endocarditis. Am J Cardiol 2013;112(8):1171–6.
Chirillo F, Scotton P, Rocco F, Rigoli R, Pedrocco A, Martire P, et al. Management strategies and outcome for
prosthetic valve endocarditis. Am J Cardiol 2013;112(8):1177–81.
Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Del Zotti F, et al. 2015 ESC Guidelines for the
management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the
European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery
(EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015;36(44):3075–128.
Kiefer T, Park L, Tribouilloy C, Cortes C, Casillo R, Chu V, et al. Association between valvular surgery and
mortality among patients with infective endocarditis complicated by heart failure. JAMA 2011;306(20):2239–47.
Lalani T, Cabell CH, Benjamin DK, Lasca O, Naber C, Fowler VG, Jr., et al. Analysis of the impact of early
surgery on in-hospital mortality of native valve endocarditis: use of propensity score and instrumental variable
methods to adjust for treatment-selection bias. Circulation 2010;121(8):1005–13.
Mestres CA, Pare JC, Miro JM. Organization and functioning of a multidisciplinary team for the diagnosis and
treatment of infective endocarditis: A 30-year Perspective (1985-2014). Rev Esp Cardiol (Engl Ed)
2015;68(5):363–8.
Oliver L, Lavoute C, Giorgi R, Salaun E, Hubert S, Casalta JP, Gouriet F, Renard S, Saby L, Avierinos JF, Maysou
LA, Riberi A, Grisoli D, Casalta AC, Collart F, Raoult D, Habib G, et al. Infective endocarditis in octogenarians.
Heart 2017;103(20):1602–1609. .
Park LP, Chu VH, Peterson G, Skoutelis A, Lejko-Zupa T, Bouza E, et al. Validated risk score for predicting 6-
month mortality in infective endocarditis. J Am Heart Assoc 2016;5(4):e003016.
Wang A, Gaca JG, Chu VH. Management considerations in infective endocarditis: A Review. JAMA
2018;320(1):72–83.
Principles of antimicrobial therapy for infective endocarditis
diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare
professionals from the American Heart Association. Circulation 2015;132(15):1435–86.
Elyasi S, Khalili H, Dashti-Khavidaki S, Mohammadpour A. Vancomycin-induced nephrotoxicity: mechanism,

incidence, risk factors and special populations. A literature review. Eur J Clin Pharmacol 2012;68(9):1243–55.
Goetz MB, Sayers J. Nephrotoxicity of vancomycin and aminoglycoside therapy separately and in combination. J
Heldman AW, Hartert TV, Ray SC, Daoud EG, Kowalski TE, Pompili VJ, et al. Oral antibiotic treatment of right-
sided staphylococcal endocarditis in injection drug users: prospective randomized comparison with parenteral
therapy. Am J Med 1996;101(1):68–76.
Iversen K, Ihlemann N, Gill SU, Madsen T, Elming H, Jensen KT, et al. Partial oral versus intravenous antibiotic
treatment of endocarditis. N Engl J Med 2018;[epub]:doi: 10.1056/NEJMoa1808312.
Rybak MJ, Abate BJ, Kang SL, Ruffing MJ, Lerner SA, Drusano GL. Prospective evaluation of the effect of an
aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother
1999;43(7):1549–55.
Turnidge J, Coombs G, Daley D, Nimmo C, Australian Group on Antimicrobial Resistance (AGAR) participants
2000-14. MRSA: A tale of three types. 15 years of survey data from AGAR. Sydney: Australian Commission on
Safety and Quality in Health Care; 2016. https://www.safetyandquality.gov.au/antimicrobial-use-and-resistance-in-
australia/resources-page/
Empirical therapy for infective endocarditis
Empirical therapy for native valve infective endocarditis
Organisms that commonly cause native valve infective endocarditis include Staphylococcus aureus, viridans
streptococci, coagulase-negative staphylococci, enterococci, Streptococcus bovis group (now classified as
Streptococcus gallolyticus or Streptococcus infantarius) and the HACEK group of oral Gram-negative bacilli.
Other Gram-negative bacteria and fungi are less common causes. Blood culture–negative endocarditis is generally
due to prior antibiotic therapy, but consider unusual pathogens as alternative causes (see Culture-negative
endocarditis).
For information on assessment and management of infective endocarditis (including principles of antimicrobial
therapy), see Principles of managing infective endocarditis.
Patients with infective endocarditis may have sepsis or septic shock (see Early recognition of sepsis or septic
shock in adults or Early recognition of sepsis or septic shock in neonates, infants and children for definitions). For
patients with sepsis or septic shock, start antibiotic therapy within 1 hour of presentation to medical care or, for
ward-based patients, development of sepsis or septic shock, immediately after appropriate samples are taken for
culture. For nonantibiotic management of sepsis or septic shock, see Early intervention for sepsis or septic shock.
For empirical treatment of native valve endocarditis, after taking three sets of blood for culture (from separate
venipuncture sites), as a three-drug regimen, use:
benzylpenicillin 1.8 g (child: 50 mg/kg up to 1.8 g) intravenously, 4-hourly
PLUS
flucloxacillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 4-hourly
PLUS

child younger than 10 years: 7.5 mg/kg up to 320 mg, for the first dose. See Principles of
child 10 years or older with septic shock or requiring intensive care support: 7 mg/kg, for
the first dose. See Principles of aminoglycoside use for subsequent dosing [Note 6]
child 10 years or older without septic shock and not requiring intensive care support: 6
mg/kg up to 560 mg, for the first dose. See Principles of aminoglycoside use for
subsequent dosing [Note 6].
Flucloxacillin is more effective than vancomycin for methicillin-susceptible strains of Staphylococcus aureus
(MSSA). If methicillin-resistant S. aureus (MRSA) endocarditis is suspected (eg people who inject drugs, people
at increased risk of MRSA infection [see Box 2.31]) or for patients with sepsis or septic shock, replace
benzylpenicillin in the above regimen with vancomycin. Use:
vancomycin (adult and child) 25 to 30 mg/kg intravenously, as a loading dose; see

Principles of vancomycin use for subsequent dosing and principles of use.
If gentamicin is contraindicated (see Box 2.42), seek expert advice.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, as a three-drug
regimen, use:
cefazolin 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly; for adults with septic

shock or requiring intensive care support, use 6-hourly dosing
PLUS

Principles of vancomycin use for subsequent dosing and principles of use
PLUS

For patients with immediate severe hypersensitivity to penicillins, the above cephalosporin-containing regimen
can be considered in a critical situation, after undertaking a risk–benefit analysis and assessment of potential side-
chain cross-reactivity (see Cross-reactivity between beta lactams). Seek expert advice. If cefazolin is not suitable,
or for patients with delayed severe hypersensitivity to penicillins, use gentamicin plus vancomycin (dosages as
above).
Modify therapy based on the results of culture and susceptibility testing. Ideally, establish the minimum inhibitory
concentration (MIC) of the chosen antimicrobial once the pathogen has been identified.
Stop gentamicin when susceptibilities are known, except for streptococcal endocarditis or enterococcal
endocarditis, when it may be necessary to continue low-dose gentamicin for several weeks for synergistic therapy
—see also Gentamicin for the treatment of infective endocarditis.
Note 1: Consider monitoring from the first dose; see also Gentamicin for the treatment of infective endocarditis.
calculate the dose.
function.
Note 4: For patients with sepsis, prompt antibiotic initiation is essential, so do not delay gentamicin
administration to ascertain kidney function.
Note 5: The dose cap does not apply to children with septic shock or requiring intensive care support.
Empirical therapy for prosthetic valve and cardiac implantable

electronic device–associated infective endocarditis
Organisms that can cause prosthetic valve infective endocarditis include staphylococci (Staphylococcus aureus and
coagulase-negative staphylococci), Corynebacterium species, Streptococcus species, enterococci,
Enterobacteriaceae, Pseudomonas aeruginosa, Candida albicans and other fungi.
Endocarditis associated with cardiac implantable electronic devices (CIEDs) (including pacemakers) is most
commonly caused by staphylococci (S. aureus and coagulase-negative staphylococci). Other pathogens include
Gram-negative bacteria.
For information on assessment and management of infective endocarditis (including principles of antimicrobial
therapy), see Principles of managing infective endocarditis.
Cardiac surgery is often required. Early consultation with a cardiac surgeon (or a specialist in cardiac implantable
electronic devices) and an infectious diseases physician or clinical microbiologist is essential (see Approach to
managing infective endocarditis).
Patients with infective endocarditis may have sepsis or septic shock (see Early recognition of sepsis or septic
shock in adults or Early recognition of sepsis or septic shock in neonates, infants and children for definitions). For
patients with sepsis or septic shock, start antibiotic therapy within 1 hour of presentation to medical care or, for
ward-based patients, development of sepsis or septic shock, immediately after appropriate samples are taken for
For empirical treatment of prosthetic valve and cardiac implantable electronic device–associated endocarditis, after
taking three sets of blood for culture from separate venipuncture sites, as a three-drug regimen, use:
PLUS

PLUS

If gentamicin is contraindicated (see Box 2.42), seek expert advice.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, replace
flucloxacillin in the above regimen with:

shock or requiring intensive care support, use 6-hourly dosing.
chain cross-reactivity (see Cross-reactivity between beta lactams). Seek expert advice. If cefazolin is not suitable,
or for patients with delayed severe hypersensitivity to penicillins, use gentamicin plus vancomycin (dosages as
above).
Modify therapy based on the results of culture and susceptibility testing. Ideally, establish the minimum inhibitory
concentration (MIC) of the chosen antimicrobial once the pathogen has been identified.
Stop gentamicin when susceptibilities are known, except for streptococcal endocarditis or enterococcal
endocarditis, when it may be necessary to continue low-dose gentamicin for several weeks for synergistic therapy
—see also Gentamicin for the treatment of infective endocarditis.
Note 7: Consider monitoring from the first dose; see also Gentamicin for the treatment of infective endocarditis.
calculate the dose.
function.
Key references
Ambrosioni J, Hernandez-Meneses M, Tellez A, Pericas J, Falces C, Tolosana JM, et al. The changing epidemiology
of infective endocarditis in the twenty-first century. Curr Infect Dis Rep 2017;19(5):21.
diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals
from the American Heart Association. Circulation 2015;132(15):1435–86.
Baltimore RS, Gewitz M, Baddour LM, Beerman LB, Jackson MA, Lockhart PB, et al. Infective endocarditis in
childhood: 2015 update: a scientific statement from the American Heart Association. Circulation 2015;132(15):1487–
515.
Cahill TJ, Baddour LM, Habib G, Hoen B, Salaun E, Pettersson GB, et al. Challenges in infective endocarditis. J Am
Coll Cardiol 2017;69(3):325–44.
Fukunaga M, Goya M, Nagashima M, Hiroshima K, Yamada T, An Y, et al. Identification of causative organism in

cardiac implantable electronic device infections. J Cardiol 2017;70(5):411–15. .
management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European
Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European
Association of Nuclear Medicine (EANM). Eur Heart J 2015;36(44):3075–128.
Li J, Echevarria KL, Traugott KA. Beta-lactam therapy for methicillin-susceptible Staphylococcus aureus bacteremia: a
comparative review of cefazolin versus antistaphylococcal penicillins. Pharmacotherapy 2017;37(3):346–60.
Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the Infectious
Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and
children. Clin Infect Dis 2011;52(3):e18–55.
Marti-Carvajal AJ, Dayer M, Conterno LO, Gonzalez Garay AG, Marti-Amarista CE, Simancas-Racines D. A
comparison of different antibiotic regimens for the treatment of infective endocarditis. Cochrane Database Syst Rev
2016;4:CD009880.
Sandoe JA, Barlow G, Chambers JB, Gammage M, Guleri A, Howard P, et al. Guidelines for the diagnosis, prevention
and management of implantable cardiac electronic device infection. Report of a joint Working Party project on behalf of
the British Society for Antimicrobial Chemotherapy (BSAC, host organization), British Heart Rhythm Society (BHRS),
British Cardiovascular Society (BCS), British Heart Valve Society (BHVS) and British Society for Echocardiography
(BSE). J Antimicrob Chemother 2015;70(2):325–59.
Turnidge J, Coombs G, Daley D, Nimmo C, Australian Group on Antimicrobial Resistance (AGAR) participants 2000-
14. MRSA: A tale of three types. 15 years of survey data from AGAR. Sydney: Australian Commission on Safety and
Quality in Health Care; 2016. https://www.safetyandquality.gov.au/antimicrobial-use-and-resistance-in-
Vogkou CT, Vlachogiannis NI, Palaiodimos L, Kousoulis AA. The causative agents in infective endocarditis: a
systematic review comprising 33,214 cases. Eur J Clin Microbiol Infect Dis 2016;35(8):1227–45.
Published April 2019. Amended December 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Directed therapy for infective endocarditis
Staphylococcal endocarditis
Approach to managing staphylococcal endocarditis
Staphylococcus aureus is the most common cause of native and prosthetic valve infective endocarditis in
developed countries. Endocarditis caused by S. aureus often has a more aggressive course compared with other
common causes of endocarditis. It is associated with increased rates of embolism and stroke, a prolonged duration
of bacteraemia and a higher mortality (particularly in prosthetic valve endocarditis).
Coagulase-negative staphylococci are an important cause of prosthetic valve endocarditis, particularly in the first
year after insertion of the valve. Coagulase-negative staphylococci are becoming a more common cause of native
valve endocarditis. Staphylococcus lugdunensis, a coagulase-negative staphylococci, has similar pathogenicity to
S. aureus and requires similar management.
Management of staphylococcal endocarditis should involve a multidisciplinary team-based approach; see

Approach to managing infective endocarditis. Close monitoring is essential, including repeat blood culture to
confirm clearance of bacteraemia—see also Assessing and monitoring patients with Staphylococcus
aureus bacteraemia.
The choice of antibiotic therapy for staphylococcal endocarditis depends on whether the pathogen is methicillin-
susceptible or -resistant, not whether it is a coagulase-negative staphylococcus or S. aureus. Coagulase-negative
staphylococci are often methicillin-resistant.
Do not use clindamycin or lincomycin for staphylococcal endocarditis because rates of treatment failure with these
drugs are unacceptably high.
For principles of antimicrobial therapy for infective endocarditis (including duration of therapy following valve
surgery and considerations for community-based parenteral antimicrobial therapy), see Principles of antimicrobial
therapy for infective endocarditis.
Native valve endocarditis caused by methicillin-susceptible staphylococci
Antibiotic regimens
When used to treat methicillin-susceptible S. aureus, including penicillin-susceptible S. aureus, beta-lactam

antibiotics are associated with improved outcomes, including mortality, compared with other antibiotics, such as
vancomycin.
For native valve endocarditis caused by methicillin-susceptible staphylococci, use:
flucloxacillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 4-hourly for 4 to 6 weeks; see

Duration of therapy.
Some strains of S. aureus in Australia are penicillin-susceptible. If penicillin susceptibility is confirmed by a

clinical microbiologist, consider using benzylpenicillin—seek expert advice.
Do not add gentamicin to the treatment regimen for native valve staphylococcal endocarditis because it does not
improve outcomes.
Assess patients reporting hypersensitivity to penicillins for immune-mediated hypersensitivity (see Types of
antimicrobial hypersensitivity). Management depends on the type of hypersensitivity and whether spread of
infection to the central nervous system is suspected.
cefazolin 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly for 4 to 6 weeks; see

Duration of therapy; for adults with septic shock or requiring intensive care support, use 6-
hourly dosing.
Cefazolin does not reliably penetrate the blood–brain barrier; if spread of infection to the central nervous system is
suspected, add vancomycin (see below) to cefazolin.
For patients with immediate severe hypersensitivity to penicillins, perform desensitisation if possible—seek
expert advice. Use vancomycin (see below) until the patient has been desensitised or if desensitisation is not
possible.
For patients with delayed severe hypersensitivity to penicillins, use:
vancomycin intravenously for 4 to 6 weeks; see Duration of therapy. See Principles of

vancomycin use for dosage and principles of use.
Duration of therapy
For patients with uncomplicated native valve endocarditis caused by methicillin-susceptible staphylococci, 4
weeks of antibiotic therapy is often adequate. For patients with complicated infections (eg perivalvular abscess,
septic metastatic complications), use 6 weeks of therapy.
Patients with right-sided (tricuspid valve) methicillin-susceptible staphylococcal endocarditis (usually people who
inject drugs) can be treated with a short course (2 weeks) of flucloxacillin if all the following criteria are met:
no associated prosthetic valve or left-sided valve infection

no metastatic infection, such as osteomyelitis, lung abscess or empyema
no cardiac or extracardiac complications
no right-sided heart failure or acute respiratory failure
vegetation smaller than 20 mm
clinical and microbiological response within 72 to 96 hours of starting therapy
no severe immune compromise.
Native valve endocarditis caused by methicillin-resistant staphylococci

For native valve endocarditis caused by methicillin-resistant staphylococci, use:
vancomycin intravenously for 6 weeks; see Principles of vancomycin use for dosage and
principles of use.
For patients who do not respond to therapy and are unable to have surgery, combination therapy may be necessary
—seek expert advice.
Do not add gentamicin to the treatment regimen for native valve staphylococcal endocarditis because it does not
improve outcomes.
Experience in the treatment of endocarditis caused by S. aureus with intermediate susceptibility to vancomycin
(vancomycin-intermediate S. aureus [VISA]) or high-level resistance to vancomycin (vancomycin-resistant S.
aureus [VRSA]) is limited. Treatment options include daptomycin or linezolid—seek expert advice.
Prosthetic valve endocarditis caused by methicillin-susceptible staphylococci
The management of prosthetic valve staphylococcal endocarditis is complex—consult an endocarditis team in all
cases; see Approach to managing infective endocarditis.
When used to treat methicillin-susceptible S. aureus, including penicillin-susceptible S. aureus, beta-lactam

antibiotics are associated with improved outcomes, including mortality, compared with other antibiotics, such as
vancomycin.
For prosthetic valve endocarditis caused by methicillin-susceptible staphylococci, use:
flucloxacillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 4-hourly for 6 weeks.
Some strains of S. aureus in Australia are penicillin-susceptible. If penicillin susceptibility is confirmed by a

clinical microbiologist, consider using benzylpenicillin—seek expert advice.
Evidence to guide antibiotic therapy for prosthetic valve staphylococcal endocarditis is poor. Because this infection
is associated with a high rate of mortality, some international consensus-based guidelines suggest adding
gentamicin and rifampicin to flucloxacillin (based on experimental endocarditis models and limited clinical
experience). However, combination therapy is associated with significant toxicity, antimicrobial resistance and
drug interactions; seek expert advice.
antimicrobial hypersensitivity). Management depends on the type of hypersensitivity and whether spread of
infection to the central nervous system is suspected.
cefazolin 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly for 6 weeks; for adults

with septic shock or requiring intensive care support, use 6-hourly dosing.
Cefazolin does not reliably penetrate the blood–brain barrier; if spread of infection to the central nervous system is
suspected, add vancomycin (see below) to cefazolin.
For patients with immediate severe hypersensitivity to penicillins, perform desensitisation if possible—seek
possible.
principles of use.
Prosthetic valve endocarditis caused by methicillin-resistant staphylococci
The management of prosthetic valve staphylococcal endocarditis is complex—consult an endocarditis team in all
cases—see Approach to managing infective endocarditis.
For prosthetic valve endocarditis caused by methicillin-resistant staphylococci, use:
principles of use.
Evidence to guide antibiotic therapy for prosthetic valve staphylococcal endocarditis is poor. Because this infection
is associated with a high rate of mortality, some international consensus-based guidelines suggest adding
gentamicin and rifampicin to vancomycin (based on experimental endocarditis models and limited clinical
experience). However, combination therapy is associated with significant toxicity, antimicrobial resistance and
drug interactions; seek expert advice.
Experience in the treatment of endocarditis caused by S. aureus with intermediate susceptibility to vancomycin
(vancomycin-intermediate S. aureus [VISA]) or high-level resistance to vancomycin (vancomycin-resistant S.
aureus [VRSA]) is limited. Treatment options include daptomycin or linezolid—seek expert advice.
Streptococcal endocarditis
Approach to managing streptococcal endocarditis
Streptococci are the second most common cause of infective endocarditis. Endocarditis caused by viridans
streptococci and Streptococcus bovis group (now classified as Streptococcus gallolyticus or Streptococcus
infantarius) is usually susceptible to penicillin, but up to 20% of viridans streptococci may have resistance or
intermediate susceptibility to penicillin. Therefore, the minimum inhibitory concentration (MIC) for penicillin
must be obtained to guide therapy.
Patients with endocarditis secondary to S. bovis group should be investigated for a concurrent bowel neoplasm.
Endocarditis caused by other non-viridans streptococci is rare—seek expert advice.
Management of infective endocarditis should involve a multidisciplinary team-based approach; see Approach to
managing infective endocarditis.
Treatment of streptococcal endocarditis may require weeks of gentamicin therapy. Monitor the gentamicin plasma
concentration and regularly assess for nephrotoxicity as well as vestibular and auditory toxicity—see Gentamicin
for the treatment of infective endocarditis. Although multiple-daily dosing of gentamicin is recommended for the
treatment of streptococcal endocarditis, once-daily dosing (3 mg/kg) may be appropriate for patients receiving
community-based parenteral antimicrobial therapy.
Treatment of streptococcal endocarditis with benzylpenicillin involves multiple-daily intermittent doses. To avoid
multiple-daily doses, benzylpenicillin can also be given as a 24-hour continuous infusion (using the buffered
solution; see Table 2.70). The recommended dose for 24-hour continuous infusion is the sum of intermittent doses
given over 24 hours.
Treatment recommendations for endocarditis caused by viridans streptococci and S. bovis group are given below:
Endocarditis caused by viridans streptococci and S. bovis group with penicillin MIC 0.125 mg/L or lower
Native valve endocarditis
Prosthetic valve endocarditis
Endocarditis caused by viridans streptococci and S. bovis group with penicillin MIC more than 0.125 mg/L
and up to 0.5 mg/L
Endocarditis caused by viridans streptococci and S. bovis group with penicillin MIC more than 0.5 mg/L and
up to 2 mg/L
Endocarditis caused by viridans streptococci and S. bovis group resistant to penicillin (MIC more than 2
mg/L).
Endocarditis caused by viridans streptococci and S. bovis group with penicillin MIC 0.125
mg/L or lower
Native valve endocarditis is considered uncomplicated if there is rapid response to treatment, and no large
vegetation or extracardiac infection.
For adults with uncomplicated native valve endocarditis caused by viridans streptococci or S. bovis group with
penicillin 0.125 mg/L or lower, use:
benzylpenicillin 1.8 g intravenously, 4-hourly for 2 weeks
PLUS
gentamicin 1 mg/kg intravenously, 8-hourly for 2 weeks (monitor plasma concentration;

see Principles of aminoglycoside use) [Note 1].
Alternatively, as a single-drug regimen for adults, use:
1 benzylpenicillin 1.8 g intravenously, 4-hourly for 4 weeks
OR
2 ceftriaxone 2 g intravenously, daily for 4 weeks; for adults with septic shock or requiring
intensive care support, use 1 g intravenously, 12-hourly.
Native valve endocarditis is considered complicated if there is large vegetation or perivalvular abscess, or there
are secondary septic events or multiple emboli.
For adults with complicated native valve endocarditis, use either of the single-drug regimens above for 4 weeks.
For children with uncomplicated or complicated native valve endocarditis caused by viridans streptococci or S.
bovis group with penicillin MIC 0.125 mg/L or lower, use:
benzylpenicillin 50 mg/kg up to 1.8 g intravenously, 4-hourly for 4 weeks.
If hypersensitivity to penicillins is reported, assess whether the patient has immune-mediated hypersensitivity
(see Types of antimicrobial hypersensitivity).
For treatment of streptococcal endocarditis in children with hypersensitivity to penicillins, seek expert advice.
For adults with immediate hypersensitivity to penicillins, consider desensitisation—seek expert advice.
For adults with uncomplicated or complicated native valve endocarditis caused by viridans streptococci or S.
bovis group with penicillin MIC 0.125 mg/L or lower who have immediate nonsevere or delayed nonsevere
hypersensitivity to penicillins, use ceftriaxone as a single drug for 4 weeks (as above).
Alternatively, for adults with uncomplicated native valve endocarditis who have immediate nonsevere or
delayed nonsevere hypersensitivity to penicillins, use:
ceftriaxone 2 g intravenously, daily for 2 weeks; for adults with septic shock or requiring
intensive care support, use 1 g intravenously, 12-hourly
PLUS
gentamicin 1 mg/kg intravenously, 8-hourly for 2 weeks (monitor plasma concentration;

see Principles of aminoglycoside use) [Note 1].
For adults with uncomplicated or complicated native valve endocarditis caused by viridans streptococci or S.
bovis group with penicillin MIC 0.125 mg/L or lower who have immediate severe or delayed severe
principles of use.
When vancomycin is used for streptococcal endocarditis, the minimum duration of vancomycin therapy is 4
weeks. There is no evidence to support a 2-week course of vancomycin given synergistically with gentamicin.
calculate the dose.
For prosthetic valve endocarditis caused by viridans streptococci or S. bovis group with penicillin MIC 0.125 mg/L
or lower, use:
benzylpenicillin 1.8 g (child: 50 mg/kg up to 1.8 g) intravenously, 4-hourly for 6 weeks
Although the addition of gentamicin has not been shown to improve cure rates, the evidence is limited. For
complicated cases (ie those with large vegetation, perivalvular abscess, multiple emboli, secondary septic events),
consider adding:
gentamicin (adult and child) 1 mg/kg intravenously, 8-hourly for 2 weeks (monitor plasma
concentration; see Principles of aminoglycoside use) [Note 2].
For adults with prosthetic valve endocarditis caused by viridans streptococci or S. bovis group with penicillin MIC
0.125 mg/L or lower who have immediate nonsevere or delayed nonsevere hypersensitivity to penicillins,
replace benzylpenicillin in the above regimen with:
For adults with immediate severe or delayed severe hypersensitivity to penicillins, replace benzylpenicillin in
the above regimen with:
principles of use.
Note 2: If the patient is obese (for adults, body mass index 30 kg/m2 or more), use adjusted body weight (see
Box 2.46) to calculate the dose.
Endocarditis caused by viridans streptococci and S. bovis group with penicillin MIC more
than 0.125 mg/L and up to 0.5 mg/L
For native valve endocarditis caused by viridans streptococci or S. bovis group with penicillin MIC more than
0.125 mg/L and up to 0.5 mg/L, use:
PLUS
For adults with native valve endocarditis caused by viridans streptococci or S. bovis group with penicillin MIC
more than 0.125 mg/L and up to 0.5 mg/L who have immediate nonsevere or delayed nonsevere hypersensitivity
to penicillins, if the isolate is susceptible to ceftriaxone (depending on the MIC—seek expert advice), replace
benzylpenicillin in the above regimen with:
principles of use.
For prosthetic valve endocarditis caused by viridans streptococci or S. bovis group with penicillin MIC more than
0.125 mg/L and up to 0.5 mg/L, use:
PLUS
more than 0.125 mg/L and up to 0.5 mg/L who have immediate nonsevere or delayed nonsevere hypersensitivity
to penicillins, if the isolate is susceptible to ceftriaxone (depending on the MIC—seek expert advice), replace
principles of use.
Endocarditis caused by viridans streptococci and S. bovis group with penicillin MIC more
than 0.5 mg/L and up to 2 mg/L
For native valve endocarditis caused by viridans streptococci or S. bovis group with penicillin MIC more than 0.5
mg/L and up to 2 mg/L, use:
PLUS
Patients with complicated infection may require a 6-week course.
For adults with native valve endocarditis caused by viridans streptococci or S. bovis group with penicillin MIC
more than 0.5 mg/L and up to 2.0 mg/L who have immediate nonsevere or delayed nonsevere hypersensitivity to
penicillins, if the isolate is susceptible to ceftriaxone (depending on the MIC—seek expert advice), replace
principles of use.
For prosthetic valve endocarditis caused by viridans streptococci or S. bovis group with penicillin MIC more than
0.5 mg/L and up to 2 mg/L, use:
PLUS
more than 0.5 mg/L and up to 2.0 mg/L who have immediate nonsevere or delayed nonsevere hypersensitivity to
penicillins, if the isolate is susceptible to ceftriaxone (depending on the MIC—seek expert advice), replace
For adults with immediate severe or delayed severe hypersensitivity to penicillins, replace benzylpenicillin in the
above regimen with:
principles of use.
Endocarditis caused by viridans streptococci and S. bovis group resistant to penicillin

(MIC more than 2 mg/L)
There is no established regimen for native or prosthetic valve endocarditis caused by viridans streptococci or S.
bovis group resistant to penicillin (MIC more than 2 mg/L)—seek expert advice. Data from animal studies and
case reports support the use of:
vancomycin intravenously for 4 to 6 weeks; see Principles of vancomycin use for dosage
and principles of use
PLUS
gentamicin (adult and child) 1 mg/kg intravenously, 8-hourly for 4 to 6 weeks (monitor
plasma concentration; see Principles of aminoglycoside use) [Note 7].
The duration of therapy for patients with prosthetic valve endocarditis is 6 weeks. Depending on clinical
progress, patients with native valve endocarditis may require between 4 and 6 weeks of therapy.
Although evidence is limited, ceftriaxone plus gentamicin may be considered as an alternative to vancomycin plus
gentamicin in patients with viridans streptococci or S. bovis group resistant to penicillin, depending on the
ceftriaxone MIC—seek expert advice.
Enterococcal endocarditis
Approach to managing enterococcal endocarditis
Enterococci are the third most common cause of infective endocarditis. The majority of these cases (at least 90%)
are caused by Enterococcus faecalis. Enterococcus faecium accounts for approximately 5% of cases. Enterococci
are intrinsically more resistant to bactericidal antibiotics than other common causes of infective endocarditis, so
require a synergistic combination of bactericidal antibiotics for a prolonged duration (usually 6 weeks). Therefore,
even if the pathogen is susceptible to penicillin or vancomycin, treat enterococcal endocarditis concomitantly with
gentamicin (unless there is high-level gentamicin resistance, or gentamicin is contraindicated or relevant
precautions preclude its use). Antibiotic resistance in enterococci is an increasing problem—test all enterococcal
isolates for high-level aminoglycoside resistance.
Treatment of enterococcal endocarditis may require weeks of gentamicin therapy. Monitor the gentamicin plasma
concentration and regularly assess for nephrotoxicity as well as vestibular and auditory toxicity—see Gentamicin
for the treatment of infective endocarditis. Patients with enterococcal endocarditis are often older and more
debilitated than patients with other types of endocarditis and may have significant medical comorbidities (eg
chronic kidney disease); the potential harm associated with completing a 4 to 6 week course of gentamicin may
exceed the benefit in these patients. For such patients with enterococcal endocarditis, a shortened (2 week) course
of gentamicin may be appropriate—seek expert advice.
Treatment of enterococcal endocarditis with benzylpenicillin involves multiple-daily intermittent doses of

benzylpenicillin. To avoid multiple-daily doses, benzylpenicillin can also be given as a 24-hour continuous
infusion (using the buffered solution; see Table 2.70). The recommended dose for 24-hour continuous infusion is
the sum of intermittent doses given over 24 hours.
Endocarditis caused by enterococci susceptible to penicillin and gentamicin
For native or prosthetic valve enterococcal endocarditis susceptible to penicillin and gentamicin, as a two-drug
regimen, use:
1 benzylpenicillin 2.4 g (child: 50 mg/kg up to 2.4 g) intravenously, 4-hourly for 4 to 6

weeks
OR
2 amoxicillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 4-hourly for 4 to 6 weeks
OR
2 ampicillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 4-hourly for 4 to 6 weeks
PLUS (with any of the above regimens)
gentamicin (adult and child) 1 mg/kg intravenously, 8-hourly for 4 to 6 weeks (monitor
plasma concentration; see Principles of aminoglycoside use) [Note 8].
For most patients, the duration of therapy is 6 weeks, and cardiac surgery is often required. Patients with
uncomplicated native valve enterococcal endocarditis who respond well to treatment may be treated for 4 weeks.
Treat patients who have prosthetic valve enterococcal endocarditis with 6 weeks of antibiotic therapy.
For patients with E. faecalis endocarditis and relevant contraindications or precautions that preclude the use of
gentamicin (see Box 2.42), use the regimen in Endocarditis caused by enterococci susceptible to penicillin but with
high-level resistance to gentamicin. For patients with other types of enterococcal endocarditis, seek expert advice.
For patients with immediate hypersensitivity to penicillins, perform desensitisation—seek expert advice. Use the
vancomycin-containing regimen below until the patient is desensitised.
For patients with endocarditis caused by enterococci susceptible to penicillin and gentamicin who have immediate
hypersensitivity to penicillins and cannot be desensitised, or delayed hypersensitivity to penicillins, a suitable
regimen is:
principles of use
PLUS
Vancomycin is intrinsically not as effective against enterococci as penicillin; therefore, treatment must be given for
6 weeks. For patients with hypersensitivity to penicillins, if either gentamicin or vancomycin is contraindicated,
seek expert advice.
Endocarditis caused by enterococci susceptible to penicillin but with high-level resistance

to gentamicin
Gentamicin has no role in the treatment of endocarditis caused by enterococci susceptible to penicillin but with
high-level gentamicin resistance. Alternative regimens must be considered and cardiac surgery may be required.
Some strains remain susceptible to streptomycin—seek expert advice [Note 9].
For patients with native or prosthetic valve E. faecalis endocarditis susceptible to penicillin, but with either high-
level aminoglycoside resistance, or relevant contraindications or precautions that preclude the use of gentamicin
(see Box 2.42), as a two-drug regimen, use:
1 amoxicillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 4-hourly for 6 weeks
OR
1 ampicillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 4-hourly for 6 weeks
PLUS (with either of the above drugs)
ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously, 12-hourly for 6

weeks.
This regimen is supported by several observational studies and is based on the in vitro synergistic effect of
amoxicillin and broad-spectrum cephalosporins against E. faecalis. This synergistic effect has not been shown for
other species of enterococci (including E. faecium); for these organisms, use monotherapy with benzylpenicillin
(see dosage in Endocarditis caused by enterococci susceptible to penicillin and gentamicin), amoxicillin or
ampicillin (see dosage above) for penicillin-susceptible isolates and seek expert advice.
For patients with immediate hypersensitivity to penicillins, perform desensitisation—seek expert advice.
For patients with immediate hypersensitivity to penicillins and who cannot be desensitised, or patients with
delayed hypersensitivity to penicillins, seek expert advice.
A switch to benzylpenicillin may be appropriate for continuation therapy for patients receiving community-based
parenteral antimicrobial therapy for infective endocarditis—seek expert advice.
Note 9: Streptomycin is not registered for use in Australia but is available via the Special Access Scheme.
Endocarditis caused by enterococci resistant to penicillin but susceptible to gentamicin

For native or prosthetic valve enterococcal endocarditis resistant to penicillin but susceptible to gentamicin, use:
principles of use
PLUS
Ceftriaxone does not have a role in the treatment of penicillin-resistant enterococcal endocarditis.
Endocarditis caused by enterococci resistant to vancomycin

E. faecalis and E. faecium resistant to vancomycin usually also exhibit penicillin and high-level resistance to
aminoglycosides. Treatment of endocarditis caused by these resistant organisms requires combination regimens
that include antibiotics such as linezolid or daptomycin, often in addition to cardiac surgery—seek expert advice.
Endocarditis caused by the HACEK group

The HACEK group of oral Gram-negative bacilli (Haemophilus parainfluenzae, Aggregatibacter [formerly
Haemophilus or Actinobacillus] species, Cardiobacterium species, Eikenella corrodens, and Kingella species) are
slow to grow in traditional culture media and isolation may require specialised microbiological techniques.
HACEK group organisms cause fewer than 5% of cases of endocarditis, and approximately one-third of these
cases involve prosthetic valves.
Susceptibility testing is difficult in the majority of HACEK group strains because they are fastidious, and many
also produce beta-lactamase enzymes.
Treat native and prosthetic valve endocarditis caused by HACEK group strains that produce beta-lactamase
enzymes or strains for which susceptibility testing is difficult as if they are penicillin-resistant. For these patients,
broad-spectrum cephalosporins are the treatment of choice. Use:
1 ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously, daily for 4 to 6

weeks; for patients with septic shock or requiring intensive care support, use 1 g (child 1
month or older: 50 mg/kg up to 1 g) intravenously, 12-hourly
OR
1 cefotaxime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly for 4 to 6 weeks; for

patients with septic shock or requiring intensive care support, use 2 g (child: 50 mg/kg up
to 2 g) intravenously, 6-hourly.
Treat endocarditis caused by HACEK group strains that are clearly susceptible to penicillin and are beta-lactamase
negative with:
benzylpenicillin 2.4 g (child: 50 mg/kg up to 2.4 g) intravenously, 4-hourly for 4 to 6

weeks.
Duration of therapy for native valve endocarditis is usually 4 weeks. Prosthetic valve endocarditis requires 6
weeks of therapy, and surgery is often required.
For complicated cases of native valve or prosthetic valve endocarditis, gentamicin is sometimes required for
synergy in the first 2 weeks—seek expert advice.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use ceftriaxone or
cefotaxime (as above).
For patients with immediate severe hypersensitivity to penicillins, strongly consider desensitisation—seek expert
advice.
For patients with immediate severe hypersensitivity to penicillins who cannot be desensitised, or patients with
delayed severe hypersensitivity to penicillins, seek expert advice.
For principles of antimicrobial therapy for infective endocarditis (including postoperative duration of therapy
following valve surgery and considerations for community-based parenteral antimicrobial therapy), see Principles
of antimicrobial therapy for infective endocarditis.
Endocarditis caused by Abiotrophia and Granulicatella species

Endocarditis caused by Abiotrophia and Granulicatella species (formerly known as nutritionally variant
streptococci) is often associated with a complicated course. Susceptibility testing can be difficult; seek advice from
a clinical microbiologist or an infectious diseases physician to select the antibiotic regimen—see also Approach to
managing infective endocarditis. A commonly used regimen is:
PLUS
Alternative regimens include ceftriaxone or vancomycin for 6 weeks, combined with an aminoglycoside for at
least the first 2 weeks.
Endocarditis caused by other organisms

Endocarditis caused by organisms other than those covered in these guidelines is uncommon—always seek expert
advice from an endocarditis team; see Approach to managing infective endocarditis.
Endocarditis caused by enteric Gram-negative organisms or Pseudomonas aeruginosa has high mortality and
frequently requires cardiac surgery in combination with prolonged antimicrobial therapy.
Candidal endocarditis predominantly occurs in people who inject drugs, but can also occur in patients with
immune compromise, an intravenous catheter in situ or a prosthetic heart valve. Endocarditis caused by
noncandidal fungi is rare.
Culture-negative endocarditis
Endocarditis with negative culture results is commonly associated with prior antibiotic therapy, but may be caused
by unusual pathogens, such as fastidious Gram-positive cocci, Bartonella species, Coxiella burnetii (Q fever),
Tropheryma whipplei (Whipple disease), Brucella species, fungi or Legionella species. Perform Q fever and
Bartonella (cat-scratch) serology and consider performing Brucella serology in recent immigrants and travellers
from endemic areas (eg Middle East, southern Europe) and in hunters of feral pigs. Mycobacterium chimaera is a
rare cause of culture-negative endocarditis, particularly in the setting of recent cardiac surgery [Note 12]. Seek
expert advice for all cases of culture-negative endocarditis—see Approach to managing infective endocarditis.
Evaluate the patient for alternative, noninfective diagnoses. If microbiological tests remain negative, consider a
neoplastic or autoimmune cause.
If the patient requires cardiac surgery, histopathology and 16S ribosomal RNA sequencing of valve tissue may
provide a diagnosis.
If a pathogen is not identified despite investigation and an infection remains the likely diagnosis, treat empirically
with 4 to 6 weeks of antibiotics. The choice of antibiotics depends on the clinical setting, including whether
antibiotic therapy was given before samples for blood culture were taken, and whether the endocarditis involves
native or prosthetic valves.
Management of Q fever endocarditis is complex and should include consultation with an endocarditis team.
Treatment of Q fever endocarditis requires combined therapy with doxycycline plus hydroxychloroquine, often for
longer than 18 months. For further information on Q fever, see Q fever.
For the management of Bartonella endocarditis, see Bartonella infections.
Note 12: For further information about M. chimaera endocarditis, see Stewardson AJ, Stuart RL, Cheng AC,
Johnson PD. Mycobacterium chimaera and cardiac surgery. Med J Aust 2017;206(3):132-5. [URL]
Key references
Staphylococcal endocarditis
Australian Group on Antimicrobial Resistance (AGAR) Australian Staphylococcal Sepsis Outcome Program (ASSOP)
2017: final report. Murdoch, WA: AGAR; 2018. http://www.agargroup.org/agar-surveys.
Cahill TJ, Baddour LM, Habib G, Hoen B, Salaun E, Pettersson GB, et al. Challenges in infective endocarditis. J Am
Coll Cardiol 2017;69(3):325–44.
Li J, Echevarria KL, Traugott KA. Beta-lactam therapy for methicillin-susceptible Staphylococcus aureus bacteremia: a
comparative review of cefazolin versus antistaphylococcal penicillins. Pharmacotherapy 2017;37(3):346–60.
.
children. Clin Infect Dis 2011;52(3):e18–55.
Paul M, Bishara J, Yahav D, Goldberg E, Neuberger A, Ghanem-Zoubi N, et al. Trimethoprim-sulfamethoxazole versus

vancomycin for severe infections caused by methicillin resistant Staphylococcus aureus: randomised controlled trial.
BMJ 2015;350:h2219.
Ramos-Martinez A, Munoz Serrano A, de Alarcon Gonzalez A, Munoz P, Fernandez-Cruz A, Valerio M, et al.

Gentamicin may have no effect on mortality of staphylococcal prosthetic valve endocarditis. J Infect Chemother
2018;24(7):555–62.
Saeed K, Bal A, Gould IM, David MZ, Dryden M, Giannitsioti E, et al. An update on Staphylococcus aureus infective
endocarditis from the International Society of Antimicrobial Chemotherapy (ISAC). Int J Antimicrob Agents
2019;53(1):9–15. .
Tong SY, Davis JS, Eichenberger E, Holland TL, Fowler VG, Jr. Staphylococcus aureus infections: epidemiology,
pathophysiology, clinical manifestations, and management. Clin Microbiol Rev 2015;28(3):603–61.
Streptococcal endocarditis
Baltimore RS, Gewitz M, Baddour LM, Beerman LB, Jackson MA, Lockhart PB, et al. Infective endocarditis in
childhood: 2015 update: a scientific statement from the American Heart Association. Circulation 2015;132(15):1487–
515.
Gould FK, Denning DW, Elliott TS, Foweraker J, Perry JD, Prendergast BD, et al. Guidelines for the diagnosis and
antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial
Chemotherapy. J Antimicrob Chemother 2012;67(2):269–89.
McDougall DA, McWhinney BC. Stability of buffered benzylpenicillin solutions for outpatient parenteral antimicrobial
therapy. Journal of Pharmacy Practice and Research 2014;44(1):26–
8. https://onlinelibrary.wiley.com/doi/abs/10.1002/j.2055-2335.2014.tb00012.x.
Olmos C, Vilacosta I, Sarria C, Lopez J, Ferrera C, Saez C, et al. Streptococcus bovis endocarditis: update from a
multicenter registry. Am Heart J 2016;171(1):7–13.
Sandoe JA, Patel PA, Baig MW, West R. What is the effect of penicillin dosing interval on outcomes in streptococcal
infective endocarditis? J Antimicrob Chemother 2013;68(11):2660–3.
Vella-Brincat JW, Begg EJ, Gallagher K, Kirkpatrick CM, Zhang M, Frampton C, et al. Stability of benzylpenicillin
during continuous home intravenous therapy. J Antimicrob Chemother 2004;53(4):675–7.
Enterococcal endocarditis
from the American Heart Association. Circulation 2015;132(15):1435-86.
Beganovic M, Luther MK, Rice LB, Arias CA, Rybak MJ, LaPlante KL. A review of combination antimicrobial therapy
for Enterococcus faecalis bloodstream infections and infective endocarditis. Clin Infect Dis 2018;67(2):303–9.
Chirouze C, Athan E, Alla F, Chu VH, Ralph Corey G, Selton-Suty C, et al. Enterococcal endocarditis in the beginning
of the 21st century: analysis from the International Collaboration on Endocarditis-Prospective Cohort Study. Clin
Microbiol Infect 2013;19(12):1140–7. http://dx.doi.org/10.1111/1469-0691.12166.
Dahl A, Bruun NE. Enterococcus faecalis infective endocarditis: focus on clinical aspects. Expert Rev Cardiovasc Ther
2013;11(9):1247–57.
Dahl A, Rasmussen RV, Bundgaard H, Hassager C, Bruun LE, Lauridsen TK, et al. Enterococcus faecalis infective
endocarditis: a pilot study of the relationship between duration of gentamicin treatment and outcome. Circulation
2013;127(17):1810–7.
El Rafei A, DeSimone DC, Narichania AD, Sohail MR, Vikram HR, Li Z, et al. Comparison of dual beta-lactam therapy
to penicillin-aminoglycoside combination in treatment of Enterococcus faecalis infective endocarditis. J Infect
2018;77(5):398–404. .
McDougall DA, McWhinney BC. Stability of buffered benzylpenicillin solutions for outpatient parenteral antimicrobial
therapy. J Pharm Practice Res 2014;44(1):26–8. https://doi.org/10.1002/j.2055-2335.2014.tb00012.x.
Peterson SC, Lau TTY, Ensom MHH. Combination of ceftriaxone and ampicillin for the treatment of enterococcal
endocarditis: a qualitative systematic review. Ann Pharmacother 2017;51(6):496–503.
Culture-negative endocarditis
diagnosis, antimicrobial therapy, and management of complications: A scientific statement for healthcare professionals
Stewardson AJ, Stuart RL, Cheng AC, Johnson PD. Mycobacterium chimaera and cardiac surgery. Med J Aust
2017;206(3):132–5.
Subedi S, Jennings Z, Chen SC. Laboratory approach to the diagnosis of culture-negative infective endocarditis. Heart
Lung Circ 2017;26(8):763–71. .
Wang A, Gaca JG, Chu VH. Management considerations in infective endocarditis: a review. JAMA 2018;320(1):72–83.
Cardiac implantable electronic device infections
Approach to managing cardiac implantable electronic device infections
Cardiac implantable electronic devices (CIED), including permanent pacemaker devices, implanted
cardioverter defibrillators and cardiac resynchronisation therapy devices, can become infected. Infection may
involve the device pocket, leads, cardiac valve leaflets or endocardial surface (or any combination of these sites).
Infective endocarditis may result from a pocket site infection or spread from a lead infection. The risk of cardiac
implantable electronic device infection is reduced by good surgical technique and antibiotic prophylaxis at the time
of device insertion or replacement (see Surgical prophylaxis for cardiac surgery).
Cardiac implantable electronic device infections are most commonly caused by staphylococci (Staphylococcus
aureus or coagulase-negative staphylococci), but many other pathogens can be involved. Up to 45% of patients
with a cardiac implantable electronic device and S. aureus bacteraemia have an underlying cardiac implantable
electronic device infection, as do approximately 30% of patients with a cardiac implantable electronic device and
other Gram-positive bacteraemias. Underlying cardiac implantable electronic device infection is much less
common in patients with Gram-negative bacteraemia. For patients with a cardiac implantable electronic device and
a single positive S. aureus blood culture result, exclude cardiac implantable electronic device infection. For
patients with other bacteraemias, exclude device infection if positive blood culture results persist despite
appropriate antibiotic therapy.
Perform an echocardiogram for patients with suspected cardiac implantable electronic device infection and, before
starting antibiotic therapy, take three sets of blood for culture (from separate venipuncture sites).
Transthoracic echocardiography (TTE) has low sensitivity but high specificity for the detection of vegetations on
cardiac implantable electronic device leads. Transoesophageal echocardiography (TOE) is significantly more
sensitive for detecting vegetations and can also provide information about valve infection and dysfunction.
Transoesophageal echocardiography is recommended if cardiac implantable electronic device–associated lead
infection or endocarditis is suspected. If the diagnosis or exclusion of cardiac implantable electronic device
infection remains unclear following transoesophageal echocardiography, additional imaging (eg fluorine-18
positron emission tomography/computed tomography [18F-FDG PET] scanning) may be considered; seek expert
advice.
Except for superficial or incisional infections, removal of the device (including the leads) is essential to cure
cardiac implantable electronic device infections. Antibiotic therapy alone without removal of the device is
associated with a higher rate of infection recurrence and mortality. Early referral to a specialist in cardiac
implantable electronic device infection and removal, and an infectious diseases physician, is required.
For patients with bacteraemia, even if investigations indicate that the cardiac implantable electronic device is not
infected, monitor the patient closely for signs of cardiac implantable electronic device infection or relapse of
bacteraemia.
Superficial or incisional infection following cardiac implantable

electronic device insertion
For empirical therapy of superficial or incisional infection following cardiac implantable electronic device (CIED)
insertion, use:
1 dicloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 to 10 days
OR
1 flucloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 to 10 days.
For patients with delayed nonsevere hypersensitivity to penicillins, cefalexin can be used in most cases [Note 1].
Use:
cefalexin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 to 10 days.
For patients at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31), or
with immediate (nonsevere or severe) or delayed severe hypersensitivity to penicillins, use:

160+800 mg) orally, 12-hourly for 7 to 10 days
OR
2 clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly for 7 to 10 days.
Modify therapy based on the results of wound culture and susceptibility testing. If the results of culture are
negative, complete 7 to 10 days of therapy using the empirical regimen.
these drugs is possible. For patients who have had a recent delayed nonsevere reaction to amoxicillin or ampicillin, use the drugs recommended for
Cardiac implantable electronic device pocket infection

Suspect a pocket infection in patients with signs of inflammation around the cardiac implantable electronic device
(CIED), including localised erythema, cellulitis, swelling, pain, skin erosion, wound dehiscence, purulent
discharge or sinus formation at the pocket site. Early postimplantation inflammatory changes can be difficult to
distinguish from infection. Perform an echocardiogram for patients with a pocket infection to check for
involvement of the leads and cardiac valves. Do not aspirate a suspected pocket infection because this can cause
infection to spread. See Approach to managing cardiac implantable electronic device infections for further
information on investigations and additional management.
A pocket infection is considered complicated if signs of sepsis or septic shock are present (see Early recognition
of sepsis or septic shock in adults or Early recognition of sepsis or septic shock in neonates, infants and
children for definitions). For empirical therapy of a complicated pocket infection, treat as for Empirical therapy for
prosthetic valve and cardiac implantable electronic device–associated infective endocarditis and seek expert advice
for duration of therapy.
For empirical therapy of uncomplicated pocket infection, after taking three sets of blood for culture (from
separate venipuncture sites), use:
use.
Modify therapy based on the results of culture and susceptibility testing.
Continue antibiotic therapy after the device and leads are removed. For uncomplicated infections, 2 weeks of
therapy is usually sufficient, provided the device has been completely removed and local soft tissue infection has
resolved. If the cardiac implantable electronic device is not removed, seek expert advice for antibiotic therapy
choice and duration.
Cardiac implantable electronic device–associated lead infection and

endocarditis
Diagnosis of cardiac implantable electronic device–associated lead infection or endocarditis can be challenging
because the presenting symptoms are usually nonspecific. In addition to the modified Duke diagnostic criteria
[Note 2], the diagnostic criteria for cardiac implantable electronic device endocarditis include a relapsing
bacteraemia, signs of pocket infection, and pulmonary embolism. See Approach to managing cardiac implantable
electronic device infections for further information on investigations and additional management.
For empirical treatment of cardiac implantable electronic device lead infection or endocarditis, treat as for
Empirical therapy for prosthetic valve and cardiac implantable electronic device–associated infective endocarditis.
Continue antibiotic therapy after the device and leads are removed. The duration of therapy depends on whether
native or prosthetic cardiac valves are involved, the initial clinical response to antimicrobials and the presence of
extracardiac infection—seek expert advice.
If the cardiac implantable electronic device is not removed, seek expert advice for antibiotic therapy choice and
duration.
Note 2: Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis
2000;30:633-8. [URL]
Key references
Ambrosioni J, Hernandez-Meneses M, Tellez A, Pericas J, Falces C, Tolosana JM, et al. The changing epidemiology
of infective endocarditis in the twenty-first century. Curr Infect Dis Rep 2017;19(5):21.
DeSimone DC, Sohail MR. Management of bacteremia in patients living with cardiovascular implantable electronic
devices. Heart Rhythm 2016;13(11):2247–52.
Fernandes A, Cassandra M, Trigo J, Nascimento J, Carmo Cachulo M, Providencia R, et al. Cardiac device infection:
review based in the experience of a single center. Rev Port Cardiol 2016;35(6):351–8.
Fukunaga M, Goya M, Nagashima M, Hiroshima K, Yamada T, An Y, et al. Identification of causative organism in

cardiac implantable electronic device infections. J Cardiol 2017;70(5):411–5. .
Kusumoto FM, Schoenfeld MH, Wilkoff BL, Berul CI, Birgersdotter-Green UM, Carrillo R, et al. 2017 HRS expert
consensus statement on cardiovascular implantable electronic device lead management and extraction. Heart Rhythm
2017;14(12):e503–e51. .
Sandoe JA, Barlow G, Chambers JB, Gammage M, Guleri A, Howard P, et al. Guidelines for the diagnosis, prevention
and management of implantable cardiac electronic device infection. Report of a joint Working Party project on behalf of
the British Society for Antimicrobial Chemotherapy (BSAC, host organization), British Heart Rhythm Society (BHRS),
British Cardiovascular Society (BCS), British Heart Valve Society (BHVS) and British Society for Echocardiography
(BSE). J Antimicrob Chemother 2015;70(2):325–59.
Wang A, Gaca JG, Chu VH. Management considerations in infective endocarditis: a review. JAMA 2018;320(1):72–83.
Infected aneurysms
Aetiology of infected aneurysms
Infected aneurysms (also known as mycotic aneurysms) can be characterised anatomically as intracavitary (within
thorax or abdomen), peripheral (primarily in the extremities and, less commonly, the carotid arteries) or
intracranial.
Infected intracavitary aneurysms are most commonly caused by Staphylococcus aureus, coagulase-negative
staphylococci, nontyphoidal Salmonella species, and streptococci. Other rare causes include Haemophilus species,
anaerobes and mycobacteria. In some cases, culture results are negative; see Culture-negative endocarditis for
pathogens to consider in these cases.
Patients with infected peripheral aneurysms often have a history of injecting drugs. Infected peripheral
aneurysms occasionally develop following trauma or a vascular procedure, or in patients with infective
endocarditis. S. aureus is the most common pathogen, and is often methicillin-resistant. Other pathogens include
Gram-negative bacilli and fungi. People who inject drugs can have polymicrobial infections.
Infected intracranial aneurysms are usually associated with infective endocarditis. Infection can also result from
contiguous spread from infected meninges, cavernous sinus or sinusitis. S. aureus and viridans streptococci are the
most common pathogens, but many other pathogens can be involved.
Treatment of infected aneurysms

Management of infected aneurysms is complex and should be undertaken by a multidisciplinary team that includes
a vascular, cardiovascular or neurosurgeon, cardiologist, radiologist, and an infectious diseases physician or
clinical microbiologist.
Infected aneurysms are rare in children; seek expert paediatric advice for management.
Patients with infective aneurysms may have sepsis or septic shock (see Early recognition of sepsis or septic shock
in adults for definitions). For patients with sepsis or septic shock, start antibiotic therapy within 1 hour of
presentation to medical care or, for ward-based patients, development of sepsis or septic shock, immediately after
appropriate samples are taken for culture. For nonantibiotic management of sepsis or septic shock, see Early
intervention for sepsis or septic shock.
For empirical therapy of infected aneurysms associated with infective endocarditis, treat as for Empirical therapy
for native valve infective endocarditis or Empirical therapy for prosthetic valve and cardiac implantable electronic
device–associated infective endocarditis.
For empirical therapy of healthcare-associated infected aneurysms, seek expert advice.
For empirical therapy of community-associated infected aneurysms, take three sets of blood for culture (from
separate venipuncture sites) before starting antibiotic therapy. A suitable regimen is:
use. Consider a 25 to 30 mg/kg loading dose for adults with septic shock or requiring
intensive care support
PLUS EITHER
1 ceftriaxone 2 g intravenously, daily; for adults with septic shock or requiring intensive
care support, use 1 g intravenously, 12-hourly
OR
1 cefotaxime 2 g intravenously, 8-hourly; for adults with septic shock or requiring intensive
care support, use 2 g intravenously, 6-hourly.
Flucloxacillin or cefazolin is more effective than vancomycin for methicillin-susceptible strains of Staphylococcus
aureus.
For adults with sepsis or septic shock, add to the above regimen:
For adults with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use vancomycin plus
ceftriaxone or cefotaxime as above. If sepsis or septic shock is present, add:
cefazolin 2 g intravenously, 8-hourly; for adults with septic shock or requiring intensive
care support, use 6-hourly dosing.
For adults with immediate severe or delayed severe hypersensitivity to penicillins, seek expert advice.
Modify therapy based on the results of culture and susceptibility testing. The optimal duration of therapy has not
been established; however, a minimum of 4 weeks for intracranial aneurysms and a minimum of 6 weeks for all
other types of aneurysm is usually recommended—seek expert advice. Long-term oral antibiotic therapy following
the completion of intravenous therapy is required for some patients (particularly if prosthetic graft material was
inserted during an active infection).
Key references
Alawieh A, Chaudry MI, Turner RD, Turk AS, Spiotta AM. Infectious intracranial aneurysms: a systematic review of
epidemiology, management, and outcomes. J Neurointerv Surg 2018;10(7):708–16. .
Ducruet AF, Hickman ZL, Zacharia BE, Narula R, Grobelny BT, Gorski J, et al. Intracranial infectious aneurysms: a
comprehensive review. Neurosurg Rev 2010;33(1):37–46.
Lin CH, Hsu RB. Primary infected aortic aneurysm: clinical presentation, pathogen, and outcome. Acta Cardiol Sin
2014;30(6):514–21.
Sorelius K, Wanhainen A, Furebring M, Bjorck M, Gillgren P, Mani K. Nationwide study of the treatment of mycotic
abdominal aortic aneurysms comparing open and endovascular repair. Circulation 2016;134(23):1822–32.
Wilson WR, Bower TC, Creager MA, Amin-Hanjani S, O'Gara PT, Lockhart PB, et al. Vascular graft infections, mycotic
aneurysms, and endovascular infections: a scientific statement from the American Heart Association. Circulation
2016;134(20):e412–e60.
Bloodstream infections associated with an
intravascular device
Overview of bloodstream infections associated with an intravascular
device
Coagulase-negative staphylococci and Staphylococcus aureus are the most common causes of bacteraemia
associated with intravascular devices. Many other organisms also cause infection, including Gram-negative bacilli
and Candida species. Sepsis or septic shock associated with an intravascular device, and superficial septic
thrombophlebitis, are usually caused by S. aureus.
Remove peripheral intravascular catheters immediately if they are suspected to be the source of infection. Send the
tip for culture, together with two sets of blood samples (ie four bottles) taken from another site.
A central catheter suspected to be the source of infection should usually be removed. It must be removed if the
patient has sepsis or septic shock; tunnel infection; disseminated intravascular coagulation; thromboembolism; or
if the pathogen is a Candida species or S. aureus. If possible, consult the treating team before catheter removal.
For patients without the above features, or if the potential harms of removal outweigh potential benefits, catheter
salvage can sometimes be attempted. Salvage involves administration of intravenous antibiotics via the infected
lumen(s), or an antibiotic or ethanol lock—seek expert advice.
Empirical therapy for bloodstream infections associated with an

intravascular device
Initial antibiotic therapy
The following empirical regimens are not appropriate for neutropenic patients with an intravascular device in situ.
For patients with febrile neutropenia and intravascular device infection, see Empirical therapy for febrile
neutropenia.
If the patient has sepsis or septic shock, start antibiotic therapy within 1 hour of the patient presenting to medical
care or, for a ward-based patient, developing sepsis; antibiotics should be given immediately after appropriate
samples are taken for culture. For definitions of sepsis and septic shock, see here for adults or here for children.
For non-neutropenic patients with a bloodstream infection associated with an intravascular device, use gentamicin
plus vancomycin:

subsequent dosing [Note 6]
PLUS
use. Consider a 25 to 30 mg/kg loading dose for adults and children with septic shock or
requiring intensive care support.
calculate the dose.
function.
Modification and duration of therapy

The results of culture and susceptibility testing guide ongoing therapy. If susceptibility results are not available by
72 hours and empirical intravenous therapy is still required, stop the gentamicin-containing regimen and seek
expert advice.
After removal of the infected device, sepsis can resolve quickly when caused by a pathogen with low virulence (eg
a coagulase-negative staphylococcus), so it may not be necessary to continue antimicrobial therapy.
If infection is caused by a more virulent pathogen (eg Staphylococcus aureus, a Candida species), continue therapy
after the device is removed; treatment duration may need to be prolonged in these cases, because deep-seated
infection (such as endocarditis, osteomyelitis or endophthalmitis) can develop.
Vascular graft and endovascular device infections
Aetiology of vascular graft and endovascular device infections
Staphylococcus aureus and Staphylococcus epidermidis are the most common pathogens associated with vascular
graft and endovascular device infections. However, the pathogen varies depending on the surgical site; Gram-
negative bacteria are often involved in infections at aortofemoral sites or in the setting of graft–enteric erosion or
fistula.
Treatment of vascular graft and endovascular device infections

Management of vascular graft and endovascular device infections is complex and should be undertaken by a
multidisciplinary team that includes a vascular or cardiovascular surgeon, cardiologist, radiologist and an
Patients with vascular graft or endovascular device infections may have sepsis or septic shock (see Early
recognition of sepsis or septic shock in adults or Early recognition of sepsis or septic shock in neonates, infants
and children for definitions). For patients with sepsis or septic shock, start antibiotic therapy within 1 hour of
For empirical therapy of vascular graft and endovascular device infections, take three sets of blood for culture
(from separate venipuncture sites) before starting antibiotic therapy. A suitable regimen is:
piperacillin+tazobactam 4+0.5 g (child: 100+12.5 mg/kg up to 4+0.5 g) intravenously, 6-

hourly
PLUS
For patients with penicillin hypersensitivity, seek expert advice.
Modify therapy based on the results of culture and susceptibility testing. The optimal duration of therapy has not
been established; a minimum of 4 to 6 weeks is usually recommended—seek expert advice. Long-term oral
antibiotic therapy following the completion of intravenous therapy is required for some patients (particularly when
prosthetic graft material was inserted during an active infection).
Key references
Kilic A, Arnaoutakis DJ, Reifsnyder T, Black JH, 3rd, Abularrage CJ, Perler BA, et al. Management of infected vascular
grafts. Vasc Med 2016;21(1):53–60.
Wilson WR, Bower TC, Creager MA, Amin-Hanjani S, O'Gara PT, Lockhart PB, et al. Vascular graft infections, mycotic
aneurysms, and endovascular infections: A scientific statement from the American Heart Association. Circulation
2016;134(20):e412–e60.
Meningitis
Clinical presentation of meningitis
The two most common serious central nervous system (CNS) infections are bacterial meningitis and viral
encephalitis. Differentiating between meningitis and encephalitis can be difficult. Meningitis typically presents
with an acute history of fever, neck stiffness and altered conscious state, with headache, photophobia and nausea or
vomiting often prominent. The hallmark of encephalitis is an acute change in mental status, which can range from
a subtle change to confusion to coma; for information about encephalitis, see Encephalitis.
Aseptic meningitis often has a milder clinical presentation than bacterial meningitis, but these conditions cannot be
distinguished on clinical grounds alone.
Invasive meningococcal or pneumococcal disease can present with sepsis. Nonspecific symptoms and signs of
sepsis (leg pain, cold hands and feet, peripheral mottling) may precede meningism. For information about
recognition of sepsis, see Early recognition of sepsis or septic shock.
Neonates and infants with meningitis often present with nonspecific signs of sepsis rather than the classical signs
of meningitis. Early consultation with an experienced clinician is required for all cases of suspected meningitis in
neonates and infants.
Aetiology of meningitis
The most common pathogens in bacterial meningitis are Streptococcus pneumoniae, Neisseria meningitidis and, in
young children who are not fully vaccinated, Haemophilus influenzae type b (Hib). In neonates and infants
younger than 2 months, Streptococcus agalactiae (group B streptococcus), Escherichia coli and other aerobic
Gram-negative bacilli are important pathogens. Listeria monocytogenes is more common in adults older than 50
years, immunocompromised patients and neonates.
Key principles in managing meningitis

The key principles in managing meningitis are outlined in Box 2.1.
Key principles in managing meningitis (Box 2.1)
Clinical differentiation of bacterial meningitis from other diagnoses (such as aseptic meningitis,
encephalitis or subarachnoid haemorrhage) can be difficult.
Lumbar puncture to obtain CSF for culture is key to diagnosis and directed therapy for bacterial
meningitis.
Neuroimaging (typically CT scan) may be required for patients with possible raised ICP; it can also be
important for differential diagnoses.
Ideally, obtain microbiological samples (eg CSF, blood) before starting empirical antibiotic therapy.
Early empirical antibiotic therapy is appropriate when clinical suspicion of bacterial meningitis is high,
ideally within 60 minutes of presentation to hospital. Do not withhold treatment if there is a significant
delay in performing investigations.
CSF = cerebrospinal fluid; CT = computed tomography; ICP = intracranial pressure
When choosing antibiotics for suspected meningitis, consider the antimicrobial susceptibility of likely pathogens,
as well as CSF penetration. With some exceptions, most antibiotics need to be given intravenously to achieve
adequate CSF concentrations. Intrathecal therapy is not recommended, except in rare cases that require treatment
with drugs that do not adequately penetrate the CSF.
Current evidence favours early treatment with dexamethasone to improve outcomes in adults with Streptococcus
pneumoniae (pneumococcal) meningitis (mortality) and children with Haemophilus influenzae type b (Hib)
meningitis (hearing loss). Evidence for benefit in Neisseria meningitidis (meningococcal) meningitis is lacking. if
corticosteroids are not available, do not delay administration of antibiotics.
Seek expert advice from an infectious diseases physician, a clinical microbiologist or an experienced paediatrician
if there is any uncertainty in treating a patient with meningitis.
Some patients with uncomplicated bacterial meningitis can complete their course of treatment at home as part of
an established community-based parenteral antibiotic therapy program.
Prehospital management of suspected meningitis

Transfer patients with suspected bacterial meningitis to hospital urgently. For management of the patient in
hospital, see Immediate and early hospital management of meningitis.
Transfer patients with suspected bacterial meningitis to hospital urgently.
Prompt treatment of bacterial meningitis improves mortality and morbidity outcomes. Administration of
antibiotics before arrival in hospital is indicated if there are signs of meningococcaemia, because meningococcal
sepsis can be rapidly fatal.
The choice of antibiotic for prehospital management of suspected meningococcaemia is contentious. While there is
clinical experience with prehospital administration of ceftriaxone for this indication, clinical evidence to support
its use is lacking. Benzylpenicillin is widely available in primary care and is recommended on the basis of
retrospective studies that showed prehospital administration reduced mortality. However, epidemiological data
show increasing N. meningitidis resistance to penicillin in vitro in Australia (notably in serogroup W isolates,
which at the time of writing are increasing in incidence). The clinical significance of the epidemiological data is
difficult to determine. In the absence of robust clinical outcome data, it is not possible to preferentially recommend
either ceftriaxone or benzylpenicillin.
If meningococcaemia is suspected on clinical grounds in the community setting, administer an immediate dose of ceftriaxone or
benzylpenicillin.
If meningococcaemia is suspected on clinical grounds (fever plus purpuric rash, sepsis plus meningeal
symptoms, unexplained septic shock in young adults) in the community setting, administer an immediate dose of
ceftriaxone or benzylpenicillin.
If possible, collect blood samples for culture, and swabs or aspirates of punctured skin lesions (for Neisseria
meningitidis), before the administration of antibiotics. Send all samples with the patient to hospital.
If meningococcaemia is suspected in the community setting, use:
1 ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously or

intramuscularly [Note 1]
OR
1 benzylpenicillin 2.4 g (child: 60 mg/kg up to 2.4 g) intravenously or intramuscularly

[Note 2].
Use ceftriaxone preferentially in the following situations:
in remote areas where further parenteral therapy may be substantially delayed (more than 6 hours)
in patients hypersensitive to penicillins, but not in those with a history of severe delayed hypersensitivity (eg
a severe cutaneous adverse reaction such as drug rash with eosinophilia and systemic symptoms [DRESS] or
Stevens–Johnson syndrome / toxic epidermal necrolysis [SJS/TEN]). Closely observe patients with
immediate hypersensitivity to penicillins because there is a small chance of cross-reactivity with
cephalosporins (see Cross-reactivity between beta lactams).
Note 1: Intramuscular injection of ceftriaxone is painful; consider reconstituting with lidocaine 1%. Split large
intramuscular doses into two injections.
Note 2: For a 300 mg/mL solution (ie 2.4 g/8 mL), reconstitute a 600 mg vial with 1.6 mL of water for injection,
a 1.2 g vial with 3.2 mL of water for injection, or a 3 g vial with 8 mL of water for injection. The maximum
intravenous injection rate is 300 mg/minute.
Immediate and early hospital management of meningitis
Early hospital management of suspected bacterial meningitis in adults and children is summarised in Figure 2.1.
Do not withhold treatment for suspected bacterial meningitis if there is a significant delay in performing investigations.
Do not withhold treatment for suspected bacterial meningitis if there is a significant delay in performing
investigations.
As soon as a patient with suspected bacterial meningitis arrives in hospital, collect blood samples for culture, and
swabs or aspirates of punctured skin lesions (for Neisseria meningitidis) (unless collected before hospitalisation).
This maximises the chance of isolating the pathogen.
Lumbar puncture is key to diagnosis and directed therapy for bacterial meningitis.
Perform a lumbar puncture as soon as possible, unless contraindicated (see Box 2.2). Cerebrospinal fluid (CSF)
microscopy and culture is key to diagnosis and directed therapy for bacterial meningitis. The measurement of CSF
lactate is a rapid, objective test that can reliably distinguish bacterial from aseptic meningitis; bacterial meningitis
is more likely if CSF lactate is 3.5 mmol/L or more. Gram stain of CSF may enable an immediate aetiological
diagnosis. Pneumococcal antigen assays of CSF are a rapid test for the diagnosis of pneumococcal meningitis, and
are particularly useful when administration of antibiotics has rendered the CSF culture-negative. Nucleic acid
amplification testing (eg polymerase chain reaction [PCR]) of blood or CSF for N. meningitidis and Streptococcus
pneumoniae is especially useful when patients have already received antibiotics.
In adults, a CT scan may be indicated before lumbar puncture in patients with possible raised intracranial pressure
(ICP), or to investigate alternative diagnoses such as brain abscess or subarachnoid haemorrhage (see Box 2.2). If
the CT scan is normal but the patient has signs of raised ICP, consider the balance of benefits and harms of lumbar
puncture (better outcomes associated with diagnosis and directed therapy for meningitis versus the very small risk
of brain herniation).
In children, CT scans are not performed routinely in patients with possible raised ICP, but may be used to
investigate alternative diagnoses.
If lumbar puncture was performed but CSF test results are not yet known, and clinical suspicion of bacterial
meningitis is high, do not delay therapy while waiting for results.
If lumbar puncture cannot be performed urgently, review and reassess the patient regularly, and perform lumbar
puncture when feasible or when contraindication(s) resolve. If clinical suspicion of bacterial meningitis is high, do
not delay therapy while waiting for lumbar puncture or scans to be performed.
Management of suspected bacterial meningitis in adults and children (Figure 2.1)

CSF = cerebrospinal fluid; CT = computed tomography
NB1: If clinical suspicion of bacterial meningitis is high, do not delay therapy while waiting for CSF test results.
Can a lumbar puncture be done urgently? (Box 2.2)
Situations in which lumbar puncture may be delayed or not possible:
1. Logistical delay
2. Contraindication to lumbar puncture
anticoagulant therapy [NB1]

bleeding diathesis
suspected disseminated intravascular coagulation (including evolving petechial/purpuric rash)
localised infection overlying the lumbar region
Chiari malformation
significant cardiorespiratory compromise that may further deteriorate with positioning for lumbar puncture
3. CT scan indicated before considering lumbar puncture
Possible raised ICP:
focal neurological signs

papilloedema
new-onset seizures (within last 7 days)
rapidly deteriorating conscious state
Possible alternative diagnosis:
suspected focal CNS disease

subarachnoid haemorrhage
immunocompromised (including HIV infection)—increased risk of mass lesions
CT = computed tomography; ICP = intracranial pressure
NB1: If available, consider use of a reversal agent in consultation with a haematologist.
Empirical therapy for meningitis in hospital (pathogen or susceptibility

unknown)
Timing of therapy
If the patient has not received a dose of ceftriaxone or benzylpenicillin before hospital, and the pathogen or
susceptibility is unknown, give empirical antibiotics and dexamethasone as soon as possible, ideally within 60
minutes of presentation to hospital.
Neonates and children younger than 2 months

For neonates and children younger than 2 months, the most likely pathogens are Streptococcus agalactiae
(group B streptococcus), enteric Gram-negative bacilli or, rarely, and generally only in children up to 1 month of
age, Listeria monocytogenes. Treat as for sepsis or septic shock, using the regimens for infants in whom meningitis
has not been excluded. For neonates, choice of empirical therapy depends on the time since birth and whether the
infant has been in the community since birth; see Empirical regimens for sepsis or septic shock. For infants aged 1
to 2 months, treat as for community-acquired sepsis or septic shock; see Empirical regimens for community-
acquired sepsis or septic shock in infants 1 month to younger than 2 months, source not apparent. Complications
during therapy, such as ventriculitis or abscess, are not infrequent—seek expert advice. Dexamethasone is not
indicated in neonates (up to 1 month of age) because there is insufficient evidence to support its use.
Adults and children 2 months or older
For adults and children 2 months or older, including those with immediate nonsevere or delayed nonsevere
1 ceftriaxone 2 g (child: 50 mg/kg up to 2 g) intravenously, 12-hourly [Note 3]
OR
1 cefotaxime 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly
dexamethasone 10 mg (child: 0.15 mg/kg up to 10 mg) intravenously, preferably starting

before or with the first dose of antibiotic, then 6-hourly for 4 days [Note 4].
Do not delay administration of antibiotics if corticosteroids are not available. Corticosteroids can be administered
up to 4 hours after starting antibiotic therapy.
Listeria monocytogenes is intrinsically resistant to cephalosporins. For patients who are older than 50 years,
immunocompromised, pregnant or debilitated, or those with a history of hazardous alcohol consumption, to treat
Listeria, add to the above regimen:
benzylpenicillin 2.4 g (child: 60 mg/kg up to 2.4 g) intravenously, 4-hourly.
Benzylpenicillin is the preferred drug for Listeria infection. For patients who report penicillin hypersensitivity,
carefully assess the nature and severity of the reaction (see Management of patients reporting hypersensitivity to
penicillin), and consider whether use of benzylpenicillin is precluded. If benzylpenicillin is not suitable, add to the
cephalosporin-based regimen:
trimethoprim+sulfamethoxazole (adult and child 1 month or older) 5+25 mg/kg up to

480+2400 mg intravenously, 8-hourly.
Add vancomycin if Gram-positive diplococci are seen on Gram stain, if pneumococcal antigen assay of CSF is
positive, or if the patient has known or suspected otitis media or sinusitis, or has been recently treated with a beta-
lactam antibiotic. This is to ensure that empirical therapy is adequate for Streptococcus pneumoniae isolates that
have reduced susceptibility or resistance to penicillin or cephalosporins. Also consider vancomycin if Gram-
positive cocci resembling staphylococci are seen on Gram stain, or if CSF tests are not possible because lumbar
puncture is contraindicated. Add:

If vancomycin is used, administer after ceftriaxone or cefotaxime due to the long infusion time required.
For patients with immediate severe [Note 5] or delayed severe hypersensitivity to penicillins, use as a single
drug:
moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, daily [Note 6].
When the pathogen has been identified and the results of susceptibility testing are available, choose the appropriate
directed regimen; see:
Neisseria meningitidis (meningococcal) meningitis

Streptococcus pneumoniae (pneumococcal) meningitis
Haemophilus influenzae type b meningitis
Listeria monocytogenes meningoencephalitis
Streptococcus agalactiae (group B streptococcus) meningitis
Streptococcus suis meningitis
Enterobacteriaceae meningitis
Cryptococcal meningitis.
If a pathogen is not isolated, continue the empirical antibiotic regimen for a minimum of 10 days, depending on
response.
If the CSF examination is consistent with viral meningitis, consider stopping antibiotics and dexamethasone.
Continue dexamethasone if corticosteroids are indicated, for example if the pathogen is S. pneumoniae,
Streptococcus suis or Haemophilus influenzae type b (Hib), or if the patient has tuberculous meningitis or
eosinophilic meningitis.
Note 3: In children, a single daily dose of ceftriaxone (100 mg/kg up to 4 g intravenously, daily) is used in some
centres. A single daily dose of ceftriaxone may also be used when patients complete their course of treatment at
home in a community-based parenteral antimicrobial therapy program (adult: 4 g intravenously, daily; child: 100
mg/kg up to 4 g intravenously, daily).
Note 4: If dexamethasone is not available, hydrocortisone (200 mg [child: 4 mg/kg up to 200 mg] intravenously)
may be used for the initial dose.
Note 5: In a critical situation, the cephalosporin-based regimen for empirical therapy of meningitis can be
considered in patients with immediate severe penicillin hypersensitivity, after weighing the benefits and harms
and assessing potential side-chain cross-reactivity (see Cross-reactivity between beta lactams). Seek expert
advice.
Note 6: Moxifloxacin is not licensed for use in children on the basis of animal studies that showed an adverse
effect on cartilage development with quinolone use; however, there are few data from human trials to support
this finding. Moxifloxacin can be used in children when it is the drug of choice.
Neisseria meningitidis (meningococcal) meningitis

For meningitis caused by Neisseria meningitidis (meningococcal meningitis), including in patients with
immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use:
1 ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously, 12-hourly for

5 days [Note 7]
OR
1 cefotaxime 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly for 5 days.
If susceptibility to benzylpenicillin is confirmed and the patient is not hypersensitive to penicillin, de-escalate
therapy and use:
benzylpenicillin 2.4 g (child: 60 mg/kg up to 2.4 g) intravenously, 4-hourly for 5 days.
For patients with immediate severe [Note 8] or delayed severe hypersensitivity to penicillins, use:
ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 8-hourly for 5 days
[Note 9].
When N. meningitidis infection is confirmed, stop dexamethasone therapy because it is of unproven benefit.
Antibiotics for nasopharyngeal clearance of N. meningitidis are required if the patient was treated with
benzylpenicillin alone, because it does not reliably clear nasopharyngeal carriage. Patients treated with ceftriaxone,
cefotaxime or ciprofloxacin do not require clearance antibiotics. Close contacts of the patient require clearance
antibiotics (‘meningitis prophylaxis’ or ‘chemoprophylaxis’), with or without immunisation. For more information,
see Clearance antibiotics for invasive meningococcal or Hib disease.
Clearance antibiotics are required in some patients with meningococcal meningitis, and in close contacts.
Note 7: In children, a single daily dose of ceftriaxone (100 mg/kg up to 4 g intravenously, daily) is used in some
centres. A single daily dose of ceftriaxone may also be used when patients complete their course of treatment at
home in a community-based parenteral antimicrobial therapy program (adult: 4 g intravenously, daily; child: 100
mg/kg up to 4 g intravenously, daily).
Note 8: In a critical situation, the cephalosporin-based regimen above can be considered in patients with
immediate severe penicillin hypersensitivity, after weighing the benefits and harms and assessing potential side-
chain cross-reactivity (see Cross-reactivity between beta lactams). Seek expert advice.
Note 9: Ciprofloxacin is not licensed for use in children on the basis of animal studies that showed an adverse
this finding. Ciprofloxacin can be used in children when it is the drug of choice.
Determine the minimum inhibitory concentrations (MICs) of penicillin and ceftriaxone or cefotaxime for all
Streptococcus pneumoniae isolates.
For strains susceptible to penicillin (MIC less than 0.125 mg/L), use:
benzylpenicillin 2.4 g (child: 60 mg/kg up to 2.4 g) intravenously, 4-hourly for 10 to 14

days.
For strains resistant to penicillin (MIC 0.125 mg/L or more) but susceptible to ceftriaxone or cefotaxime (MIC less
than 1.0 mg/L), including in patients with immediate nonsevere or delayed nonsevere hypersensitivity to
penicillins, use:

10 to 14 days [Note 10]
OR
1 cefotaxime 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly for 10 to 14 days.
For strains with a penicillin MIC 0.125 mg/L or more, and a ceftriaxone or cefotaxime MIC 1.0 to 2.0 mg/L, add
moxifloxacin or vancomycin to ceftriaxone or cefotaxime. If using moxifloxacin, start treatment and confirm
susceptibility when results are available. Add:
1 moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, daily for 10 to 14

days [Note 11]
OR
1 vancomycin intravenously, see Principles of vancomycin use for dosing and principles of
use. Administer for 10 to 14 days.
If the MIC of ceftriaxone or cefotaxime is more than 2.0 mg/L, seek expert advice.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, use as a single drug:
moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, daily for 10 to 14

days [Note 11].
Note 10: In children, a single daily dose of ceftriaxone (100 mg/kg up to 4 g intravenously, daily) is used in
some centres. A single daily dose of ceftriaxone may also be used when patients complete their course of
treatment at home in a community-based parenteral antimicrobial therapy program (adult: 4 g intravenously,
daily; child: 100 mg/kg up to 4 g intravenously, daily).
Haemophilus influenzae type b meningitis

For meningitis caused by Haemophilus influenzae type b (Hib), including in patients with immediate nonsevere
or delayed nonsevere hypersensitivity to penicillins, use:

7 days [Note 12]
OR
If susceptibility to benzylpenicillin is confirmed and the patient is not hypersensitive to penicillin, de-escalate
therapy and use:
benzylpenicillin 2.4 g (child: 60 mg/kg up to 2.4 g) intravenously, 4-hourly for 7 days.
ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 8-hourly for 7 days
[Note 14].
In patients younger than 5 years who have not been fully vaccinated, give age-appropriate catch-up Hib
vaccination after recovery—see the Australian Immunisation Handbook [URL].
Antibiotics for nasopharyngeal clearance of Hib are required if the patient was not treated with ceftriaxone,
cefotaxime or ciprofloxacin. Close contacts of the patient may require clearance antibiotics (‘meningitis
prophylaxis’ or ‘chemoprophylaxis’), with or without immunisation. For more information, see Clearance
antibiotics for invasive meningococcal or Hib disease.
Clearance antibiotics are required in some patients with Hib meningitis, and in some close contacts.
Note 12: In children, a single daily dose of ceftriaxone (100 mg/kg up to 4 g intravenously, daily) is used in
some centres. A single daily dose of ceftriaxone may also be used when patients complete their course of
treatment at home in a community-based parenteral antimicrobial therapy program (adult: 4 g intravenously,
daily; child: 100 mg/kg up to 4 g intravenously, daily).
Note 13: In a critical situation, the cephalosporin-based regimen above can be considered in patients with
immediate severe penicillin hypersensitivity, after weighing the benefits and harms and assessing potential side-
chain cross-reactivity (see Cross-reactivity between beta lactams). Seek expert advice.

For meningoencephalitis caused by Listeria monocytogenes, use:
benzylpenicillin 2.4 g (child: 60 mg/kg up to 2.4 g) intravenously, 4-hourly. For

information on duration and intravenous to oral switch, see below.
Benzylpenicillin is the preferred drug for Listeria infection. For patients who report penicillin hypersensitivity,
carefully assess the nature and severity of the reaction (see Management of patients reporting hypersensitivity to
penicillin), and consider whether use of benzylpenicillin is precluded. If benzylpenicillin is not suitable, use:

480+2400 mg intravenously, 8-hourly. For information on duration and intravenous to oral
switch, see below.
There is limited evidence that combination therapy with a beta lactam plus trimethoprim+sulfamethoxazole
improves outcomes. Addition of an aminoglycoside to the regimen is not beneficial.
Duration of therapy and intravenous to oral switch: the usual duration is 3 weeks, extended to 6 weeks in
immunocompromised patients. For treatment extending beyond 3 weeks, oral therapy with
trimethoprim+sulfamethoxazole can be used to complete the course if clinical features of infection have resolved
with intravenous therapy, and the patient is able to tolerate oral medication. Use:
trimethoprim+sulfamethoxazole (adult more than 60 kg: 320+1600 mg; adult 40 to 60 kg:

240+1200 mg; child 1 month or older: 6+30 mg/kg up to 240+1200 mg) orally, 12-hourly.
When Listeria infection is confirmed, stop dexamethasone therapy because it is of unproven benefit.
Listeriosis is a notifiable disease, and may be associated with contamination of food. Discuss all confirmed cases
with the local public health authority [Note 15].
Note 15: Contact details for Australian state and territory government health departments and public health units
are available here.

Streptococcus agalactiae (group B streptococcus) is the most common cause of meningitis in neonates; it
occasionally causes meningitis in adults.
For term neonates (gestational age 37 weeks or older), use:
benzylpenicillin 90 mg/kg intravenously, 8-hourly for at least 14 days; extend to 21 days

for complicated infection.
For adults and children, use:
benzylpenicillin 2.4 g (child: 60 mg/kg up to 2.4 g) intravenously, 4-hourly for at least 14

days; extend to 21 days for complicated infection.
For patients hypersensitive to penicillins, seek expert advice. When S. agalactiae infection is confirmed, stop
dexamethasone therapy because it is of unproven benefit.
Streptococcus suis meningitis

Streptococcus suis is a cause of acute bacterial meningitis, especially in Southeast Asia. It is associated with
substantial morbidity (hearing loss). Give directed therapy for 10 to 14 days, as for pneumococcal meningitis (see
Streptococcus pneumoniae (pneumococcal) meningitis). Dexamethasone therapy, preferably started before or with
the first dose of antibiotic, reduces the risk of severe hearing loss (see Empirical therapy for meningitis in
hospital for dosage).
Enterobacteriaceae meningitis
Enterobacteriaceae (enteric Gram-negative bacilli, notably Escherichia coli and Klebsiella species) can cause
meningitis, most commonly in neonates and children younger than 2 months, and healthcare-associated or shunt-
related meningitis. In neonates, broad-spectrum cephalosporins have been considered standard therapy for enteric
Gram-negative bacilli, but resistance to these drugs is increasing, so select therapy based on local susceptibility
data.
Cryptococcal meningitis
Clinical presentation
Cryptococcal meningitis often presents as a subacute or chronic illness characterised by headache, fever and
altered mental state. It is caused by Cryptococcus gattii (particularly in immunocompetent patients) or
Cryptococcus neoformans (particularly in immunocompromised patients such as patients with HIV infection or
organ transplant recipients). It may be associated with cerebral mass lesions (cryptococcomas), particularly in
patients without HIV infection.
Consultation with a clinician experienced in the management of cryptococcal meningitis is essential. For more
detailed information about management, see the Australian and New Zealand antifungal guidelines [Note 16].
Patients with undiagnosed HIV infection may present initially with cryptococcal meningitis. In patients with
cryptococcal meningitis and newly diagnosed HIV, the timing of antiretroviral therapy initiation is complex—seek
expert advice. In patients with HIV infection taking antiretroviral therapy, check for drug interactions when
prescribing antimicrobials (see Antiretroviral drug interactions).
Note 16: Chen SC, Sorrell TC, Chang CC, Paige EK, Bryant PA, Slavin MA. Consensus guidelines for the
treatment of yeast infections in the haematology, oncology and intensive care setting, 2014. Intern Med J
2014;44(12b):1315-32. [URL]
Managing raised intracranial pressure in cryptococcal meningitis

Management of raised cerebrospinal fluid (CSF) pressure by drainage or shunting is critical to prevent
complications of cryptococcal meningitis, including vision and hearing loss. Check CSF pressure at baseline and,
depending on progress, during follow-up.
Repeated therapeutic lumbar punctures are often necessary in cryptococcal meningitis, for example in patients with
recurrent headaches, new seizures, symptoms and signs of raised intracranial pressure, or documented high
opening pressures.
Drug therapy
Antifungal therapy for cryptococcal meningitis is in consecutive phases—induction, consolidation and eradication
(or suppression in patients who do not have HIV infection but are persistently immunocompromised). A flare in
disease activity may occur in patients with HIV infection after starting antiretroviral therapy (immune
reconstitution inflammatory syndrome [IRIS]) and in patients without HIV infection after starting antifungal
therapy.
Treatment with corticosteroids is of no benefit in patients with cryptococcal meningitis, except possibly in the
setting of IRIS.
For induction therapy, as a two-drug regimen, use:
1 amphotericin B liposomal (adult and child) 3 to 4 mg/kg intravenously, daily
OR
1 amphotericin B lipid complex (adult and child) 5 mg/kg intravenously, daily
OR
1 amphotericin B desoxycholate (adult and child) 0.7 to 1 mg/kg intravenously, daily [Note
17]
flucytosine (adult and child) 25 mg/kg orally, 6-hourly. Monitor plasma concentration and
full blood count for bone marrow suppression (see Monitoring flucytosine) [Note 18]
OR if oral therapy is not tolerated
flucytosine (adult and child) 25 mg/kg intravenously, 6-hourly. Monitor plasma

concentration and full blood count for bone marrow suppression (see Monitoring
flucytosine).
The duration of induction therapy is typically 2 to 6 weeks, depending on culture conversion, the presence of
neurological dysfunction or cerebral cryptococcomas, whether the patient is immunocompromised, and the species
of Cryptococcus (gattii or neoformans). Seek expert advice.
Alternative drugs and regimens used for induction include amphotericin-based therapy without flucytosine, and
high-dose fluconazole (800 to 1200 mg daily) with or without flucytosine.
For consolidation and eradication therapy, use:
fluconazole 400 to 800 mg (child: 6 to 12 mg/kg up to 800 mg) orally, daily. For
information on duration, see below.
Fluconazole can cause nausea at higher doses. A dose at the lower end of the range (400 mg) is suitable for most
patients for consolidation and eradication. Higher doses may be required for heavier patients and when induction
therapy cannot be completed, particularly in the consolidation phase. Most guidelines recommend higher doses of
fluconazole (400 to 800 mg daily) for the consolidation phase and lower doses (200 to 400 mg daily) for
eradication or suppression therapy. Dosage may vary depending on patient factors, response to treatment and the
susceptibility of the pathogen.
Patients should receive a minimum of 10 weeks therapy (induction plus consolidation) before starting eradication
therapy.
Seek expert advice on alternative consolidation and eradication therapy (eg voriconazole or other azoles) if tests
suggest the pathogen is not susceptible to fluconazole.
The total duration of therapy is typically 12 to 18 months, depending on whether the patient remains
immunocompromised, and the presence or resolution of cerebral cryptococcomas. Seek expert advice.
In patients with HIV infection who respond to antiretroviral therapy, continue eradication therapy for at least 1
year, and until CD4 count is more than 100 cells/microlitre for 3 months or longer.
For patients who do not have HIV infection but are persistently immunocompromised (eg transplant recipients),
long-term suppression therapy may be required.
Note 17: Amphotericin B desoxycholate is not marketed in Australia but is available via the Special Access
Scheme.
Note 18: Oral flucytosine is not registered for use in Australia but is available via the Special Access Scheme.
Healthcare-associated meningitis (including CSF shunt–related

ventriculitis)
Meningitis or ventriculitis can follow cranial trauma, neurosurgery, spinal surgery, or insertion of an intracranial
device, or can occur spontaneously in patients with ventricular shunts. The presence of white cells in cerebrospinal
fluid (CSF), especially following surgery, and in the absence of other clinical features of bacterial infection, does
not always indicate healthcare-associated meningitis—consider alternative diagnoses.
For empirical therapy for healthcare-associated meningitis, use:

PLUS EITHER
1 ceftazidime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly
OR
1 cefepime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly.
Modify therapy according to Gram stain and results of CSF culture and susceptibility testing—seek expert advice.
If CSF cultures are negative after 5 to 7 days, stop antibiotics and monitor the patient.
For culture-positive cases, the duration of therapy usually ranges from 10 to 21 days, depending on the:
pathogen—shorter duration for coagulase-negative staphylococci or Cutibacterium acnes (formerly

Propionibacterium acnes); longer duration for Staphylococcus aureus and Gram-negative bacilli
clinical findings—shorter duration if few systemic features
CSF findings—shorter duration if minimal CSF pleocytosis or normal CSF glucose concentration.
For patients with repeatedly positive CSF cultures despite appropriate antimicrobial therapy, continue treatment for
10 to 14 days after the last positive culture.
Remove temporary external ventricular catheters (used for drainage and management of intracranial pressure) that
become infected. Whenever possible, remove permanent shunts that are infected.
Addition of intraventricular antimicrobial therapy can be considered if response to systemic antimicrobial therapy
is poor—seek expert advice. The choice of antibiotic depends on Gram stain and the results of CSF culture and
susceptibility testing. Daily doses for intraventricular administration (using preservative-free preparations) that are
reported in the literature for adults are: vancomycin 10 to 20 mg, gentamicin 4 to 8 mg, amikacin 30 mg.
Eosinophilic meningitis
Eosinophilic meningitis is usually caused by Angiostrongylus cantonensis and sometimes by Gnathostoma species.
Confirm the presence of eosinophils in the cerebrospinal fluid (CSF) by Giemsa stain—standard CSF stains cannot
distinguish eosinophils from neutrophils.
Eosinophilic meningitis due to A. cantonensis has occurred following ingestion of snails and slugs on the east
coast of Australia. Some authorities recommend postexposure prophylaxis with albendazole (20 mg/kg up to 400
mg orally with fatty food, daily for 7 days) for people in endemic areas who have ingested whole snails or slugs;
however, evidence to support the effectiveness of this approach is limited.
There is conflicting evidence about the treatment of A. cantonensis meningoencephalitis—seek expert advice.
Corticosteroid therapy improves symptoms. The benefits of anthelmintic treatment (usually in combination with
corticosteroids) are thought to outweigh the risks if started within 3 weeks of exposure.
Recurrent benign lymphocytic meningitis

Recurrent benign lymphocytic meningitis (Mollaret meningitis) is usually caused by herpes simplex virus type 2. It
has a benign self-limited course. Studies have not demonstrated a benefit for either antiviral treatment or
prophylaxis; however, anecdotal experience suggests valaciclovir or famciclovir may be helpful as episodic or
suppressive therapy in patients with frequent confirmed recurrences.
Key references
Clinical presentation of meningitis
Thompson MJ, Ninis N, Perera R, Mayon-White R, Phillips C, Bailey L, et al. Clinical recognition of meningococcal
disease in children and adolescents. Lancet 2006;367(9508):397–403.
Aetiology of meningitis
Bijlsma MW, Brouwer MC, Kasanmoentalib ES, Kloek AT, Lucas MJ, Tanck MW, et al. Community-acquired bacterial
meningitis in adults in the Netherlands, 2006-14: a prospective cohort study. Lancet Infect Dis 2016;16(3):339–47.
Prehospital management of suspected meningitis
Alam N, Oskam E, Stassen PM, Exter PV, van de Ven PM, Haak HR, et al. Prehospital antibiotics in the ambulance for
sepsis: a multicentre, open label, randomised trial. Lancet Respir Med 2018;6(1):40–50.
Australian Commission on Safety and Quality in Health Care (ACSQHC). AURA 2017: second Australian report on
antimicrobial use and resistance in human health. Sydney: ACSQHC 2017.
https://www.safetyandquality.gov.au/antimicrobial-use-and-resistance-in-australia/aura-2017/ .
Australian Government, Department of Health. Meningococcal - Australian Meningococcal Surveillance Programme

annual reports [online]. Canberra: Commonwealth of Australia; Accessed August 2018.
http://www.health.gov.au/internet/main/publishing.nsf/content/cda-pubs-annlrpt-menganrep.htm.
Costerus JM, Brouwer MC, Sprengers MES, Roosendaal SD, van der Ende A, van de Beek D. Cranial CT, lumbar
puncture, and clinical deterioration in bacterial meningitis: A nationwide cohort study. Clin Infect Dis 2018.
Glimaker M, Sjolin J, Akesson S, Naucler P. Lumbar puncture performed promptly or after neuroimaging in acute
bacterial meningitis in adults: A prospective national cohort study evaluating different guidelines. Clin Infect Dis
2018;66(3):321–8.
Lahra MM, Enriquez RP, Robert George CR for the National Neisseria Network. Australian Meningococcal Surveillance
Programme annual report, 2017. Commun Dis Intell Q Rep 2019?;[in press].
https://www.health.gov.au/internet/main/publishing.nsf/Content/cda-pubs-cdi-cdiintro.htm.
Public Health England. Guidance for the public health management of meningococcal disease in the UK: Updated
February 2018. London: Public Health England; 2018. https://www.gov.uk/government/publications/meningococcal-
disease-guidance-on-public-health-management
Immediate and early hospital management of meningitis
Buch K, Bodilsen J, Knudsen A, Larsen L, Helweg-Larsen J, Storgaard M, et al. Cerebrospinal fluid lactate as a
marker to differentiate between community-acquired acute bacterial meningitis and aseptic meningitis/encephalitis in
adults: a Danish prospective observational cohort study. Infect Dis (Lond) 2018;50(7):514–21.
Miner JR, Heegaard W, Mapes A, Biros M. Presentation, time to antibiotics, and mortality of patients with bacterial
meningitis at an urban county medical center. J Emerg Med 2001;21(4):387–92.
Mowlaboccus S, Jolley KA, Bray JE, Pang S, Lee YT, Bew JD, et al. Clonal expansion of new penicillin-resistant clade
of Neisseria meningitidis serogroup W clonal complex 11, Australia. Emerg Infect Dis 2017;23(8):1364–7.
Sakushima K, Hayashino Y, Kawaguchi T, Jackson JL, Fukuhara S. Diagnostic accuracy of cerebrospinal fluid lactate
for differentiating bacterial meningitis from aseptic meningitis: a meta-analysis. J Infect 2011;62(4):255–62.
Empirical therapy for meningitis in hospital (pathogen or susceptibility unknown)
Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database
Syst Rev 2015;(9):CD004405.
van de Beek D, Cabellos C, Dzupova O, Esposito S, Klein M, Kloek AT, et al. ESCMID guideline: diagnosis and
treatment of acute bacterial meningitis. Clin Microbiol Infect 2016;22 Suppl 3:S37–62.
Saez-Llorens X, McCoig C, Feris JM, Vargas SL, Klugman KP, Hussey GD, et al. Quinolone treatment for pediatric
bacterial meningitis: a comparative study of trovafloxacin and ceftriaxone with or without vancomycin. Pediatr Infect Dis
J 2002;21(1):14–22.
Toms C, de Kluyver R, Enhanced Invasive Pneumococcal Disease Surveillance Working Group for the Communicable
Diseases Network A. Invasive pneumococcal disease in Australia, 2011 and 2012. Commun Dis Intell Q Rep
2016;40(2):E267–84.
Drevets DA, Canono BP, Leenen PJ, Campbell PA. Gentamicin kills intracellular Listeria monocytogenes. Infect Immun
1994;62(6):2222–8.
Grant MH, Ravreby H, Lorber B. Cure of Listeria monocytogenes meningitis after early transition to oral therapy.
Antimicrob Agents Chemother 2010;54(5):2276–7.
Hof H, Nichterlein T, Kretschmar M. Management of listeriosis. Clin Microbiol Rev 1997;10(2):345–57.
Mylonakis E, Hohmann EL, Calderwood SB. Central nervous system infection with Listeria monocytogenes. 33 years'
experience at a general hospital and review of 776 episodes from the literature. Medicine (Baltimore) 1998;77(5):313–
36 .
Neonatal Medicines Formulary Consensus Group Benzylpenicillin (Penicillin G) Version 1.2 [Neomed formulary]
Sydney: South Eastern Sydney Local Health District. NSW Government; 2017.
https://www.seslhd.health.nsw.gov.au/royal-hospital-for-women/neomed-formularies.
Cryptococcal meningitis
Chen SC, Sorrell TC, Chang CC, Paige EK, Bryant PA, Slavin MA. Consensus guidelines for the treatment of yeast
infections in the haematology, oncology and intensive care setting, 2014. Intern Med J 2014;44(12b):1315–32.
Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment
of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease
Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases
Society of America. Rockville, MD: US Department of Health and Human Services (DHHS); 2013.
http://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/0
Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the prevention and
treatment of opportunistic infections in HIV-exposed and HIV-infected children. Rockville, MD: US Department of Health
and Human Services (DHHS); 2016. https://aidsinfo.nih.gov/guidelines/html/5/pediatric-opportunistic-infection/0
Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the
management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis
2010;50(3):291–322.
Healthcare-associated meningitis (including CSF shunt–related ventriculitis)
Huang CR, Lu CH, Chang WN. Adult Enterobacter meningitis: a high incidence of coinfection with other pathogens
and frequent association with neurosurgical procedures. Infection 2001;29(2):75–9.
Klugman KP, Dagan R. Randomized comparison of meropenem with cefotaxime for treatment of bacterial meningitis.
Meropenem Meningitis Study Group. Antimicrob Agents Chemother 1995;39(5):1140–6.
Tunkel AR, Hasbun R, Bhimraj A, Byers K, Kaplan SL, Michael Scheld W, et al. 2017 Infectious Diseases Society of
America's clinical practice guidelines for healthcare-associated ventriculitis and meningitis. Clin Infect Dis 2017.
Eosinophilic meningitis
Barratt J, Chan D, Sandaradura I, Malik R, Spielman D, Lee R, et al. Angiostrongylus cantonensis: a review of its
distribution, molecular biology and clinical significance as a human pathogen. Parasitology 2016;143(9):1087–118.
Children's Health Queensland Hospital and Health Service. Paediatric guideline: Snail and slug ingestion [CHQ-GDL-
01219 v2.0]. Brisbane: Queensland Government; 2019.
Cowie RH. Pathways for transmission of angiostrongyliasis and the risk of disease associated with them. Hawaii J
Med Public Health 2013;72(6 Suppl 2):70–4.
Prociv P, Turner M. Neuroangiostrongyliasis: The "subarachnoid phase" and its implications for anthelminthic therapy.
Am J Trop Med Hyg 2018;98(2):353–9.
Sydney Children's Hospitals Network (SCHN). Snail and slug ingestion: practice guideline [No: 2018-163 v1]. Sydney:
SCHN; 2018. https://www.schn.health.nsw.gov.au/our-policies/index/clinical/s.
Published April 2019. Amended March 2020. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Brain abscess and subdural empyema
Aetiology of brain abscess and subdural empyema
In brain abscess or subdural empyema, pathogens depend on the predisposing cause. In immunocompetent
patients, brain abscess is usually polymicrobial; microaerophilic cocci, including Streptococcus anginosus (milleri)
group (S. anginosus, S. constellatus, S. intermedius), and anaerobic bacteria predominate. When the origin of
infection is the ear, enteric Gram-negative bacilli are commonly involved. After trauma or surgery, Staphylococcus
aureus is the predominant cause. In immunocompromised patients, Nocardia species, Toxoplasma gondii and fungi
such as Cryptococcus species, Aspergillus species or Scedosporium species are more likely.
Initial management of brain abscess and subdural empyema

Seek a surgical opinion because aspiration or biopsy is essential to guide antimicrobial therapy, and subdural
empyema requires urgent surgical drainage. Consultation with an infectious diseases physician or clinical
microbiologist is recommended.
For empirical therapy for brain abscess or subdural empyema, use:
1 ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously, 12-hourly

[Note 1]
OR
metronidazole 500 mg (child: 12.5 mg/kg up to 500 mg) intravenously, 8-hourly.
For ongoing management and duration of therapy, see below.
For patients who are at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box
2.31), consider adding to either of the above regimens:
use.
For brain abscess after neurosurgery or trauma, use:
use
PLUS EITHER
OR
1 cefepime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly.
For ongoing management and duration of therapy, see below.
Note 1: In children, a single daily dose of ceftriaxone (100 mg/kg up to 4 g intravenously, daily) is used in some centres. A single daily dose of
ceftriaxone may also be used when patients complete their course of treatment at home in a community-based parenteral antimicrobial therapy
program (adult: 4 g intravenously, daily; child: 100 mg/kg up to 4 g intravenously, daily).
Ongoing management and duration of therapy for brain abscess and
subdural empyema
Modify therapy according to Gram stain and the results of culture and susceptibility testing. If applicable, see
Cryptococcal meningitis, Nocardiosis or Toxoplasma gondii encephalitis.
The duration of therapy is usually 4 to 8 weeks, with a minimum of 2 weeks of intravenous treatment, depending
on whether surgical drainage was performed, the clinical response, and radiological evidence of resolution.
In patients who show prompt clinical improvement, particularly those who have had surgical drainage of the
abscess, and after a minimum of 2 weeks of intravenous therapy, a switch to oral antibiotics may be appropriate to
complete a total of 4 to 8 weeks of therapy (intravenous + oral). Only oral antibiotics active against the pathogen
and with high bioavailability and adequate cerebrospinal fluid (CSF) penetration are suitable (eg
trimethoprim+sulfamethoxazole, moxifloxacin), and the patient must be able to adhere to oral therapy. Do not use
oral beta lactams because these have only moderate bioavailability and poor CSF penetration in the absence of
meningeal inflammation. Seek expert advice.
Spinal epidural abscess
Assessment of spinal epidural abscess
Spinal epidural abscess is commonly caused by Staphylococcus aureus, but can also be caused by Gram-negative
bacilli and other organisms. Use magnetic resonance imaging (MRI) for diagnosis because abscesses may be
missed with a computed tomography (CT) scan. Spinal epidural abscess can be associated with adjacent
osteomyelitis or disc infection; see Osteomyelitis for information about vertebral osteomyelitis.
Urgent surgical assessment is essential. If surgery is not performed for diagnostic or therapeutic purposes,
neurological status must be closely monitored.
Empirical therapy for spinal epidural abscess in adults

Initial therapy in adults
Take blood for culture before starting antibiotic therapy.
Start empirical therapy for spinal epidural abscess as soon as possible, but do not delay surgery. For adults, use:
flucloxacillin 2 g intravenously, 6-hourly. For critically ill patients, use a 4-hourly dosing
interval
PLUS EITHER
1 ceftriaxone 2 g intravenously, 12-hourly [Note 1]
OR
If there is an increased risk of methicillin-resistant Staphylococcus aureus (MRSA) (see Box 2.31) or evidence of
neurological compromise, or if surgery is likely to be delayed, add to the above regimen:
use.
1 ceftriaxone 2 g intravenously, 12-hourly [Note 1]
OR
use.
PLUS
use.
For patients who have postneurosurgical spinal epidural abscess or implanted prosthetic material, use:
cefepime 2 g intravenously, 8-hourly
PLUS
use.
Note 1: A single daily dose of ceftriaxone may be used when patients complete their course of treatment at home
in a community-based parenteral antimicrobial therapy program (adult: 4 g intravenously, daily).
Note 2: In a critical situation, the cephalosporin-based regimen for patients with nonsevere (immediate or
delayed) penicillin hypersensitivity can be considered in patients with immediate severe hypersensitivity, after
weighing the benefits and harms and assessing potential side-chain cross-reactivity (see Cross-reactivity between
beta lactams). Seek expert advice.
Ongoing management and duration of therapy in adults

Modify therapy according to the results of culture and susceptibility testing of operative material.
If a microbiological diagnosis is not obtained, modify empirical therapy based on the most likely cause and
whether community-based parenteral antimicrobial therapy is being considered. If there is a low risk of resistant
organisms, use intravenous flucloxacillin alone. Seek expert advice if there is a higher risk of resistant organisms,
or if an early switch to oral antibiotics is being considered.
Continue therapy for at least 6 weeks, with a minimum of 2 weeks of intravenous treatment. The duration depends
on whether the abscess was surgically drained, the clinical response, normalisation of inflammatory markers,
susceptibility of the pathogen, presence of implanted material, and radiological evidence of improvement or
resolution. It may be appropriate to switch to oral therapy in patients who are clinically improving, and after a
minimum of 2 weeks of intravenous therapy—this depends on the availability of suitable oral antibiotics (active
against the pathogen, good bioavailability, adequate tissue penetration) and patient adherence. Seek expert advice.
Empirical therapy for spinal epidural abscess in children

Initial therapy in children
Spinal epidural abscess is usually caused by Staphylococcus aureus in children.
Take blood for culture before starting antibiotic therapy.
Start empirical therapy for spinal epidural abscess as soon as possible, but do not delay surgery. For children, use:
flucloxacillin 50 mg/kg up to 2 g intravenously, 6-hourly.
Use a 4-hourly flucloxacillin dosing interval (ie 50 mg/kg up to 2 g intravenously, 4-hourly) for critically ill
children.
For children with immediate severe [Note 3] or delayed severe hypersensitivity to penicillins, use:
use.
If there is an increased risk of methicillin-resistant Staphylococcus aureus (MRSA) (see Box 2.31), add to the
flucloxacillin or cefazolin regimens above:
use.
In some regions, based on local MRSA susceptibility patterns, clindamycin or lincomycin may be a suitable
alternative to vancomycin; add to the flucloxacillin or cefazolin regimens above:
OR
For children who have postneurosurgical spinal epidural abscess, seek expert advice.
Note 3: In a critical situation, cefazolin can be considered in patients with immediate severe hypersensitivity,
after weighing the benefits and harms and assessing potential side-chain cross-reactivity (see Cross-reactivity
between beta lactams). Seek expert advice.
Ongoing management and duration of therapy in children

Continue therapy for at least 6 weeks, with a minimum of 2 weeks of intravenous treatment. The duration depends
on whether the abscess was surgically drained, the clinical response, normalisation of inflammatory markers,
susceptibility of the pathogen, presence of implanted material, and radiological evidence of improvement or
resolution. It may be appropriate to switch to oral therapy in patients who are clinically improving, and after a
minimum of 2 weeks of intravenous therapy—this depends on the availability of suitable oral antibiotics (active
against the pathogen, good bioavailability, adequate tissue penetration) and patient adherence. Seek expert advice.
Encephalitis
Clinical presentation and diagnosis of encephalitis
The two most common serious central nervous system (CNS) infections are viral encephalitis and bacterial
meningitis. The hallmark of encephalitis is an acute change in mental status, which may range from a subtle
change to confusion to coma. Meningitis typically presents with an acute history of fever, neck stiffness and
altered conscious state, with headache, photophobia and nausea or vomiting often prominent.
Suspect encephalitis in patients with acute fever and focal neurological symptoms and signs, including seizures,
behavioural changes, focal neurological deficits and coma.
Diagnostic tests for encephalitis should include analysis of cerebrospinal fluid (CSF), serum, respiratory samples
and faecal samples, as well as magnetic resonance imaging (MRI) and electroencephalogram (EEG). A mild CSF
pleocytosis is usually present, which can make it difficult to distinguish encephalitis from bacterial or viral
meningitis. Seek expert advice, particularly for immunocompromised patients, returned travellers and those with
unusual epidemiological exposures.
For detailed information on investigation and management of encephalitis, see the Australian and New Zealand
consensus guidelines [Note 1].
Note 1: Britton PN, Eastwood K, Paterson B, Durrheim DN, Dale RC, Cheng AC, et al. Consensus guidelines
for the investigation and management of encephalitis in adults and children in Australia and New Zealand. Intern
Med J 2015;45(5):563-76. [URL]
Aetiology of encephalitis
The most common cause of encephalitis in Australia is herpes simplex virus, but also consider varicella-zoster
encephalitis, Murray Valley encephalitis virus, Hendra virus and enterovirus, and other pathogens if the patient has
recently travelled overseas. Listeria monocytogenes infection may present with meningoencephalitis, especially in
elderly and immunocompromised patients, and in neonates. Toxoplasma gondii encephalitis can occur, particularly
in patients with HIV infection and in other immunocompromised patients. There are also noninfective causes of
encephalitis, including autoimmune disorders such as anti-N-methyl-D-aspartate receptor (anti-NMDAR)
encephalitis.
Empirical therapy for encephalitis

Start aciclovir therapy in all patients with suspected acute encephalitis while further investigations are underway,
because herpes simplex virus (HSV) is the most common treatable cause. If bacterial meningitis or sepsis is
possible, also start treatment with antibiotics—see Empirical therapy for meningitis in hospital.
Use:
aciclovir 10 mg/kg (child 12 years or younger: 500 mg/m2) intravenously, 8-hourly [Note
2] [Note 3].
For management of neonates with suspected herpes simplex infection, see Neonatal herpes simplex infection.
Herpes simplex encephalitis can usually be excluded and empirical therapy stopped based on negative CSF nucleic
acid amplification tests (eg polymerase chain reaction [PCR]) and a normal MRI. However, tests for herpes
simplex virus in CSF can be negative in very early disease (before day 3 of illness); consider a repeat lumbar
puncture and PCR if clinical suspicion is high.
Empirical therapy for Listeria monocytogenes infection should be added for patients at risk. This includes neonates
and patients who are older than 50 years, immunocompromised, pregnant or debilitated, or those with a history of
hazardous alcohol consumption. For adults, add to aciclovir:
benzylpenicillin 2.4 g intravenously, 4-hourly.
Benzylpenicillin is the preferred drug for L. monocytogenes infection. For patients who report penicillin
hypersensitivity, carefully assess the nature and severity of the reaction (see Management of patients reporting
hypersensitivity to penicillin), and consider whether use of benzylpenicillin is precluded. If benzylpenicillin is not
suitable, for adults, use:
trimethoprim+sulfamethoxazole 5+25 mg/kg up to 480+2400 mg intravenously, 8-hourly.
For management of neonates and children with possible L. monocytogenes infection, seek expert advice.
When the diagnosis is confirmed and a pathogen has been identified, modify treatment accordingly. If applicable,
see Herpes simplex encephalitis, Listeria monocytogenes meningoencephalitis or Toxoplasma gondii encephalitis.
Note 2: Use the online calculator to determine body surface area.
Note 3: A dose of 500 mg/m2 is approximately equal to 20 mg/kg for children younger than 5 years and 15
mg/kg for children 5 years to 12 years.
Herpes simplex encephalitis

The diagnosis of herpes simplex encephalitis is confirmed when viral DNA is detected in the CSF. Treat all
patients with suspected herpes simplex encephalitis—do not delay treatment while investigations are being
performed.
For adults and children, use:
aciclovir 10 mg/kg (child 12 years or younger: 500 mg/m2) intravenously, 8-hourly for 14
to 21 days [Note 4] [Note 5].
For management of neonates with herpes simplex encephalitis, see Neonatal herpes simplex infection.
Toxoplasma gondii encephalitis

Toxoplasma gondii encephalitis most commonly occurs in patients with HIV infection and in other
immunocompromised patients. In these patients, cerebral infection with T. gondii usually presents with multiple
ring-enhancing brain lesions on magnetic resonance imaging (MRI).
Patients with undiagnosed HIV infection may present initially with T. gondii infection. In patients with T. gondii
encephalitis and newly diagnosed HIV, the timing of antiretroviral therapy initiation is complex—seek expert
advice. In patients with HIV infection taking antiretroviral therapy, check for drug interactions when prescribing
antibiotics (see Antiretroviral drug interactions).
Information on the management of children with T. gondii encephalitis is available in the Guidelines for the
Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children [URL].
For primary treatment of T. gondii encephalitis in adults, as a three-drug regimen, use:
pyrimethamine 200 mg orally for the first dose, then 50 mg daily (or 75 mg daily if weight
over 60 kg) for 6 weeks [Note 6]
PLUS
calcium folinate 15 mg orally, daily for 6 weeks [Note 7]
PLUS EITHER
1 sulfadiazine 1 g (or 1.5 g if weight over 60 kg) orally, 6-hourly for 6 weeks [Note 6]
[Note 8] [Note 9]
OR
2 clindamycin 600 mg orally or intravenously, 6-hourly for 6 weeks.
If the above regimens are not appropriate, as a single preparation, use:
1 trimethoprim+sulfamethoxazole 5+25 mg/kg up to 480+2400 mg orally, 12-hourly for 6

weeks
OR
1 trimethoprim+sulfamethoxazole 5+25 mg/kg up to 480+2400 mg intravenously, 12-

hourly for 6 weeks.
A combination of pyrimethamine, calcium folinate and atovaquone can be used if none of the above regimens are
suitable.
For T. gondii encephalitis maintenance therapy (secondary prophylaxis) in adults, use:
sulfadiazine 1 g orally, 12-hourly [Note 8]
PLUS
pyrimethamine 25 mg orally, daily
PLUS
calcium folinate 15 mg orally, daily [Note 7].
For patients hypersensitive to sulfonamides, replace sulfadiazine with:
clindamycin 600 mg orally, 8-hourly.
Continue maintenance therapy while the patient remains immunocompromised. For patients with HIV infection
who are responding to antiretroviral therapy, continue maintenance therapy until CD4 count is more than 200
cells/microlitre for 6 months or longer.
Note 6: Lower dosages may be required in patients with advanced HIV infection because of poor tolerability
and the potential for pancytopenia; seek expert advice.
Note 7: Calcium folinate reduces the incidence of neutropenia with pyrimethamine.
Note 8: Sulfadiazine is not marketed in Australia but is available via the Special Access Scheme.
Note 9: In patients who report sulfadiazine hypersensitivity, consider desensitisation (seek expert advice) or use
clindamycin.
Key references
Clinical presentation and diagnosis of encephalitis
Britton PN, Eastwood K, Paterson B, Durrheim DN, Dale RC, Cheng AC, et al. Consensus guidelines for the
investigation and management of encephalitis in adults and children in Australia and New Zealand. Intern Med J
2015;45(5):563–76.
Empirical therapy for encephalitis
Britton PN, Eastwood K, Paterson B, Durrheim DN, Dale RC, Cheng AC, et al. Consensus guidelines for the
investigation and management of encephalitis in adults and children in Australia and New Zealand. Intern Med J
2015;45(5):563–76.

Carme B, Bissuel F, Ajzenberg D, Bouyne R, Aznar C, Demar M, et al. Severe acquired toxoplasmosis in
immunocompetent adult patients in French Guiana. J Clin Microbiol 2002;40(11):4037–44.
Cytomegalovirus (CMV) infection
Clinical manifestations of cytomegalovirus disease
This topic covers treatment of active cytomegalovirus (CMV) disease and secondary prophylaxis. For information
about primary prophylaxis and pre-emptive therapy in transplant recipients, see Cytomegalovirus prophylaxis in
immunocompromised adults without HIV infection.
Up to 60% of adults are seropositive for CMV; in the majority of cases, asymptomatic infection is acquired in
childhood.
In immunocompetent adults, CMV can cause a self-limited mononucleosis-like syndrome or self-limited hepatitis
—these do not require antiviral therapy.
CMV disease—including colitis, oesophagitis, pneumonitis, hepatitis, encephalitis and retinitis—usually occurs in
immunocompromised patients. It can also complicate established ulcerative colitis, and may present as an apparent
exacerbation of the disease; this is more common in patients treated with immunosuppressive therapy but can also
occur in untreated patients.
A CMV syndrome is also seen in transplant recipients; this consists of CMV viraemia plus other features that may
include fever, malaise, cytopenias, atypical lymphocytosis or elevated liver aminotransferases, in the absence of
tissue invasive disease.
CMV can infect babies in utero (approximately 7 per 1000 live births). Although the majority of infected babies
are asymptomatic at birth, CMV can cause significant disease including multisystem organ failure, growth
retardation, neurodevelopmental problems and sensorineural hearing loss. Sensorineural hearing loss is the most
common sequela, occurring in 10 to 15% of infected infants.
Diagnosis of cytomegalovirus disease

The diagnosis of cytomegalovirus (CMV) disease involves CMV serology, CMV DNA nucleic acid amplification
testing (NAAT) (eg polymerase chain reaction [PCR]) of peripheral whole blood or plasma, and demonstration of
CMV in biopsy tissue or samples such as aqueous or vitreous humour, bronchoalveolar lavage fluid or
cerebrospinal fluid (CSF). Seek expert advice about diagnosis in immunocompromised patients.
The correlation between peripheral blood CMV viral load (quantitative NAAT result) and the presence and
severity of disease is not well defined, although disease is more likely with a higher viral load.
Approach to treating cytomegalovirus disease

Treatment of cytomegalovirus (CMV) disease is complex—seek expert advice.
In neonates with congenital CMV disease, ganciclovir (or valganciclovir) may reduce hearing impairment and
improve neurodevelopmental outcomes when started within the first 4 weeks of life. Valganciclovir is often
preferred because it can be given orally and has fewer adverse effects. Seek expert advice and see the Australasian
Society for Infectious Diseases (ASID) guideline Management of Perinatal Infections [URL] for information on
management.
In transplant recipients, either a prophylactic strategy or selective pre-emptive treatment may be used to reduce
the risk of CMV disease; for details, see Cytomegalovirus prophylaxis in immunocompromised adults without
HIV infection. Treatment of CMV syndrome and active disease in transplant recipients is addressed in this topic.
Management of CMV disease in immunocompromised patients includes reducing the level of

immunosuppression if possible (seek expert advice), and treatment with antiviral therapy. Systemic antiviral
therapy is always recommended. Oral valganciclovir has been shown to be equally effective to intravenous
ganciclovir in some settings, but has not been studied in all situations. In cases of severe CMV retinitis, local
antiviral therapy may be used in addition to systemic therapy. (In patients with CMV disease who need to be
started on antiretroviral therapy for HIV, see Cytomegalovirus (CMV) disease in adults with HIV infection).
Antiviral therapy is considered in two phases—treatment of active disease, followed by secondary prophylaxis in
some patients (see Table 2.3). The evidence for secondary prophylaxis in most settings is weak.
The duration of therapy is determined by response to treatment, which is defined clinically and with suppression
of CMV viraemia. Active disease is treated for a minimum of 2 weeks, although longer durations are often needed
in patients with colitis or high initial viral loads. Treatment should be monitored with at least weekly measurement
of CMV viral load to ensure response. If CMV viraemia persists, treatment may need to be extended because there
is a risk of relapse.
See Table 2.3 for a summary of recommendations for antiviral therapy of CMV disease, including drug selection,
duration of treatment and role of secondary prophylaxis. Drug dosage regimens are provided in Antiviral therapy
for cytomegalovirus disease in adults and Antiviral therapy for cytomegalovirus disease in children. For
information on dosage adjustment in adults with kidney impairment, see here; for children, seek expert advice.
Monitor blood count and kidney function closely. For information on monitoring blood concentrations of
ganciclovir and valganciclovir, see Monitoring guanine analogue antivirals.
CMV disease: Summary of recommendations for antiviral therapy of active disease and
secondary prophylaxis (Table 2.3)
Indication Antiviral therapy for active Duration of Secondary prophylaxis [NB3]

disease [NB1] therapy [NB2]
CMV
Generally not indicated although some
syndrome in Oral valganciclovir or
2 to 6 weeks centres recommend 1 to 3 months in selected
transplant intravenous ganciclovir
patients or recurrent disease.
recipients
Adults with HIV infection: Not routinely
recommended if patient is on effective
antiretroviral therapy, unless there is
concurrent retinitis or relapses have
Mild disease: Oral occurred.
valganciclovir
In recurrent disease, continue until CD4 cell
Colitis Moderate to severe disease: 2 to 6 weeks count is greater than 100 cells/microlitre for
Intravenous ganciclovir (consider 3 to 6 months in response to antiretroviral
switch to oral valganciclovir therapy.
once improved)
Solid organ transplant recipients:
centres recommend 1 to 3 months in selected
patients or recurrent disease.
Mild disease: Oral
CMV disease valganciclovir
complicating
Moderate to severe disease: 2 to 6 weeks centres recommend 1 to 3 months in selected
ulcerative Intravenous ganciclovir (consider patients or recurrent disease.
colitis switch to oral valganciclovir
once improved)
Intravenous ganciclovir (with or
Encephalitis without foscarnet for severe 3 to 6 weeks As for ‘Colitis’ above.
disease with obtundation)
Intravenous ganciclovir (consider
Pneumonitis switch to oral valganciclovir 2 to 6 weeks As for ‘Colitis’ above.
once improved)
Adults with HIV infection: Recommended.
Continue until CD4 cell count is greater than
100 cells/microlitre for 3 to 6 months in
Oral valganciclovir (plus response to antiretroviral therapy, with
2 to 3 weeks
Retinitis intravitreal therapy if severe or inactive retinitis.
[NB5]
sight-threatening [NB4])
Solid organ transplant recipients: Retinitis
is a rare manifestation in transplant and
benefit of secondary prophylaxis is unclear.
NB1: For drug dosage regimens, see Antiviral therapy for cytomegalovirus disease in adults and Antiviral therapy for cytomegalovirus disease in
children. Management in immunocompromised patients also includes reducing the level of immunosuppression if possible—seek expert advice.
NB2: The duration of therapy is determined by response to treatment, which is defined clinically and with suppression of CMV viraemia.
NB3: For secondary prophylaxis in allogeneic haematopoietic stem cell transplant recipients, seek expert advice or refer to local protocols and
guidelines.
NB4: For immediate sight-threatening CMV retinitis, in addition to oral valganciclovir or other systemic therapy, consider intravitreal foscarnet 2.4 mg
per injection or intravitreal ganciclovir 2 mg per injection. Management by an ophthalmologist is required.
NB5: Treatment should be continued until retinitis is inactive and CMV viral suppression has been achieved.
Antiviral therapy for cytomegalovirus disease in adults
Treatment of active disease in adults
See Approach to treating cytomegalovirus disease before starting antiviral therapy. For information on drug
selection, including switch from intravenous to oral therapy, see Table 2.3.
For treatment of active cytomegalovirus (CMV) disease in adults, when initial intravenous therapy is indicated,
and ganciclovir resistance is not suspected, use:
ganciclovir 5 mg/kg intravenously, 12-hourly.
When initial oral therapy is indicated, or when clinical improvement has occurred and a switch to oral therapy is
feasible, use:
valganciclovir 900 mg orally, 12 hourly.
If ganciclovir is contraindicated or CMV resistance is proven by resistance testing or CMV resistance is suspected
due to a failure in clinical response, failure to control CMV viraemia or a rebound in CMV viraemia, use:
foscarnet 90 mg/kg intravenously, 12-hourly.
If ganciclovir and foscarnet are not suitable, use:
cidofovir 5 mg/kg intravenously, weekly; administer with probenecid (see cidofovir

product information for dosage of probenecid) [Note 1].
Duration of therapy is determined by response to treatment, which is defined clinically and with suppression of
CMV viraemia; for more information, see Approach to treating cytomegalovirus disease.
In patients with HIV who are taking antiretroviral therapy, check for potential drug interactions when prescribing
therapy for CMV disease (see Antiretroviral drug interactions).
Note 1: Cidofovir does not penetrate the CNS and should not be used to treat CMV encephalitis.
Secondary prophylaxis in adults

Choice of antiviral therapy for secondary prophylaxis after an episode of active CMV disease is based on factors
including CMV resistance, response to treatment and drug contraindications.
When secondary prophylaxis is indicated (see Table 2.3), use:
1 valganciclovir 900 mg orally, daily
OR
2 ganciclovir 5 mg/kg intravenously, daily. Switch to oral valganciclovir (see dosage above)
when possible [Note 2]
OR
3 foscarnet 90 to 120 mg/kg intravenously, daily
OR
4 cidofovir 5 mg/kg intravenously, every 2 weeks; administer with probenecid (see

cidofovir product information for dosage of probenecid) [Note 3].
For information about duration of therapy, see Table 2.3.
Note 2: Ganciclovir regimens in local guidelines vary; some centres reduce the frequency of administration (eg to 5 days a week, or use a higher dose
3 times a week)—seek expert advice or refer to local protocols and guidelines.
Antiviral therapy for cytomegalovirus disease in children

Treatment of active disease in children 1 month and older
See Approach to treating cytomegalovirus disease before starting antiviral therapy (includes discussion about
congenital CMV disease in neonates). For information on drug selection, including switch from intravenous to oral
therapy, see Table 2.3. Suggested regimens to treat active CMV disease in children are provided below—seek
expert advice about dosing.
For treatment of active cytomegalovirus (CMV) disease in children, when initial intravenous therapy is indicated,
and ganciclovir resistance is not suspected, use:
ganciclovir 5 mg/kg intravenously, 12-hourly.
When initial oral therapy is indicated, or when clinical improvement has occurred and a switch to oral therapy is
feasible, use valganciclovir. Use:
valganciclovir
child 1 to 12 months: 16 mg/kg orally, 12-hourly
child older than 12 months: dose (mg) = 7 x body surface area (m2) x estimated
glomerular filtration rate (mL/minute/1.73 m2) (up to 900 mg) orally, 12-hourly [Note 4].
If ganciclovir is contraindicated or CMV resistance is proven by resistance testing or CMV resistance is suspected
due to a failure in clinical response, failure to control CMV viraemia or a rebound in CMV viraemia, use:
foscarnet
child 1 month to younger than 12 years: 60 mg/kg intravenously, 8-hourly
child 12 years or older: 90 mg/kg intravenously, 12-hourly.
If ganciclovir and foscarnet are not suitable, use:
cidofovir 5 mg/kg intravenously, weekly, administer with probenecid (refer to local

protocols or guidelines for dosage of probenecid) [Note 5].
Duration of therapy is determined by response to treatment, which is defined clinically and with suppression of
CMV viraemia; for more information, see Approach to treating cytomegalovirus disease.
In patients with HIV who are taking antiretroviral therapy, check for potential drug interactions when prescribing
therapy for CMV disease (see Antiretroviral drug interactions.
Note 4: Use the online calculator to determine body surface area. Use the modified Schwartz formula to calculate estimated glomerular filtration rate
(GFR) in children older than 1 year.
Secondary prophylaxis in children 1 month and older

Choice of antiviral therapy for secondary prophylaxis after an episode of active CMV disease is based on factors
including CMV resistance, response to treatment and drug contraindications.
If secondary prophylaxis is indicated (see Table 2.3), suggested regimens are provided below. Seek expert advice
about dosing in children. Use:
1 valganciclovir
child 1 to 12 months: 16 mg/kg orally, once daily

child older than 12 months: dose (mg) = 7 x body surface area (m2) x estimated
glomerular filtration rate (mL/minute/1.73 m2) (up to 900 mg) orally, once daily [Note 6]
OR
2 ganciclovir 5 mg/kg intravenously, daily. Switch to oral valganciclovir (see dosage above)
when possible [Note 7]
OR
3 foscarnet 90 to 120 mg/kg intravenously, daily
OR
4 cidofovir 5 mg/kg intravenously, every 2 weeks, administer with probenecid (refer to

local protocols or guidelines for dosage of probenecid) [Note 8].
For information about duration of therapy, see Table 2.3.
Note 6: Use the online calculator to determine body surface area. Use the modified Schwartz formula to calculate estimated glomerular filtration rate
(GFR) in children older than 1 year.
Note 7: Ganciclovir regimens in local guidelines vary; some centres use a higher dose and reduce the frequency of administration (eg 6 mg/kg
intravenously 5 days a week)—seek expert advice or refer to local protocols and guidelines.
Key references
Clinical manifestations of cytomegalovirus disease
Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, et al. Definitions of Cytomegalovirus
Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis 2017;64(1):87–91.
Approach to treating cytomegalovirus disease
Asberg A, Humar A, Rollag H, Jardine AG, Mouas H, Pescovitz MD, et al. Oral valganciclovir is noninferior to
intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J
Transplant 2007;7(9):2106–13.
Gardiner BJ, Chow JK, Price LL, Nierenberg NE, Kent DM, Snydman DR. Role of secondary prophylaxis with
valganciclovir in the prevention of recurrent cytomegalovirus disease in solid organ transplant recipients. Clin Infect Dis
2017;65(12):2000–7.
Kadambari S, Williams EJ, Luck S, Griffiths PD, Sharland M. Evidence based management guidelines for the
detection and treatment of congenital CMV. Early Hum Dev 2011;87(11):723–8.
Kimberlin DW, Acosta EP, Sanchez PJ, Sood S, Agrawal V, Homans J, et al. Pharmacokinetic and pharmacodynamic
assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease. J Infect Dis
2008;197(6):836–45.
Kimberlin DW, Jester PM, Sanchez PJ, Ahmed A, Arav-Boger R, Michaels MG, et al. Valganciclovir for symptomatic
congenital cytomegalovirus disease. N Engl J Med 2015;372(10):933–43.
Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, et al. Effect of ganciclovir therapy on hearing
in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled
trial. J Pediatr 2003;143(1):16–25.
Martin DF, Sierra-Madero J, Walmsley S, Wolitz RA, Macey K, Georgiou P, et al. A controlled trial of valganciclovir as
induction therapy for cytomegalovirus retinitis. N Engl J Med 2002;346(15):1119–26.
Palasanthiran P, Starr M, Jones C, Giles M, editors. Management of perinatal infections. Sydney: Australasian Society
for Infectious Diseases; 2014. http://www.asid.net.au/resources/clinical-guidelines
Pett S. Cytomegalovirus. In: HIV management in Australasia: a guide for clinical care [online]. Sydney, NSW:
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine; 2016.
http://hivmanagement.ashm.org.au/index.php/clinical-manifestations-of-hiv/key-opportunistic-
infections/cytomegalovirus#
Antiviral therapy for cytomegalovirus disease in adults
European AIDS Clinical Society (EACS). EACS Guidelines 2017 version 9.0. Brussels: EACS; 2017.
http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html
Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, et al. The Third International Consensus
Guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2018;102(6):900–31.
Nelson M, Dockrell D, Edwards S, Angus B, Barton S, Beeching N, et al. British HIV Association and British Infection
Association guidelines for the treatment of opportunistic infection in HIV-seropositive individuals 2011. HIV Med
2011;12 Suppl 2:1–140.
Antiviral therapy for cytomegalovirus disease in children
Taketomo CK, editor. Pediatric & Neonatal Dosage Handbook. 24th ed. Hudson, Ohio: Lexi-Comp; 2017.
Acute infectious diarrhoea
Causes of acute infectious diarrhoea
Acute gastrointestinal infections often present with diarrhoea, but in some cases upper gastrointestinal symptoms
such as nausea and vomiting are prominent.
Acute diarrhoea is defined by an increase in the frequency of stools or decrease in stool form that lasts less than 14
days. Most cases of acute infectious diarrhoea are viral, self-limiting and resolve without specific treatment.
Most cases of acute infectious diarrhoea are viral, self-limiting and resolve without specific treatment.
Clinical clues that may help differentiate between viral, bacterial and toxin-mediated diarrhoea are summarised in
Table 2.4.
A viral pathogen (eg rotavirus, norovirus, adenovirus, astrovirus) is more likely in the following situations: when
there is a history of contact with a person who has acute infectious diarrhoea; in an outbreak with secondary cases;
or with prominent upper gastrointestinal symptoms such as vomiting and nausea. In contrast, fever, tenesmus and
bloody stool are commonly found in acute diarrhoea with bacterial aetiology (eg Campylobacter enteritis,
Clostridium difficile infection, Salmonella enteritis, Shigella enteritis). A bacterial cause is also commonly
identified in returned travellers with diarrhoea.
Toxin-mediated gastroenteritis is characterised by a short incubation period (typically several hours only) and
closely clustered cases. Vomiting, nausea and abdominal pain are usually prominent symptoms. Diarrhoea, if
present, occurs later in the course of illness. A number of bacterial toxins cause acute gastroenteritis, including
those produced by Staphylococcus aureus and Bacillus cereus. Rarely, toxin-mediated gastroenteritis may be
caused by nonbacterial toxins (eg ciguatoxins, tetrodotoxins).
Immunocompromised patients are susceptible to a wide range of diarrhoea-causing pathogens, including

bacteria, viruses (eg cytomegalovirus [CMV]), and parasites (eg Cryptosporidium species, Cystoisospora
[Isospora] belli and microsporidia).
Several infectious and noninfectious conditions can mimic acute infectious diarrhoea; for example, sepsis,
pyelonephritis, diverticulitis in the elderly, ischaemic colitis, inflammatory bowel disease, irritable bowel
syndrome and retrocaecal appendicitis.
In individuals who engage in receptive anal sex, infective proctitis caused by sexually transmitted pathogens (eg
Neisseria gonorrhoeae, Chlamydia trachomatis) and amoebiasis should be considered.
Features of viral, bacterial and toxin-mediated acute diarrhoea (Table 2.4)
Viral Bacterial Toxin-mediated

Prominent upper gastrointestinal
symptoms such as vomiting and Vomiting, nausea and abdominal pain
nausea. Fever, tenesmus and bloody stool. are usually prominent symptoms, and
diarrhoea, if present, occurs later in
Typically acute, and resolves within Returned travellers and the course of illness.
24 to 48 hours. immunocompromised patients at
greater risk. Short incubation period (typically
Often history of contact with a several hours only).
person who has acute infectious May be associated with recent
diarrhoea (person-to-person antibiotic use or hospital admission, Closely clustered cases.
transmission). which should prompt investigation
for Clostridium difficile. Infections arise from a single point
May be part of an outbreak with source.
secondary cases.
Severity of acute infectious diarrhoea

Severity is related to the degree of incapacity caused by the acute diarrhoea:
mild—the patient is able to undertake normal activities
moderate—the patient is able to function but needs to modify normal activities
severe—the patient is incapacitated and may require admission to hospital.
In addition, the following specific clinical features are markers of severity that may prompt microbiological
testing and consideration of treatment, including any of: high fever, tachycardia, leucocytosis, abdominal
tenderness or severe abdominal pain, high-volume diarrhoea with hypovolaemia, bloody stool or prolonged
symptoms.
Faecal testing in acute infectious diarrhoea

This section covers both traditional faecal microbiological testing and culture-independent tests such as multiplex
polymerase chain reaction (mPCR).
Faecal testing in patients with acute diarrhoea is only appropriate when the results will inform management. Faecal
testing, including for Clostridium difficile, is recommended in:
patients presenting with bloody stools, moderate to severe disease (see Severity of acute infectious
diarrhoea) or with prolonged symptoms
immunocompromised patients; in addition to faecal microbiological testing for routine pathogens, request
tests for parasites and viral pathogens
situations of public health importance (eg an outbreak, in residential aged-care facilities, food handlers);
perform testing as directed by the local public health authority [Note 1].
Traditional faecal microbiological testing—including bacterial culture, microscopy and antigen testing—continues
to have an important role in the assessment of acute infectious diarrhoea, despite the relatively low yield in
comparison to mPCR. A positive result is highly likely to be diagnostic, and, crucially, the resulting bacterial
isolates enable antimicrobial susceptibility testing and epidemiological assessment.
Culture-independent methods, including a number of commercially available mPCR assays, have recently become
widely available. mPCR presents some significant advantages over traditional faecal testing, but there are also
disadvantages (see Table 2.5).
Advantages and disadvantages of multiplex polymerase chain reaction (mPCR) faecal testing
(Table 2.5)
Advantages Disadvantages
A positive result does not necessarily indicate disease—
studies show that a high proportion of asymptomatic
Screens for a broad range of pathogens. people have positive results, with detection of at least
one potential pathogen.
Rapid results.
Multiple pathogens often identified—difficult to
Substantially improved yield. determine the principal pathogen.
Does not enable antimicrobial susceptibility testing.
The microbiological tests performed on faecal samples vary between laboratories, with each using its own testing
algorithms.
If a pathogen is identified, see:
Campylobacter enteritis
Clostridium difficile infection
Enterohaemorrhagic Escherichia coli enteritis
Salmonella enteritis
Shigella enteritis
Vibrio cholerae (Cholera)
Vibrio: Noncholera species
Yersinia enterocolitis
Cryptosporidium species
Cyclospora cayetanensis
Cystoisospora (Isospora) belli
Microsporidia.
are available here.
Empirical antibiotic therapy of acute infectious diarrhoea
Rehydration and other supportive measures
The principal aim of treatment of acute diarrhoea is to achieve and maintain adequate hydration. All patients with
diarrhoea should have their hydration status assessed so that appropriate rehydration can be given. In adults and
children, oral rehydration is indicated unless there is evidence of severe dehydration, when intravenous therapy is
necessary.
For detailed information on rehydration and other supportive measures including probiotics, antiemetics,
antidiarrhoeal drugs and zinc supplements, see the Gastrointestinal guidelines.
Empirical antibiotic therapy

Rehydration is the mainstay of therapy for acute infectious diarrhoea.
Empirical antibiotics are usually not indicated for community-acquired infectious diarrhoea.
Empirical antibiotics are usually not indicated for community-acquired infectious diarrhoea.
In children with bloody diarrhoea without fever or sepsis, empirical antibiotic therapy is not recommended due to
the risk of precipitating haemolytic uraemic syndrome if the infection is caused by enterohaemorrhagic
Escherichia coli.
Empirical antibiotic therapy is not recommended for children with bloody diarrhoea without fever or sepsis.
Empirical therapy is indicated or should be considered in some groups.
Empirical antibiotics are indicated for patients with manifestations of severe disease (see Severity of acute
infectious diarrhoea).
Consider empirical antibiotics in immunocompromised patients, even if they do not have clinical features
suggesting severe disease, because they are at greater risk of rapid deterioration and poor outcomes.
There is evidence that empirical antibiotic therapy shortens the duration of illness by 1 to 3 days in returned
travellers with acute diarrhoea.
The empirical regimens below are not appropriate for patients at risk of Clostridium difficile infection.
If empirical antibiotic therapy for acute infectious diarrhoea is indicated, obtain samples for faecal testing before
starting therapy. Use:
1 ciprofloxacin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 12-hourly for 3 days [Note
2]
OR
1 norfloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally, 12-hourly for 3 days [Note 3].
If the infection is likely to have been acquired in an area where quinolone resistance is common (eg South and East
Asia), or an oral suspension is required (eg for young children), consider:
azithromycin 500 mg (child: 10 mg/kg up to 500 mg) orally, daily for 3 days.
If oral therapy is not tolerated or absorption is likely to be impaired, consider:
ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously, daily for 3

days.
Modify therapy based on the results of culture and susceptibility testing, if these are available before the symptoms
of diarrhoea have resolved. If a pathogen is identified, see:
Shigella enteritis
Vibrio cholerae (Cholera)
Vibrio: Noncholera species
Cryptosporidium species
Cyclospora cayetanensis
Cystoisospora (Isospora) belli
Microsporidia.
Note 3: Norfloxacin is not licensed for use in children on the basis of animal studies that showed an adverse
this finding. Norfloxacin can be used in children when it is the drug of choice.
Campylobacter enteritis is a foodborne zoonosis that is usually self-limited. Rehydration is the mainstay of
therapy.
Antibiotic therapy is indicated in those with severe disease (see Severity of acute infectious diarrhoea). Therapy
may also be reasonable in the third trimester of pregnancy, infants, the frail elderly, and in patients who are
immunocompromised.
If antibiotic therapy is indicated, use:
1 azithromycin 500 mg (child: 10 mg/kg up to 500 mg) orally, daily for 3 days
OR
4] [Note 5]
OR
1 norfloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally, 12-hourly for 3 days [Note 6]
[Note 7].
The incidence of macrolide- or quinolone-resistant Campylobacter strains appears to be increasing. For resistant
infections, seek expert advice.
Asymptomatic contacts of the index case do not need faecal testing or treatment.
Note 5: An oral liquid formulation of ciprofloxacin is not commercially available; for formulation options for
children or people with swallowing difficulties, see the Don’t Rush to Crush Handbook, published by the Society
of Hospital Pharmacists of Australia [URL].
Note 7: An oral liquid formulation of norfloxacin is not commercially available; for formulation options for

Introduction
Clostridium difficile causes the most severe cases of antibiotic-associated diarrhoea. Infection can occur at any
time during, or for some months after, a course of antibiotics. Risk factors include exposure to broad-spectrum
antibiotics such as cephalosporins, quinolones and lincosamides; hospitalisation; cancer chemotherapy; and the use
of proton pump inhibitors. C. difficile infection can also occur in community dwelling people without risk factors.
Outbreaks of hypervirulent strains (including PCR ribotype 027 and 078) have been reported worldwide, including
in Australia. Some outbreaks of these hypervirulent strains have been associated with broad-spectrum quinolone
use (eg moxifloxacin).
Antimicrobial stewardship and infection control measures (additional contact precautions) in hospitals have
reduced nosocomial spread, particularly in outbreaks.
Assessment
The diagnosis of C. difficile infection is based on clinical features suggestive of C. difficile infection (diarrhoea,
ileus, toxic megacolon) and either:
microbiological evidence of toxin-producing C. difficile in stools, or

colonoscopy findings or histopathology results that demonstrate pseudomembranous colitis.
For indications to test for C. difficile, see Faecal testing in acute infectious diarrhoea. Perform testing for C.
difficile or its toxins on unformed stool only, unless the patient has ileus.
Many laboratories adopt a sequential testing algorithm, with a high-sensitivity screening test performed first (eg
nucleic acid amplification testing [eg polymerase chain reaction (PCR)]), followed by a test that increases
specificity of the final result (eg enzyme-linked immunosorbent assay [EIA]).
Always correlate clinical symptoms with test results when deciding whether to treat. Test results can be positive in
asymptomatic carriers of toxigenic C. difficile, and in the weeks following recovery after an episode of C. difficile
diarrhoea; these patients do not require treatment. Do not repeat testing during the same episode of diarrhoea, or
test for cure.
Always correlate clinical symptoms with test results when deciding whether to treat a person with a positive C. difficile result.
Colonisation with C. difficile is common in young children, particularly in those up to 2 years of age. Review a
positive result in a young child carefully because the organism may not be the cause of disease and treatment may
not be necessary.
Treatment for the first episode

In addition to antibiotic therapy, rehydration is important when treating C. difficile infection.
Seek expert advice for all patients with severe disease (eg any of: leucocytosis, severe abdominal pain, elevated
serum creatinine, elevated blood lactate, low serum albumin, high fever, or organ dysfunction). See Severe
Clostridium difficile infection for recommendations.
Stop any implicated antibiotics unless there is a strong rationale for continuing them. In up to 25% of patients,
symptom resolution follows, and the likelihood of relapse is reduced. If antibiotics cannot be stopped, seek expert
advice. Avoid proton pump inhibitors after diagnosis.
For the first episode of mild to moderate C. difficile disease, use:
1 metronidazole 400 mg (child: 10 mg/kg up to 400 mg) orally or enterally, 8-hourly for 10
days
OR
2 vancomycin 125 mg (child: 10 mg/kg up to 125 mg) orally or enterally, 6-hourly for 10
days [Note 8].
Metronidazole can be given intravenously in patients who cannot tolerate the oral formulation (see dosage regimen
in Severe Clostridium difficile infection).
There is evidence that vancomycin has similar efficacy to metronidazole in this setting; however, for antimicrobial
stewardship reasons, it is not the preferred drug.
For information about follow-up testing, see here.
Note 8: Injectable vancomycin can be given orally or enterally, as an alternative to oral capsules. Dissolve 500
mg of vancomycin powder in 10 mL of water, measure the appropriate dose (eg 125 mg = 2.5 mL), and give
orally or enterally. Flavouring syrups can be added before administration to improve palatability.
Treatment for first recurrence or refractory disease

Recurrence of C. difficile infection is common. Recurrent disease is defined as C. difficile infection occurring
within 2 months of the previous episode, after resolution of symptoms. Refractory disease is defined as lack of
clinical improvement following 3 to 4 days of recommended therapy.
serum creatinine, elevated blood lactate, low serum albumin, high fever, or organ dysfunction). See
Severe Clostridium difficile infection for recommendations.
In addition to antibiotic therapy, rehydration is important when treating C. difficile infection.
In adults and children with a first recurrence of C. difficile infection, or with refractory disease, use:
1 vancomycin 125 mg (child: 10 mg/kg up to 125 mg) orally or enterally, 6-hourly for 10
days [Note 9]
OR
2 fidaxomicin 200 mg orally, 12-hourly for 10 days [Note 10].
Note 10: At the time of writing, fidaxomicin is not available on the Pharmaceutical Benefits Scheme (PBS) for
this indication. See the PBS website for current information [URL].
Treatment for second and subsequent recurrences or ongoing refractory disease
In addition to the following recommendations, rehydration is important when treating C. difficile infection.
serum creatinine, elevated blood lactate, low serum albumin, high fever, or organ dysfunction). See
Severe Clostridium difficile infection for recommendations.
Faecal microbiota transplantation (FMT) or ‘stool transplant’ is an effective therapy for C. difficile infection, and is
the preferred treatment for adults with second and subsequent recurrences or ongoing refractory C. difficile disease.
Faecal microbiota transplantation given through a nasoduodenal tube is superior to vancomycin in patients with
recurrent C. difficile infection [Note 11]. Faecal microbiota transplantation has also been administered via
colonoscopy and using frozen stool in oral capsules.
Although faecal microbiota transplantation is not approved by the Australian Therapeutic Goods Administration
(TGA) at the time of writing, it is increasingly being undertaken at specialist centres in Australia. Safety and
ethical concerns are managed at a local level. There are considerable logistical issues to consider (including
consent, donor screening, processing, dosing, and method and route of administration). At the time of writing,
there are no long-term safety data available. Seek expert advice.
In adults, faecal microbiota transplantation is the preferred treatment for second and subsequent recurrences or ongoing
refractory disease.
In adults, faecal microbiota transplantation is the preferred treatment for second and subsequent recurrences of
C. difficile infection or ongoing refractory disease. If faecal microbiota transplantation is not available, use:
2 vancomycin 125 mg orally or enterally, 6-hourly for 14 days [Note 12] [Note 13]
OR
3 fidaxomicin 200 mg orally, 12-hourly for 10 days [Note 14].
In children with second and subsequent recurrences of C. difficile infection, or ongoing refractory disease, use:
1 vancomycin 10 mg/kg up to 125 mg orally or enterally, 6-hourly for 14 days [Note 12]
[Note 15]
OR
2 nitazoxanide 100 mg (for children aged 1 to 3 years) or 200 mg (for children aged 4 and
older) orally, 12-hourly for 10 days [Note 16].
Note 11: van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, et al. Duodenal infusion of donor feces for recurrent
Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407-15. [URL]
Note 13: Consider tapering the dose before stopping. For example: after the initial 14 days’ therapy, use 125
mg orally, 12-hourly for 1 week; then 125 mg orally, daily for 1 week; then 125 mg orally every 2 or 3 days for 2
to 8 weeks.
Note 14: At the time of writing, fidaxomicin is not available on the Pharmaceutical Benefits Scheme (PBS) for
this indication. See the PBS website for current information [URL].
Note 15: Consider tapering the dose before stopping. For example: after the initial 14 days’ therapy, use 10
mg/kg (up to 125 mg) orally, 12-hourly for 1 week; then 10 mg/kg (up to 125 mg) orally, daily for 1 week; then
10 mg/kg (up to 125 mg) orally every 2 or 3 days for 2 to 8 weeks.
Note 16: Nitazoxanide is not registered for use in Australia but is available via the Special Access Scheme.
Severe Clostridium difficile infection

serum creatinine, elevated blood lactate, low serum albumin, high fever, or organ dysfunction).
For severe Clostridium difficile infection, use:

vancomycin 125 mg (child: 10 mg/kg up to 125 mg) orally or enterally, 6-hourly for 10
days [Note 17] [Note 18].
Intravenous vancomycin is not effective against C. difficile infection due to inadequate penetration of the drug into
the lumen of the colon.
There is evidence that fidaxomicin is associated with lower rates of recurrence compared to vancomycin, but data
for its use in severe disease are lacking.
In complicated cases (eg hypotension or shock, ileus, megacolon), in addition to oral or enteral vancomycin, use:
metronidazole 500 mg (child: 12.5 mg/kg up to 500 mg) intravenously, 8-hourly for 10
days.
Consider adding intracolonic vancomycin, particularly in the presence of ileus. Use:
vancomycin 500 mg in 100 mL sodium chloride 0.9% rectally (via rectal tube),
administered as a retention enema, 6-hourly.
Early surgical referral is indicated for patients with severe disease, because outcomes are poor after organ
dysfunction is established. Patients with severe disease may require a colectomy to survive, particularly if toxic
megacolon develops. Faecal microbiota transplantation (FMT) can also be considered—recent data show lower
mortality in patients with severe C. difficile treated with faecal microbiota transplantation [Note 19]. For more
information about faecal microbiota transplantation, see Treatment for second and subsequent recurrences or
ongoing refractory disease.
The role of bezlotoxumab in the treatment of C. difficile infection is not yet defined.
Note 18: Higher doses of vancomycin (250 mg or 500 mg 6-hourly) can be used for fulminant disease.
Note 19: Hocquart M, Lagier JC, Cassir N, Saidani N, Eldin C, Kerbaj J, et al. Early fecal microbiota
transplantation improves survival in severe Clostridium difficile infections. Clin Infect Dis 2018;66(5):645-50.
[URL]
Follow-up testing
Repeat microbiological testing for C. difficile is only indicated in symptomatic patients. Tests often remain positive
for over a month, even after effective therapy, so repeat testing is not generally indicated within this time.

Infection with Shiga toxin–producing strains of Escherichia coli (eg 0157:H7 or 0111:H8) may cause bloody
diarrhoea and lead to the development of haemolytic uraemic syndrome (HUS) or thrombotic thrombocytopenic
purpura, particularly in children. Antibiotic therapy should not be given to children with enterohaemorrhagic E.
coli who do not have fever or sepsis, because antibiotics increase toxin release and therefore the risk of developing
haemolytic uraemic syndrome. Rehydration is the mainstay of therapy.
In otherwise healthy patients without risk factors for complications, nontyphoidal Salmonella enteritis is usually
self-limited. Antibiotic treatment is not indicated in these patients because it does not shorten duration of illness, is
associated with a higher rate of adverse events, and can prolong excretion of pathogens.
Antibiotic treatment of nontyphoidal Salmonella enteritis is not indicated for otherwise healthy patients without risk factors for
complications.
In most cases antibiotic therapy should be restricted to patients with severe disease, and those at risk of invasive
disease or complications:
neonates and children younger than 3 months. Before administering antibiotics, collect blood samples for
culture and, when relevant, cerebrospinal fluid samples for microscopy and culture, to exclude systemic
infection. For antibiotic choice and dosing in neonates, seek expert advice
patients of any age with severe diarrhoea
patients with invasive disease, sepsis or bacteraemia
patients with prosthetic vascular grafts or haemoglobinopathies
immunocompromised patients.
Rehydration is the mainstay of therapy.
If antibiotic therapy is indicated for Salmonella enteritis, use:
1 azithromycin 1 g (child: 20 mg/kg up to 1 g) orally on the first day, then 500 mg (child: 10
mg/kg up to 500 mg) orally, daily for a further 4 days
OR
20] [Note 21].
If the pathogen is susceptible to amoxicillin, use:
amoxicillin 1 g (child: 30 mg/kg up to 1 g) orally, 8-hourly for 5 days.
Initial intravenous therapy is recommended in the following situations:
when oral therapy is not possible

in children aged 1 to 3 months
in patients with bacteraemia, endovascular infection or osteoarticular infection.
For initial intravenous therapy, use:
1 ceftriaxone 2 g (child 1 month or older: 100 mg/kg up to 2 g) intravenously, daily; for

patients with septic shock or requiring intensive care support, use 1 g (child 1 month or
older: 50 mg/kg up to 1 g) intravenously, 12-hourly
OR
1 ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 12-hourly [Note 20].
The duration of intravenous therapy depends on the site of infection—seek expert advice. In uncomplicated
infection, a switch to oral therapy (as above) may be appropriate when the patient becomes afebrile; however, in
patients with bacteraemia, endovascular infection, osteoarticular infection, and in children younger than 3 months,
it may be appropriate to use intravenous therapy for the duration of treatment.
Antibiotics are not indicated for the asymptomatic short-term carrier state.
Shigella enteritis (shigellosis)

Shigella is easily transmitted person-to-person.
Send faecal samples for culture and susceptibility testing for cases of suspected Shigella enteritis.
Send faecal samples for culture and susceptibility testing for cases of suspected Shigella enteritis.
Antibiotic susceptibility of Shigella strains varies from country to country, and multidrug-resistant strains are
present in many regions, including Australia. The situation is dynamic—at the time of writing, there are high
levels of antimicrobial resistance in Australia among circulating Shigella species, particularly in the men who have
sex with men (MSM) community.
Although shigellosis is a self-limiting infection, antibiotic therapy reduces disease transmission and reduces
duration of symptoms by 2 days. Antibiotic therapy is indicated for patients with severe disease and in
immunocompromised patients. Treatment may also be used to reduce transmission in the following groups:
children younger than 6 years, food handlers, healthcare workers, childcare workers, and people living or working
in residential aged-care facilities, prisons and other residential facilities. However, the approach to reducing
transmission varies between states and territories.
Measures to prevent transmission are essential. These include good hygiene practices and staying away from
childcare, school or work. In particular, advise men who have sex with men to abstain from sex while symptomatic
and for 7 days after symptoms have resolved.
Rehydration is the mainstay of therapy in all patients.
Due to high rates of resistance, it is not possible to recommend an empirical oral antibiotic that will be effective in
the majority of patients. It is usually appropriate to wait for results of susceptibility testing before starting
treatment. If empirical therapy with an oral antibiotic is required before susceptibility results are available, seek
advice from the local public health authority about local susceptibility patterns [Note 22].
In patients with shigellosis who have severe disease, and in immunocompromised patients when treatment is
considered necessary, use ceftriaxone while awaiting the results of susceptibility testing:
ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously, daily.
Modify therapy based on the results of culture and susceptibility testing, if possible. The total duration of treatment
is 5 days.
are available here.
Vibrio cholerae (cholera)

Cholera is caused by Vibrio cholerae serotypes O1 and O139. It is rarely seen in Australia. A few cases have been
acquired through ingestion of contaminated water in northern Australia. More often, infection diagnosed in
Australia has been acquired overseas (eg returned travellers or recent migrants from countries where cholera is
prevalent).
Rehydration is the mainstay of treatment. Antibiotic therapy reduces the volume and duration of diarrhoea.
Consider:
1 azithromycin 1 g (child: 20 mg/kg up to 1 g) orally, as a single dose
OR
1 ciprofloxacin 1 g (child: 20 mg/kg up to 1 g) orally, as a single dose [Note 23] [Note 24].
Antibiotic-resistant strains of V. cholerae are now common in some regions. In the event of clinical failure,
treatment should be guided by the results of susceptibility testing.
An oral cholera vaccine is available; for more information see the Australian Immunisation Handbook [URL].
Vibrio: noncholera species causing enteritis

Enteritis caused by Vibrio parahaemolyticus and other noncholera vibrios occasionally occurs following ingestion
of contaminated shellfish. The disease is usually self-limiting. Rehydration is the mainstay of therapy. In cases of
severe or persistent disease, use:
doxycycline orally, 12-hourly for 10 days

adult: 100 mg
child 8 years or older and more than 35 kg: 100 mg.
For children younger than 8 years of age, seek expert advice.
Ceftriaxone, ciprofloxacin, norfloxacin, and trimethoprim+sulfamethoxazole have also been used successfully for
treatment.
Yersinia enterocolitica causes a spectrum of disease that includes acute enterocolitis, and mesenteric adenitis or
pharyngitis with or without diarrhoea. It is usually foodborne. Postinfectious complications include reactive
arthritis and erythema nodosum.
Rehydration is the mainstay of therapy. A benefit for antimicrobial therapy in immunocompetent patients with
Yersinia enterocolitis has not been demonstrated and, because most acute infections are self-limiting, antibiotics
are not indicated. In immunocompromised patients or patients with persistent or extraintestinal disease, use:
25] [Note 26]
OR
1 norfloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally, 12-hourly for 5 days [Note 27]
[Note 28]
OR

160+800 mg) orally, 12-hourly for 5 days.
Y. enterocolitica bacteraemia is usually treated with a prolonged course of ciprofloxacin (3 weeks). Moderate- and
broad-spectrum cephalosporins, doxycycline, and trimethoprim+sulfamethoxazole have also been used, but
treatment failures have been reported.
Antibiotic-associated diarrhoea
In most cases of antibiotic-associated diarrhoea, a pathogen is not identified. Clostridium difficile is the pathogen
in a significant minority of cases. If possible, stop antibiotics considered likely to be causing the symptoms.
Prophylactic probiotics are widely used to prevent antibiotic-associated diarrhoea, but a large randomised
controlled trial did not demonstrate a benefit [Note 29]. In immunocompromised patients, occasional cases of
probiotic-associated bacteraemia have occurred.
For information about C. difficile diarrhoea, see here.
Note 29: Allen SJ, Wareham K, Wang D, Bradley C, Hutchings H, Harris W, et al. Lactobacilli and
bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older
inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet
2013;382(9900):1249-57. [URL]
Travellers’ diarrhoea
Introduction
Diarrhoea is the most common illness acquired overseas, affecting 20 to 50% of people travelling short term from
developed to developing areas. It is caused by a wide range of pathogens. While strains of enterotoxigenic
Escherichia coli (ETEC) are the most common cause, the incidence of each pathogen depends on the location of
acquisition. Salmonella and Campylobacter appear to be increasing in importance in Asia; norovirus is the
predominant cause of infection on cruise ships.
Prevention of travellers’ diarrhoea

The risk of travellers’ diarrhoea can be substantially reduced by taking simple precautions in areas where clean
water and food hygiene cannot be guaranteed. These precautions include selecting: freshly cooked foods that are
served steaming hot; fruit that can be peeled; and beverages that are bottled, canned or recently boiled. Travellers
should avoid raw or undercooked food (particularly meat or seafood), fresh salads, peeled fruit, unpasteurised milk
or milk products, unboiled water, and ice. Foods sold by roadside vendors often pose the greatest infection risk.
Although antimicrobial prophylaxis is effective, early treatment (eg stand-by self-treatment) is preferred for most
travellers (including children), because there is a risk of developing antimicrobial resistance with prophylaxis.
For most travellers, early treatment is preferred because there is a risk of developing antimicrobial resistance with prophylaxis.
Prophylaxis can be considered for travellers who are at risk of severe disease (eg immunocompromised patients).
If prophylaxis is used, it should not be continued for longer than 3 weeks. In many regions, resistance to antibiotics
used to prevent travellers’ diarrhoea (eg quinolones) is increasing—if possible, consider local susceptibility data
when choosing prophylaxis. Seek expert advice.
There is insufficient evidence that the currently available cholera vaccine protects against travellers’ diarrhoea
caused by enterotoxigenic E. coli (ETEC); it is not licensed for this indication in Australia.
Treatment of travellers’ diarrhoea
Mild disease
Travellers’ diarrhoea is usually self-limiting; mild cases require symptomatic treatment only. Rehydration is the
mainstay of therapy; antimotility drugs can be considered but should not be used in children.
Moderate to severe disease
Rehydration is the mainstay of therapy, and it is essential in young children.
Antibiotics are effective for moderate to severe travellers' diarrhoea, and self-treatment is often acceptable. A
single large dose of antibiotics is usually effective, though a longer course should be used in patients with fever or
bloody stools. Consider:
1 azithromycin 1 g (child: 20 mg/kg up to 1 g) orally, as a single dose
OR
1 norfloxacin 800 mg (child: 20 mg/kg up to 800 mg) orally, as a single dose [Note 30]
[Note 31]
OR
2 ciprofloxacin 750 mg (child: 20 mg/kg up to 750 mg) orally, as a single dose [Note 32]
[Note 33].
Antimotility drugs can be used in combination with antibiotics in adult patients who do not have fever or bloody
stools.
If fever or bloody stools are present, or if symptoms do not improve after the single large dose of antibiotic,
continue with:
1 azithromycin 500 mg (child: 10 mg/kg up to 500 mg) orally, once daily for a further 2
days
OR
1 norfloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally, 12-hourly for a further 2 days
[Note 30] [Note 31]
OR
2 ciprofloxacin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 12-hourly for a further 2
days [Note 32] [Note 33].
Quinolone resistance is emerging in Gram-negative pathogens, particularly in South Asia, and should be taken into
account when choosing therapy for travellers’ diarrhoea.
Persistent diarrhoea in returned travellers
It is important to consider both infective and noninfective causes (eg postinfectious irritable bowel syndrome,
lactose intolerance, coeliac disease) of persistent diarrhoea in a returned traveller. A detailed travel history,
including potential environmental exposures, can give important aetiological clues.
Investigations should usually include microscopy and culture of stool samples. Multiple samples may be required
to diagnose some parasitic infections. Serology can be helpful in some cases (eg amoebiasis, schistosomiasis,
strongyloidiasis). A cause will not be identified in a large proportion of cases. Many patients will have developed
irritable bowel syndrome, which can be precipitated by an episode of infectious diarrhoea.
If the cause of symptoms is not identified, a trial of empirical therapy for giardiasis may be considered. If
symptoms persist, seek expert advice.
Outbreaks of diarrhoea in residential aged-care facilities

To prevent spread in residential aged-care facilities, early recognition of infectious diarrhoea in residents and rapid
implementation of infection control measures is crucial.
The following criteria, individually or in combination, have been used to define gastroenteritis in long-term care
facilities for surveillance purposes:
three or more loose bowel motions above baseline over 24 hours

two or more episodes of vomiting over 24 hours
nausea, vomiting, diarrhoea, or abdominal pain or tenderness in a patient who has a pathogen detected in a
stool sample.
Notify the local public health authority [Note 34] when an outbreak is suspected (more than two cases within 72
hours). Take stool samples from symptomatic residents if indicated. Further investigation and management should
be conducted in consultation with the public health authority; such management may include separating unwell
residents from the rest of the community to prevent the spread of infection.
Clinical management of acute infectious diarrhoea in patients in residential aged-care facilities is the same as for
other patients.
are available here.
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infants with diarrhea: a randomized placebo-controlled trial. Gastroenterology 2013;145(4):740–8.e8.
Sertan Kara S, Volkan B, Erten I. The effect of gelatin tannate in acute diarrhea in children [conference abstract].
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Sheele J, Cartowski J, Dart A, Poddar A, Gupta S, Stashko E, et al. Saccharomyces boulardii and bismuth
subsalicylate as low-cost interventions to reduce the duration and severity of cholera. Pathogens and Global Health
2015;109(6):275–82.
Virk A, Mandrekar J, Berbari EF, Boyce TG, Fischer PR, Kasten MJ, et al. A randomized, double blind, placebo-
controlled trial of an oral synbiotic (AKSB) for prevention of travelers' diarrhea. Journal of Travel Medicine
2013;20(2):88–94.
Wang W, Cui LH. Efficacy of rifaximin tablet combined with Bifid-triple viable capsule in 84 middle-aged and elderly
patients of acute infectious diarrhea. [Chinese]. Chinese Journal of New Drugs 2016;25(9):1036–9.
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Zanger P, Nurjadi D, Gabor J, Gaile M, Kremsner PG. Effectiveness of rifaximin in prevention of diarrhoea in
individuals travelling to south and southeast Asia: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet
Infect Dis 2013;13(11):946–54.
Akamine CM, Ing MB, Jackson CS, Loo LK. The efficacy of intracolonic vancomycin for severe Clostridium difficile
colitis: a case series. BMC Infect Dis 2016;16:316.
Beinortas T, Burr NE, Wilcox MH, Subramanian V. Comparative efficacy of treatments for Clostridium difficile infection:
a systematic review and network meta-analysis. Lancet Infect Dis 2018.
Gentry CA, Giancola SE, Thind S, Kurdgelashvili G, Skrepnek GH, Williams RJ, 2nd. A Propensity-Matched Analysis
Between Standard Versus Tapered Oral Vancomycin Courses for the Management of Recurrent Clostridium difficile
Infection. Open Forum Infect Dis 2017;4(4):ofx235.
Hocquart M, Lagier JC, Cassir N, Saidani N, Eldin C, Kerbaj J, et al. Early fecal microbiota transplantation improves
survival in severe Clostridium difficile infections. Clin Infect Dis 2018;66(5):645–50.
Johnson S, Louie TJ, Gerding DN, Cornely OA, Chasan-Taber S, Fitts D, et al. Vancomycin, metronidazole, or
tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis
2014;59(3):345–54.
Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, et al. Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal
Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA
2017;318(20):1985–93.
McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, et al. Clinical Practice Guidelines for
Clostridium difficile infection in adults and children: 2017 Update by the Infectious Diseases Society of America (IDSA)
and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018;66(7):e1–e48.
Moayyedi P, Yuan Y, Baharith H, Ford AC. Faecal microbiota transplantation for Clostridium difficile-associated
diarrhoea: a systematic review of randomised controlled trials. Med J Aust 2017;207(4):166–72.
Nelson RL, Suda KJ, Evans CT. Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults. Cochrane
Database Syst Rev 2017;3:CD004610.
Quraishi MN, Widlak M, Bhala N, Moore D, Price M, Sharma N, et al. Systematic review with meta-analysis: the
efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection.
Aliment Pharmacol Ther 2017;46(5):479–93.
Teasley DG, Gerding DN, Olson MM, Peterson LR, Gebhard RL, Schwartz MJ, et al. Prospective randomised trial of
metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet 1983;2(8358):1043–
6.
Trubiano JA, Cheng AC, Korman TM, Roder C, Campbell A, May ML, et al. Australasian Society of Infectious
Diseases updated guidelines for the management of Clostridium difficile infection in adults and children in Australia and
New Zealand. Intern Med J 2016;46(4):479–93.
van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces
for recurrent Clostridium difficile. N Engl J Med 2013;368(5):407–15.
Wenisch C, Parschalk B, Hasenhundl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin,

metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis
1996;22(5):813–8.
Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of
Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45(3):302–7.
Leibovitz E, Janco J, Piglansky L, Press J, Yagupsky P, Reinhart H, et al. Oral ciprofloxacin vs. intramuscular
ceftriaxone as empiric treatment of acute invasive diarrhea in children. Pediatr Infect Dis J 2000;19(11):1060–7.
Onwuezobe IA, Oshun PO, Odigwe CC. Antimicrobials for treating symptomatic non-typhoidal Salmonella infection.
Cochrane Database Syst Rev 2012;11:CD001167.
Shigella enteritis (shigellosis)
Brown J, Willcox SJ, Franklin N, Hazelton B, O'Sullivan MV. Shigellosis: high rates of antibiotic resistance necessitate
new treatment recommendations. Med J Aust 2016;204(7):261.
Christopher PR, David KV, John SM, Sankarapandian V. Antibiotic therapy for Shigella dysentery. Cochrane Database
Syst Rev 2010;(8):CD006784.
Department of Health & Human Services, Victoria. Important health message for Shigellosis – changed management
recommendations due to increased antibiotic resistance. Melbourne: State Government of Victoria; 17 November 2017.
https://www2.health.vic.gov.au/about/news-and-events/healthalerts/advisory-2017-11-shigellosis.
NSW Health. MDR shigellosis alert. Sydney: NSW Government, Ministry of Heath; 25 July 2018.
https://www.health.nsw.gov.au/Infectious/alerts/Pages/shigella-drug-resistance.aspx.
Travellers’ diarrhoea
Adachi JA, Ericsson CD, Jiang ZD, DuPont MW, Martinez-Sandoval F, Knirsch C, et al. Azithromycin found to be
comparable to levofloxacin for the treatment of US travelers with acute diarrhea acquired in Mexico. Clin Infect Dis
2003;37(9):1165–71.
Riddle MS, Connor BA, Beeching NJ, DuPont HL, Hamer DH, Kozarsky P, et al. Guidelines for the prevention and
treatment of travelers' diarrhea: a graded expert panel report. J Travel Med 2017;24(suppl_1):S57–S74.
Tribble DR, Sanders JW, Pang LW, Mason C, Pitarangsi C, Baqar S, et al. Traveler's diarrhea in Thailand:
randomized, double-blind trial comparing single-dose and 3-day azithromycin-based regimens with a 3-day levofloxacin
regimen. Clin Infect Dis 2007;44(3):338–46.
Outbreaks of diarrhoea in residential aged-care facilities
Allen SJ, Wareham K, Wang D, Bradley C, Hutchings H, Harris W, et al. Lactobacilli and bifidobacteria in the
prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a
randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2013;382(9900):1249–57.
Stone ND, Ashraf MS, Calder J, Crnich CJ, Crossley K, Drinka PJ, et al. Surveillance definitions of infections in long-
term care facilities: revisiting the McGeer criteria. Infect Control Hosp Epidemiol 2012;33(10):965–77.
Cervical lymphadenitis
Aetiology of cervical lymphadenitis
Cervical lymphadenitis (cervical lymphadenopathy) is common in children and is usually associated with a viral or
bacterial infection; noninfective causes are less common. Cervical lymphadenitis is less common in adults but is
more likely to be associated with a noninfective cause.
Noninfective causes of cervical lymphadenitis include Kawasaki disease; Kikuchi disease; periodic fever, aphthous
stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome; and malignancy (eg lymphoma).
If cervical lymphadenitis is secondary to infection at another site, manage as for the primary source of infection
(eg tonsillitis, quinsy, odontogenic infection).
Acute unilateral cervical lymphadenitis

Aetiology
Acute unilateral cervical lymphadenitis is usually caused by Staphylococcus aureus or Streptococcus pyogenes
(group A streptococcus). Anaerobic bacteria may be involved in patients with dental or periodontal disease. In
neonates, Streptococcus agalactiae (group B streptococcus) can cause a cellulitis–adenitis syndrome.
Approach to management
Children with acute unilateral lymphadenitis who are relatively well (eg afebrile) generally do not require
investigation; however, take samples of fluid or tissue for culture and susceptibility testing if incising and draining
an abscess. Start oral antibiotic therapy empirically if the child has suppurative disease (eg fluctuant or pointing
abscess).
For children with severe disease (eg febrile, ill-appearing), collect blood samples for culture and susceptibility
testing before starting intravenous antibiotic therapy.
For a fluctuant or pointing abscess, consider referral to a paediatric surgeon for incision and drainage.
Oral antibiotic therapy for acute suppurative unilateral cervical lymphadenitis

For children with acute suppurative unilateral cervical lymphadenitis who are relatively well, while awaiting the
results of culture and susceptibility tests (if they have been performed), use:
1 cefalexin 12.5 mg/kg up to 500 mg orally, 6-hourly for 7 days
OR
1 dicloxacillin 12.5 mg/kg up to 500 mg orally, 6-hourly for 7 days
OR
1 flucloxacillin 12.5 mg/kg up to 500 mg orally, 6-hourly for 7 days.
Cefalexin is often preferred in children because the liquid formulation is better tolerated. In most cases, it can also
be used for children with delayed nonsevere hypersensitivity to penicillins [Note 1].
For children with immediate (nonsevere or severe) or delayed severe hypersensitivity to penicillins, or an
increased risk of methicillin-resistant S. aureus (MRSA) infection (see Box 2.31), use:
1 trimethoprim+sulfamethoxazole (child 1 month or older) 4+20 mg/kg up to 160+800 mg

orally, 12-hourly for 7 days
OR
2 clindamycin 10 mg/kg up to 450 mg orally, 8-hourly for 7 days.
Modify treatment based on the results of culture and susceptibility testing, if available.
For children who fail to improve after several days of oral antibiotic therapy (eg children with progressive
swelling), switch to intravenous therapy and review the need for surgical drainage.
Note 1: It is safe to use cefalexin in patients who had a delayed nonsevere reaction to a penicillin in the distant
past. It is also safe to use cefalexin in patients who have had a delayed nonsevere reaction recently, unless the
reaction involved amoxicillin or ampicillin, because cross-reactivity between these drugs is possible. For patients
who have had a recent delayed nonsevere reaction to amoxicillin or ampicillin, use the drugs recommended for
Intravenous antibiotic therapy for severe acute unilateral cervical lymphadenitis

For children with severe acute unilateral cervical lymphadenitis, while awaiting the results of culture and
susceptibility testing, use:
flucloxacillin 50 mg/kg up to 2 g intravenously, 6-hourly until significant improvement,

then switch to oral therapy if tolerated.
cefazolin 50 mg/kg up to 2 g intravenously, 8-hourly until significant improvement, then

switch to oral therapy if tolerated.
For children with immediate severe or delayed severe hypersensitivity to penicillins, use:
1 clindamycin 15 mg/kg up to 600 mg intravenously, 8-hourly until significant

improvement, then switch to oral therapy if tolerated
OR
2 lincomycin 15 mg/kg up to 600 mg intravenously, 8-hourly until significant improvement,

For children at increased risk of methicillin-resistant S. aureus (MRSA) infection (see Box 2.31), use:
use. Continue until significant improvement, then switch to oral therapy if tolerated.
vancomycin:
1 clindamycin 15 mg/kg up to 600 mg intravenously, 8-hourly until significant

improvement, then switch to oral therapy if tolerated
OR
2 lincomycin 15 mg/kg up to 600 mg intravenously, 8-hourly until significant improvement,

Acute bilateral cervical lymphadenitis

Acute bilateral cervical lymphadenitis is usually caused by viruses. It is often secondary to viral upper respiratory
tract infection, but can also follow pharyngitis caused by Streptococcus pyogenes (group A streptococcus) (see
Sore throat for assessment and management). Acute bilateral cervical lymphadenitis may also be due to infectious
mononucleosis caused by Epstein–Barr virus, or rubella. Typically, viral infections resolve within 1 to 2 weeks
without complication; antibiotic therapy is not needed. If bacterial infection is suspected (eg fluctuant or pointing
abscess), treat as for acute unilateral cervical lymphadenitis.
Chronic cervical lymphadenitis

Chronic cervical lymphadenitis is usually caused by nontuberculous mycobacteria, particularly in young children,
or Bartonella henselae (see Bartonella infections for management). Toxoplasma gondii or other mycobacteria (eg
Mycobacterium tuberculosis, Mycobacterium bovis) are less common causes of infection.
In Australian children, especially those younger than 5 years, nontuberculous mycobacterial infection (in particular
Mycobacterium avium complex infection) is the most common cause of chronic cervical lymphadenitis. Referral to
an expert is required; surgical excision may be indicated. See also Nontuberculous mycobacterial infections.
Exclude M. tuberculosis in Aboriginal and Torres Strait Islander children from central and northern Australia;
people born in countries where tuberculosis is endemic; and potentially exposed persons (see Tuberculosis).
Consider HIV infection in people born in countries with high HIV prevalence or potentially exposed persons.
Adults with chronic cervical lymphadenitis require evaluation for noninfective causes (eg malignancy) if history
and examination do not explain the inflamed cervical node.
For chronic cervical lymphadenitis, consider diagnostic fine-needle aspiration of a lymph node. Send the aspirate
for Gram stain, aerobic and anaerobic culture, acid-fast stain, mycobacterial culture and nucleic acid amplification
testing (eg polymerase chain reaction [PCR]). Perform serological testing for B. henselae and T. gondii. If the
diagnosis remains in doubt, consider referral to a paediatric surgeon or otolaryngologist for lymph node biopsy
(complete excision or core biopsy) for histology, culture and nucleic acid amplification testing (eg PCR).
Key references
Barton LL, Feigin RD. Childhood cervical lymphadenitis: a reappraisal. J Pediatr 1974;84(6):846–52.
Burton MJ, Pollard AJ, Ramsden JD, Chong LY, Venekamp RP. Tonsillectomy for periodic fever, aphthous stomatitis,
pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev 2014;(9):CD008669.
Chang CC, Lee CJ, Ou LS, Wang CJ, Huang YC. Disseminated cat-scratch disease: case report and review of the
literature. Paediatr Int Child Health 2016;36(3):232–4.
Cuello-Garcia CA, Perez-Gaxiola G, Jimenez Gutierrez C. Treating BCG-induced disease in children. Cochrane
Database Syst Rev 2013;(1):CD008300.
Dajani AS, Garcia RE, Wolinsky E. Etiology of cervical lymphadenitis in children. N Engl J Med 1963;268:1329–33.
Daum RS, Miller LG, Immergluck L, Fritz S, Creech CB, Young D, et al. A placebo-controlled trial of antibiotics for
smaller skin abscesses. N Engl J Med 2017;376(26):2545–55.
Fluegge K, Greiner P, Berner R. Late onset group B streptococcal disease manifested by isolated cervical
lymphadenitis. Arch Dis Child 2003;88(11):1019–20.
Garnier C, Martin-Blondel G, Debuisson C, Dubois D, Debard A, Cuzin L, et al. Intra-nodal injection of gentamicin for
the treatment of suppurated cat scratch disease's lymphadenitis. Infection 2016;44(1):23–7.
Han PS, Orta P, Kwon DI, Inman JC. Mycobacterium bovis cervical lymphadenitis: A representative case and review.
Int J Pediatr Otorhinolaryngol 2015;79(11):1798–801.
Kwon M, Seo JH, Cho KJ, Won SJ, Woo SH, Kim JP, et al. Suggested protocol for managing acute suppurative
cervical lymphadenitis in children to reduce unnecessary surgical interventions. Ann Otol Rhinol Laryngol
2016;125(12):953–8.
Lopez-Varela E, Garcia-Basteiro AL, Santiago B, Wagner D, van Ingen J, Kampmann B. Non-tuberculous

mycobacteria in children: muddying the waters of tuberculosis diagnosis. Lancet Respir Med 2015;3(3):244–56.
Mahadevan M, Neeff M, Van Der Meer G, Baguley C, Wong WK, Gruber M. Non-tuberculous mycobacterial head and
neck infections in children: Analysis of results and complications for various treatment modalities. Int J Pediatr
Otorhinolaryngol 2016;82:102–6.
McClay JE, Garcia C. Management of cervicofacial nontuberculous lymphadenitis in children. Curr Opin Otolaryngol
Head Neck Surg 2013;21(6):581–7.
Perdikogianni C, Galanakis E. Non-tuberculous mycobacterial cervical lymphadenitis in the immunocompetent child:

diagnostic and treatment approach. Expert Rev Anti Infect Ther 2014;12(8):959–65.
Scobie WG. Acute suppurative adenitis in children: a review of 964 cases. Scott Med J 1969;14(10):352–4.
Tebruegge M, Pantazidou A, MacGregor D, Gonis G, Leslie D, Sedda L, et al. Nontuberculous mycobacterial disease
in children - epidemiology, diagnosis & management at a tertiary center. PLoS One 2016;11(1):e0147513.
Worley ML, Seif JM, Whigham AS, Mims JW, Shetty AK, Evans AK. Suppurative cervical lymphadenitis in infancy:
microbiology and sociology. Clin Pediatr (Phila) 2015;54(7):629–34.
Xu JJ, Peer S, Papsin BC, Kitai I, Propst EJ. Tuberculous lymphadenitis of the head and neck in Canadian children:
Experience from a low-burden region. Int J Pediatr Otorhinolaryngol 2016;91:11–4.
Pharyngeal diphtheria
What is pharyngeal diphtheria?
Pharyngeal diphtheria is caused by infection with toxigenic strains of Corynebacterium diphtheriae. It is rare in
Australia; infection is usually associated with C. diphtheriae exposure during overseas travel to an affected area, or
following contact with a traveller who has returned from an affected area. The diphtheria toxoid vaccine protects
against infection with toxigenic C. diphtheriae strains—check the immunisation status of patients with suspected
pharyngeal diphtheria.
Diphtheria infection can cause other manifestations (eg cutaneous disease)—seek expert advice for patient
management.
While nontoxigenic strains of C. diphtheriae can cause sore throat and more invasive disease (eg endocarditis),
they are not known to cause diphtheria. The diphtheria toxoid vaccine does not protect against nontoxigenic C.
diphtheriae strains. Seek expert advice for management of patients with infection caused by nontoxigenic strains
of C. diphtheriae.
Management of pharyngeal diphtheria

Pharyngeal diphtheria presents as gross membranous pharyngitis, with or without airway obstruction. Patients with
airway obstruction require urgent escorted transfer to hospital, intensive monitoring, and early referral to an
otolaryngologist. In patients without airway obstruction, exclude Epstein–Barr virus (EBV) infection because this
is a more common cause of severe sore throat. The diphtheria toxin can cause systemic complications including
demyelinating peripheral neuritis and myocarditis; electrocardiogram (ECG) monitoring is recommended.
Report cases of pharyngeal diphtheria to the local public health authority [Note 1] [Note 2]. In collaboration with
the public health authority, initiate vaccination and clearance antibiotics for contacts of the index case.
Diphtheria antitoxin is the primary treatment for pharyngeal diphtheria. Access to diphtheria antitoxin can be
coordinated through the local public health authority [Note 3]. The antitoxin should be administered in hospital
with expert guidance because it can cause acute allergic reactions. For more information on diphtheria antitoxin
and public health management of diphtheria, see the Australian Immunisation Handbook [URL].
In patients with pharyngeal diphtheria, antibiotics are not a substitute for treatment with diphtheria antitoxin.
In patients with pharyngeal diphtheria, the role of adjunctive antibiotic treatment is to eradicate C. diphtheriae,
which prevents further toxin production.
For patients with severe pharyngeal diphtheria (eg high fever, extensive neck swelling, upper airway
obstruction), antibiotic therapy with benzylpenicillin and azithromycin is recommended until the results of culture
and susceptibility testing are available. Use:
PLUS
azithromycin 500 mg (child: 10 mg/kg up to 500 mg) intravenously, daily.
If intravenous azithromycin is not available, seek expert advice; see also Antimicrobial drug shortages.
For patients with severe pharyngeal diphtheria who are hypersensitive to penicillins, use azithromycin alone (see
dosage above).
Once the results of culture and susceptibility testing are available, combination therapy is not necessary; change to
treatment with benzylpenicillin or azithromycin alone. See below for advice on intravenous to oral switch.
For patients with nonsevere pharyngeal diphtheria (eg afebrile, limited neck swelling, no airway compromise),
use:
benzylpenicillin 1.2 g (child: 50 mg/kg up to 1.2 g) intravenously, 6-hourly; see below for
advice on intravenous to oral switch.
For patients with nonsevere pharyngeal diphtheria who are hypersensitive to penicillins, use:
azithromycin 500 mg (child: 10 mg/kg up to 500 mg) intravenously, daily; see below for
advice on intravenous to oral switch.
Intravenous to oral switch: once the patient improves and can swallow comfortably, switch to oral therapy (see
Box 2.35 for guidance on when to switch to oral therapy). Use:
phenoxymethylpenicillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly to

complete a total of 14 days of therapy (intravenous + oral).
For oral continuation therapy in patients hypersensitive to penicillins, use:
azithromycin 500 mg (child: 12 mg/kg up to 500 mg) orally, daily to complete a total of 5
days of therapy (intravenous + oral).
If the patient is not fully vaccinated, give age-appropriate catch-up diphtheria vaccination after recovery—see the
Australian Immunisation Handbook [URL].
Note 1: For Australian national notifiable diseases and case definitions, see the Communicable Diseases Network Australia (CDNA) website.
Note 2: Contact details for Australian state and territory government health departments and public health units are available here.
Note 3: Diphtheria antitoxin is not registered for use in Australia but is available via the Special Access Scheme.
Key references
Australian Technical Advisory Group on Immunisation (ATAGI). The Australian immunisation handbook. 10th ed.
Canberra: National Health and Medical Research Council (NHMRC); 2013 [Updated 2017].
http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/Handbook10-home
Médecins Sans Frontières. Diptheria [Chapter 2: Respiratory diseases]. In: Grouzard V, Rigal J, Sutton M. Clinical
guidelines - Diagnosis and treatment manual. Geneva: Médecins Sans Frontières; 2017.
https://medicalguidelines.msf.org/viewport/CG/english/diphtheria-16689456.html
National Institute for Communicable Diseases (NICD) Guidelines writing committee. Diphtheria: NICD
recommendations for diagnosis, management and public health response. Version 3.0. Johannesburg: NICD; 2018.
http://www.nicd.ac.za/index.php/diphtheria/
Public Health England. Public health control and management of diphtheria (in England and Wales): 2015 guidelines.
London: Public Health England; 2015. https://www.gov.uk/government/publications/diphtheria-public-health-control-
and-management-in-england-and-wales
World Health Organization (WHO). Antibiotics [module 6]. In: Diphtheria: Clinical management of respiratory diphtheria
[online course]. Geneva: WHO; 2017. https://openwho.org/courses/diphtheria-clinical-management
World Health Organization (WHO). Diphtheria: Clinical management of respiratory diphtheria [online course]. Geneva:
WHO; 2017. https://openwho.org/courses/diphtheria-clinical-management
Acute epiglottitis
Treatment of acute epiglottitis
Acute epiglottitis (supraglottitis) is a life-threatening condition caused by infection of the epiglottis and
surrounding structures. Since the development and widespread use of the Haemophilus influenzae type b (Hib)
vaccine, epiglottitis has become rare in children. Epiglottitis is also rare in adults; if infection occurs,
Streptococcus pneumoniae is the most common pathogen.
Patients with epiglottitis often have sepsis or septic shock (for definitions, see here for adults or here for children).
For patients with sepsis or septic shock, start antibiotic therapy within 1 hour of the patient presenting to medical
care or, for a ward-based patient, developing sepsis or septic shock; antibiotics should be given immediately after
Patients with acute epiglottitis require urgent escorted transfer to hospital with airway management. All patients
require intensive monitoring, early referral to an otolaryngologist and intravenous antibiotic therapy.
For treatment of patients with acute epiglottitis, use:

patients with septic shock or requiring intensive care support, use ceftriaxone 1 g (child 1
month or older: 50 mg/kg up to 1 g) intravenously, 12-hourly. See below for advice on
intravenous to oral switch and duration of therapy
OR
1 cefotaxime 1 g (child: 50 mg/kg up to 1 g) intravenously, 8-hourly; for patients with

septic shock or requiring intensive care support, use cefotaxime 2 g (child: 50 mg/kg up to
2 g) intravenously, 8-hourly. See below for advice on intravenous to oral switch and
duration of therapy.
The above regimens can be used for patients with immediate nonsevere or delayed nonsevere hypersensitivity to
penicillins.
moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, daily; see below for
advice on intravenous to oral switch and duration of therapy [Note 1].
Adding corticosteroids to reduce airway inflammation is controversial. Retrospective studies have not consistently
found that corticosteroids reduce the length of intensive care or hospital admission, or the period of intubation.
Despite this, it is common practice for corticosteroids to be administered. A typical regimen is:
dexamethasone 10 mg (child: 0.15 mg/kg up to 10 mg) intravenously, as a single dose;

repeat after 24 hours if required.
Intravenous to oral switch: switch to appropriate oral therapy once the patient improves, guided by the results of
culture and susceptibility testing. See Box 2.35 for guidance on when to switch to oral therapy.
For oral continuation therapy for patients with acute epiglottitis, if microbiological results are not available, use:
amoxicillin+clavulanate 875+125 mg (child 2 months or older: 22.5+3.2 mg/kg up to

875+125 mg) orally, 12-hourly; see below for duration of therapy [Note 2].
For patients with acute epiglottitis who have immediate nonsevere or delayed nonsevere hypersensitivity to
penicillins, use:
cefuroxime 500 mg (child 3 months or older: 15 mg/kg up to 500 mg) orally, 12-hourly;
see below for duration of therapy [Note 3].
For patients with acute epiglottitis who have immediate severe or delayed severe hypersensitivity to penicillins,
use:
moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally, daily; see below for duration
of therapy [Note 1] [Note 4].
Duration of therapy: there are limited data to guide duration of therapy. Most experts recommend a total of 7 to
10 days (intravenous + oral).
Note 2: Amoxicillin+clavulanate may be suitable for children aged 1 month to younger than 2 months but a
different dosage is required.
Note 3: Cefuroxime is preferred to cefalexin or cefaclor because of its superior antipneumococcal activity.
Note 4: An oral liquid formulation of moxifloxacin is not commercially available; for formulation options for
Public health management of Haemophilus influenzae type b epiglottitis

Haemophilus influenzae type b (Hib) epiglottitis is an invasive infection; report cases to the local public health
authority [Note 5] [Note 6]. For detailed recommendations about diagnosis and management of H. influenzae type
b epiglottitis, see Haemophilus influenzae type b Invasive Infection: CDNA National Guidelines for Public Health
Units [URL].
Clearance antibiotics are used to eradicate asymptomatic nasopharyngeal carriage of H. influenzae type b, to
prevent susceptible contacts acquiring the organism and developing invasive infection. Among close contacts there
is often an asymptomatic individual who is carrying the organism that caused infection in the index case.
If the patient (index case) was not treated with ceftriaxone, cefotaxime or moxifloxacin, clearance antibiotics are
required. However, if the patient was treated with ceftriaxone, cefotaxime or moxifloxacin (as recommended
in Treatment of acute epiglottitis), additional clearance antibiotics are not required because these drugs clear
nasopharyngeal carriage. Close contacts of the index case may also require clearance antibiotics; these should be
initiated in collaboration with the local public health authority [Note 6]. For clearance antibiotic regimens and
further information, see Clearance antibiotics for invasive meningococcal or Hib disease.
If the patient (the index case) or a close contact is younger than 5 years and is not fully vaccinated, give age-
appropriate catch-up Haemophilus influenzae type b vaccination after recovery—see the Australian Immunisation
Handbook [URL].
Note 5: For Australian national notifiable diseases and case definitions, see the Communicable Diseases
Network Australia (CDNA) website.
are available here.
Key references
Communicable Diseases Network Australia (CDNA). Haemophilus influenzae type b Invasive Infection: CDNA national
guidelines for public health units [version 1.0]. Canberra: Department of Health; 2013.
http://www.health.gov.au/internet/main/publishing.nsf/Content/cdna-song-hib.htm
Glynn F, Fenton JE. Diagnosis and management of supraglottitis (epiglottitis). Curr Infect Dis Rep 2008;10(3):200–4.
Ovnat Tamir S, Marom T, Barbalat I, Spevak S, Goldfarb A, Roth Y. Adult supraglottitis: changing trends. Eur Arch
Otorhinolaryngol 2015;272(4):929–35.
Epstein–Barr virus infection
Epstein–Barr virus (EBV) infection
Epstein–Barr virus (EBV) infection (glandular fever, infectious mononucleosis) often presents with severe
sore throat, which can be purulent or exudative. Other clinical features include fever, nausea,
lymphadenopathy, splenomegaly, hepatomegaly, rash and fatigue. Epstein–Barr virus infection commonly
occurs in adolescents and young adults. Pharyngitis and tonsillitis can be difficult to differentiate from
Epstein–Barr virus infection (see Assessment of sore throat). If Epstein–Barr virus infection is suspected,
consider performing an infectious mononucleosis (IM) test (also known as a heterophile antibody test or
monospot test) or Epstein–Barr virus serology to confirm the diagnosis.
Epstein–Barr virus infection is usually self-limiting, with symptoms typically lasting 2 to 3 weeks; however,
fatigue sometimes persists for months. Encourage rest, and treat throat pain with analgesia. For suitable
regimens of paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs), see here for adults or here for
children.
Do not prescribe antibiotics for Epstein–Barr virus infection.
Antibiotics are not indicated for Epstein–Barr virus infection. Amoxicillin and ampicillin can cause a rash not
related to penicillin hypersensitivity when inadvertently (eg following a misdiagnosis) administered to a
patient with Epstein–Barr virus infection.
Rarely, patients with Epstein–Barr virus infection require urgent hospitalisation for management of
complications such as airway obstruction (for clinical features, see Table 2.7), haemolytic anaemia and severe
thrombocytopenia (ie platelet count less than 20 × 109/L). In patients with these severe complications,
corticosteroids may have a role in treatment—seek expert advice. Corticosteroids are not recommended for
treatment of uncomplicated Epstein–Barr virus infection.
Key references
Chovel-Sella A, Ben Tov A, Lahav E, Mor O, Rudich H, Paret G, et al. Incidence of rash after amoxicillin
treatment in children with infectious mononucleosis. Pediatrics 2013;131(5):e1424–7.
Rezk E, Nofal YH, Hamzeh A, Aboujaib MF, AlKheder MA, Al Hammad MF. Steroids for symptom control in
infectious mononucleosis. Cochrane Database Syst Rev 2015;(11):CD004402.
Walter RB, Hong TC, Bachli EB. Life-threatening thrombocytopenia associated with acute Epstein-Barr virus
infection in an older adult. Ann Hematol 2002;81(11):672–5.
Acute laryngitis
Acute laryngitis
Acute laryngitis is a self-limiting inflammation of the larynx, including the vocal cords. Symptoms include
hoarse voice, sore throat, dysphagia, and symptoms typical of an upper respiratory tract infection (eg fever,
nasal congestion and discharge). Symptoms typically improve within 8 days.
Viral infections are the most common cause of acute laryngitis. Other causes include vocal straining,
excessive coughing, or inhalation of irritant substances (eg smoke).
Do not prescribe antibiotics for acute laryngitis.
Antibiotics are not indicated for acute laryngitis. Manage symptoms with voice rest, humidification (eg
inhaling steam from the shower), and analgesia. For suitable regimens of paracetamol or nonsteroidal anti-
inflammatory drugs [NSAIDs]), see here for adults or here for children. Patient information on symptom
management has been created by NPS MedicineWise and is available here for adults or here for children;
alternatively, see the NPS MedicineWise website.
If hoarse voice does not significantly improve within 4 weeks, refer to an otolaryngologist for examination of
the larynx.
Key references
Reveiz L, Cardona AF. Antibiotics for acute laryngitis in adults. Cochrane Database Syst Rev 2015;
(5):CD004783.
Royal Australasian College of Surgeons, General Surgeons Australia. Tests, treatments and procedures
clinicians and consumers should question. Recommendation 10: Choosing Wisely Australia. Sydney: NPS
MedicineWise; Last reviewed 10 May 2017. http://www.choosingwisely.org.au/recommendations/racs#0|1713
Acute mastoiditis in children
What is acute mastoiditis?
Mastoiditis is a suppurative infection of the mastoid air cells within the temporal bone. In children, mastoiditis is a
rare complication of acute otitis media (AOM). It is important to distinguish mastoiditis from acute otitis media (in
which the temporal bone is not infected). Mastoiditis can be acute (symptoms present for less than 1 month) or
chronic (symptoms present for months to years). For management of chronic mastoiditis in children, seek expert
advice.
Acute mastoiditis is most common in children younger than 2 years of age, but complications of acute mastoiditis
are more frequent in children 2 years or older. Complications of mastoiditis include subperiosteal, subcutaneous,
intratemporal or intracranial collections, and facial nerve palsy.
In adults, mastoiditis can be a complication of chronic suppurative otitis media or cholesteatoma. Management is
usually surgical—refer the patient to an otolaryngologist. If a diagnosis of mastoiditis is suspected in an adult
without chronic otitis media or cholesteatoma, seek advice from an otolaryngologist or infectious diseases
physician. A bone scan may be necessary to exclude necrotising (malignant) otitis externa.
Approach to managing acute mastoiditis in children

Management of acute mastoiditis in children requires initial intravenous antibiotic therapy, and consultation with
an otolaryngologist for consideration of aspiration and drainage of the middle ear, or mastoidectomy. Collect
samples from the middle ear and, if possible, the mastoid cavity for culture and susceptibility testing.
Standard empirical therapy is active against the common pathogens implicated in acute mastoiditis, Streptococcus
pneumoniae, Streptococcus pyogenes (group A streptococcus) and Staphylococcus aureus. Anaerobic bacteria,
such as Fusobacterium species, are an uncommon cause of infection. In patients with a history of recurrent acute
otitis media or mastoiditis, use the results of previous culture and susceptibility testing to guide initial antibiotic
therapy.
Pseudomonas aeruginosa is commonly cultured from samples taken through the external auditory canal; this
usually represents external auditory canal flora rather than infection. The results of culture from mastoid cavity
samples are more likely to indicate the pathogen. Regimens with antipseudomonal activity are recommended if:
P. aeruginosa is isolated in samples taken from the mastoid cavity

the child has a tympanostomy tube in situ and P. aeruginosa was isolated in recent samples (including
samples taken through the external auditory canal)
the child is immunocompromised and P. aeruginosa was isolated in recent samples (including samples taken
through the external auditory canal).
Consider regimens with antipseudomonal activity for Aboriginal and Torres Strait Islander children who have a
history of chronic suppurative otitis media or recurrent acute otitis media.
For all other children, use standard empirical therapy.
For the management of children with intracranial complications, such as meningitis, seek expert advice.
Standard empirical therapy for acute mastoiditis in children

Standard empirical therapy is active against the common pathogens implicated in acute mastoiditis, Streptococcus
pneumoniae, Streptococcus pyogenes (group A streptococcus) and Staphylococcus aureus. Some children require
regimens with antipseudomonal activity; see Approach to managing acute mastoiditis in children.
For empirical therapy of acute mastoiditis in children, use:
1 cefotaxime 50 mg/kg up to 2 g intravenously, 8-hourly; see below for intravenous to oral

switch and duration of therapy
OR
1 ceftriaxone (child 1 month or older) 50 mg/kg up to 2 g intravenously, daily; see below

for intravenous to oral switch and duration of therapy.
For children with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use cefotaxime or
ceftriaxone as above.
use. See below for intravenous to oral switch and duration of therapy.
Intravenous to oral switch: treat with intravenous antibiotics for a minimum of 5 days, then switch to oral
therapy once the patient improves (see Box 2.35 for guidance on when to switch to oral therapy). Use the results of
culture and susceptibility testing to guide oral antibiotic therapy. In stable patients, community-based parenteral
antimicrobial therapy may be appropriate if oral therapy is not possible.
If a pathogen is not identified, for children 2 months or older, use:
amoxicillin+clavulanate 22.5+3.2 mg/kg up to 875+125 mg orally, 12-hourly; see below

For infants 1 month to younger than 2 months, use:
amoxicillin+clavulanate 15+3.75 mg/kg orally, 8-hourly; see below for duration of

therapy.
cefuroxime (child 3 months or older) 15 mg/kg up to 500 mg orally, 12-hourly; see below
azithromycin 10 mg/kg up to 500 mg orally, daily; see below for duration of therapy.
Duration of therapy: the total duration of therapy is 12 to 15 days (intravenous + oral), depending on clinical
progress. Children with intracranial complications may require a longer duration of therapy—seek expert advice.
Empirical therapy with antipseudomonal activity for acute mastoiditis

in children
Empirical regimens with antipseudomonal activity are also active against the common pathogens implicated in
acute mastoiditis (see Approach to managing acute mastoiditis in children).
Empirical regimens with antipseudomonal activity are recommended if:
P. aeruginosa is isolated in samples taken from the mastoid cavity

the child has a tympanostomy tube in situ and P. aeruginosa was isolated in recent samples (including
samples taken through the external auditory canal)
the child is immunocompromised and P. aeruginosa was isolated in recent samples (including samples taken
through the external auditory canal).
Consider regimens with antipseudomonal activity for Aboriginal and Torres Strait Islander children who have a
history of chronic suppurative otitis media or recurrent acute otitis media.
If empirical therapy with antipseudomonal activity is required for acute mastoiditis in children, use:
piperacillin+tazobactam 100+12.5 mg/kg up to 4+0.5 g intravenously, 6-hourly; see below

for intravenous to oral switch and duration of therapy.
ceftazidime 50 mg/kg up to 2 g intravenously, 8-hourly; see below for intravenous to oral

switch and duration of therapy.
For children with immediate severe or delayed severe hypersensitivity to penicillins, meropenem may be suitable
[Note 1]. Use:
meropenem 20 mg/kg up to 1 g intravenously, 8-hourly; see below for intravenous to oral
switch and duration of therapy [Note 2].
Modify therapy based on the results of culture and susceptibility testing. If a pathogen is not identified, switch to
an appropriate narrower-spectrum empirical regimen (even if P. aeruginosa was identified in previous samples),
see Standard empirical therapy for acute mastoiditis in children.
Intravenous to oral switch: treat with intravenous antibiotics for a minimum of 5 days, then switch to oral
therapy once the patient improves (see Box 2.35 for guidance on when to switch to oral therapy). Use the results of
culture and susceptibility testing to guide oral antibiotic therapy. In stable patients, community-based parenteral
antimicrobial therapy may be appropriate if oral therapy is not possible.
If P. aeruginosa is identified by culture and the isolate is susceptible to ciprofloxacin, use:
ciprofloxacin 20 mg/kg up to 750 mg orally, 12-hourly; see below for duration of therapy
[Note 3] [Note 4]
If a pathogen is not identified, switch to an appropriate narrower-spectrum empirical regimen (even if P.

aeruginosa was identified in previous samples), see Standard empirical therapy for acute mastoiditis in children.
Duration of therapy: the total duration of therapy is 12 to 15 days (intravenous + oral), depending on clinical
progress. Children with intracranial complications may require a longer duration of therapy—seek expert advice.
Note 1: In patients with penicillin hypersensitivity, the rate of immune-mediated cross-reactivity with carbapenems is approximately 1%; therefore,
meropenem can be considered in supervised settings. However, in patients with a history of a severe cutaneous adverse reaction (eg drug rash with
eosinophilia and systemic symptoms [DRESS], Stevens–Johnson syndrome / toxic epidermal necrolysis [SJS/TEN], acute generalised exanthematous
pustulosis [AGEP]), consider meropenem only in a critical situation when there are limited treatment options.
Note 2: Some centres use a meropenem dosage of 40 mg/kg up to 2 g intravenously, 8-hourly for children who are very unwell; however, no data are
available to support the use of this dosage for children who do not have central nervous system infection.
choice.
Note 4: An oral liquid formulation of ciprofloxacin is not commercially available; for formulation options for children, see the Don’t Rush to Crush
Handbook, published by the Society of Hospital Pharmacists of Australia [URL].
Key references
Bakhos D, Trijolet JP, Moriniere S, Pondaven S, Al Zahrani M, Lescanne E. Conservative management of acute
mastoiditis in children. Arch Otolaryngol Head Neck Surg 2011;137(4):346–50.
Bunik M. Mastoiditis. Pediatr Rev 2014;35(2):94–5.
Groth A, Enoksson F, Hultcrantz M, Stalfors J, Stenfeldt K, Hermansson A. Acute mastoiditis in children aged 0-16
years--a national study of 678 cases in Sweden comparing different age groups. Int J Pediatr Otorhinolaryngol
2012;76(10):1494–500.
Laulajainen-Hongisto A, Saat R, Lempinen L, Markkola A, Aarnisalo AA, Jero J. Bacteriology in relation to clinical
findings and treatment of acute mastoiditis in children. Int J Pediatr Otorhinolaryngol 2014;78(12):2072–8.
Luntz M, Brodsky A, Nusem S, Kronenberg J, Keren G, Migirov L, et al. Acute mastoiditis--the antibiotic era: a
multicenter study. Int J Pediatr Otorhinolaryngol 2001;57(1):1–9.
Mattos JL, Colman KL, Casselbrant ML, Chi DH. Intratemporal and intracranial complications of acute otitis media in a
pediatric population. Int J Pediatr Otorhinolaryngol 2014;78(12):2161–4.
Dis 2016;16(8):e139–52.
Pang LH, Barakate MS, Havas TE. Mastoiditis in a paediatric population: a review of 11 years experience in
management. Int J Pediatr Otorhinolaryngol 2009;73(11):1520–4.
Psarommatis IM, Voudouris C, Douros K, Giannakopoulos P, Bairamis T, Carabinos C. Algorithmic management of

pediatric acute mastoiditis. Int J Pediatr Otorhinolaryngol 2012;76(6):791–6.
Quesnel S, Nguyen M, Pierrot S, Contencin P, Manach Y, Couloigner V. Acute mastoiditis in children: a retrospective
study of 188 patients. Int J Pediatr Otorhinolaryngol 2010;74(12):1388–92.
Roddy MG, Glazier SS, Agrawal D. Pediatric mastoiditis in the pneumococcal conjugate vaccine era: symptom
duration guides empiric antimicrobial therapy. Pediatr Emerg Care 2007;23(11):779–84.
Otitis externa
Acute diffuse otitis externa
Diagnosis of acute diffuse otitis externa
Acute diffuse otitis externa (swimmer’s ear) is inflammation of the external ear canal that often follows water
exposure and maceration of the skin. It can usually be diagnosed with clinical history and examination. Presenting
symptoms include ear pain, pruritus and hearing loss. There may also be tenderness on manipulation of the tragus
or auricle, and discharge may be present. In more severe cases, there may be regional lymphadenitis, or cellulitis
of the pinna and adjacent skin.
Otoscopy is important to distinguish between acute diffuse otitis externa, otitis media, and other ear problems; in
acute diffuse otitis externa, the external ear canal (if visible) appears inflamed, with erythema and oedema. In
fungal infection (otomycosis), fungal debris is typically visualised in the canal on otoscopy.
Patients with diabetes or immune compromise require careful evaluation because they are susceptible to
otomycosis and necrotising otitis externa. These conditions may present similarly to bacterial acute diffuse otitis
externa but require different therapy. For management of otomycosis, see discussion below; for management of
necrotising otitis externa, see Necrotising otitis externa.
Aetiology of acute diffuse otitis externa

Pseudomonas aeruginosa and Staphylococcus aureus are the most common causes of acute diffuse otitis externa;
other bacterial causes are much less common. Fungal infection (otomycosis) occurs less frequently than bacterial
infection, and usually follows prolonged antibiotic use. Candida or Aspergillus species are the most common
fungal pathogens.
Management of acute diffuse otitis externa

Prescribe analgesia according to the severity of the patient’s pain (see here for adults or here for children).
The external ear canal must be kept as dry as possible. Discharge or other debris should be removed from the ear
canal by dry aural toilet, not by syringing with water. Dry aural toilet can be performed by a healthcare
professional, using mechanical suction or, under direct visualisation, cotton wool on a probe. Dry aural toilet can
also be performed by the patient or carer, by dry mopping the ear with rolled tissue spears or similar, 6-hourly until
the external canal is dry. Debridement and dry aural toilet are the mainstays of treatment of fungal infection
(otomycosis).
Instil combination corticosteroid and antimicrobial ear drops after performing dry aural toilet; the choice depends
on whether the tympanic membrane is perforated and fungal infection is suspected. It is not necessary to routinely
perform culture to guide antimicrobial therapy. After ear drops are instilled, apply gentle pressure to the tragus (by
pressing on it repeatedly without causing pain) for 30 seconds.
Severe cases of acute diffuse bacterial otitis externa present with intense pain and complete occlusion of the
external ear canal. Fever and extension of infection beyond the ear canal may also occur. If ear drops cannot be
instilled because the canal is occluded, inserting a wick into the occluded ear canal can facilitate ear drop
administration (see here for choice of ear drops).
In addition to topical therapy, oral antibiotics may be required for patients with fever and spread of inflammation to
the pinna, or folliculitis. Additional oral antibiotics may also be required for patients with diabetes or immune
compromise, provided otomycosis and necrotising otitis externa have been excluded. Before oral antibiotics are
started, obtain superficial swabs or samples of tissue or pus for culture.
Advise the patient to keep the ear dry during and for 2 weeks after treatment. This can be achieved by using
earplugs (although canal tenderness may limit their use) or a shower or bathing cap during showering and
swimming. Alternatively, the external ear canal can be occluded by a malleable, nonpermeable material (eg Blu
Tack) to prevent water entry.
If symptoms persist despite appropriate otitis externa treatment, consider noninfectious causes such as contact
dermatitis, atopic dermatitis or seborrhoeic dermatitis. Pruritus is the dominant symptom of these presentations.
Antimicrobial regimens for acute diffuse otitis externa

When fungal infection is not suspected, combination corticosteroid and antimicrobial ear drops are used to treat
acute diffuse otitis externa:
1 dexamethasone+framycetin+gramicidin 0.05%+0.5%+0.005% ear drops, 3 drops instilled

into the affected ear, 3 times daily for 7 days [Note 1]
OR
1 flumethasone+clioquinol 0.02%+1% ear drops, 3 drops instilled into the affected ear,
twice daily for 7 days [Note 1].
If possible, avoid products containing an aminoglycoside (eg framycetin, neomycin) in patients with a perforated
tympanic membrane or a tympanostomy tube in situ because of the risk of inner ear damage; however, this
complication appears to be rare. It is also preferable to avoid aminoglycosides if the tympanic membrane cannot be
visualised, in case it is perforated. Instead, use flumethasone+clioquinol ear drops (as above) or, if an alternative is
necessary, ciprofloxacin+hydrocortisone ear drops (as below). If aminoglycoside-containing products cannot be
avoided, they can be used with caution because treatment is of short duration.
If ciprofloxacin+hydrocortisone ear drops are required as an alternative to aminoglycoside-containing products,

use:
ciprofloxacin+hydrocortisone 0.2%+1% ear drops 3 drops instilled into the affected ear,
twice daily for 7 days.
If fungal infection is suspected, debridement and aural toilet are the mainstays of treatment. Ear drops with
antifungal activity are also needed; use:
1 flumethasone+clioquinol 0.02%+1% ear drops, 3 drops instilled into the affected ear,
twice daily for 7 days [Note 1]
OR
1 triamcinolone+neomycin+gramicidin+nystatin 0.1%+0.25%+0.025%+100 000 units/mL

ear drops, 3 drops instilled into the affected ear, 3 times daily for 3 to 7 days [Note 1].
If systemic antibiotic therapy is indicated (see Management of acute diffuse otitis externa), in the absence of
microbiology results to direct therapy, the empirical regimen should have activity against S. aureus and P.
aeruginosa. As a two-drug regimen, use:
1 dicloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 to 10 days
OR
1 flucloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 to 10 days
ciprofloxacin 750 mg (child: 20 mg/kg up to 750 mg) orally, 12-hourly for 7 to 10 days
[Note 2] [Note 3].
[Note 4]. Use:
cefalexin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 to 10 days
PLUS
[Note 2] [Note 3].
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly for 7 to 10 days
PLUS
[Note 2] [Note 3].
Note 1: This is available as a combination product.
Preventing and managing recurrent diffuse otitis externa

Recurrent diffuse otitis externa can be prevented by keeping the external ear canal free of water. This can be
achieved by using earplugs, or a shower or bathing cap, during showering and swimming, and acetic acid plus
isopropyl alcohol ear drops following exposure to water:
acetic acid plus isopropyl alcohol ear drops, 4 to 6 drops instilled into each ear, after water
exposure. Shake water out of the ear before instilling the drops [Note 5].
If recurrent infection occurs, manage as acute diffuse otitis externa.
Note 5: This is available as a combination product.
Acute localised otitis externa

Acute localised otitis externa is commonly caused by Staphylococcus aureus and associated with a boil (furuncle).
Streptococcus pyogenes (group A streptococcus) can cause painful erysipelas that involves the pinna and external
canal. Systemic antibiotics are usually curative, though surgical drainage may also be required. Use:
OR
[Note 6]. Use:
cefalexin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 5 days [Note 7].
who have had a recent delayed nonsevere reaction to amoxicillin or ampicillin, use the drug recommended for
Note 7: For mild infection, administering the total daily dose of cefalexin in two 12-hourly doses is also
effective (ie cefalexin 1 g [child: 25 mg/kg up to 1 g] orally, 12-hourly).
Necrotising otitis externa

Necrotising (malignant) otitis externa is a rare complication of acute diffuse otitis externa; consider the diagnosis
in patients whose symptoms have failed to improve after treatment of acute diffuse otitis externa. Necrotising otitis
externa mostly occurs in patients with diabetes, or in elderly or immunocompromised patients (eg patients with
advanced HIV infection, patients receiving chemotherapy for treatment of malignancy).
The condition is characterised by the spread of infection to cartilage and bone in the external ear canal and base of
the skull. Features include fever, severe persistent pain, visible granulation tissue and progressive cranial
neuropathies.
Urgently refer patients with necrotising otitis externa to an infectious diseases physician and otolaryngologist.
Antibiotics must be started promptly.
Infection is almost always caused by Pseudomonas aeruginosa. Obtain superficial swabs, or samples of tissue or
pus, for culture and susceptibility testing, preferably before starting antibiotic therapy.
Until the results of culture and susceptibility testing are available, use an antipseudomonal regimen:
OR
1 piperacillin+tazobactam 4+0.5 g (child: 100+12.5 mg/kg up to 4+0.5 g) intravenously, 6-

hourly.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, until the results of
culture and susceptibility testing are available, use ceftazidime (as above).
For patients with immediate severe or delayed severe hypersensitivity to penicillins, until the results of culture
and susceptibility testing are available, use:
ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 8-hourly [Note 8].
Modify therapy as soon as the results of culture and susceptibility testing are available. Prolonged treatment is
required because the infection involves bone or cartilage. Seek expert advice on antibiotic choice and duration of
therapy.
Key references
Hobson CE, Moy JD, Byers KE, Raz Y, Hirsch BE, McCall AA. Malignant otitis externa: Evolving pathogens and
implications for diagnosis and treatment. Otolaryngol Head Neck Surg 2014;151(1):112–6 .
Lorente J, Sabater F, Rivas MP, Fuste J, Risco J, Gómez M. Ciprofloxacin plus fluocinolone acetonide versus
ciprofloxacin alone in the treatment of diffuse otitis externa. J Laryngol Otol 2014;128(7):591–8 .
Mahdyoun P, Pulcini C, Gahide I, Raffaelli C, Savoldelli C, Castillo L, et al. Necrotizing otitis externa: a systematic
review. Otol Neurotol 2013;34(4):620–9 .
Pulcini C, Mahdyoun P, Cua E, Gahide I, Castillo L, Guevara N. Antibiotic therapy in necrotising external otitis: case
series of 32 patients and review of the literature. Eur J Clin Microbiol Infect Dis 2012;31(12):3287–94 .
Rosenfeld RM, Schwartz SR, Cannon CR, Roland PS, Simon GR, Kumar KA, et al. Clinical practice guideline: acute
otitis externa. Otolaryngol Head Neck Surg 2014;150(1 Suppl):S1–S24 .
Otitis media
Aetiology of acute otitis media
Acute otitis media is a common paediatric presentation in primary care, and antibiotics are commonly
inappropriately prescribed for this condition. Acute otitis media is commonly a viral infection, but can be bacterial
or have both a viral and bacterial aetiology. Regardless of the cause, it is usually self-limiting. Spontaneous
resolution occurs in more than 80% of children within 2 to 3 days; symptoms may persist for up to 8 days in some
children.
In bacterial acute otitis media, the most common pathogens are Streptococcus pneumoniae, nontypeable
Haemophilus influenzae and Moraxella catarrhalis. Aboriginal and Torres Strait Islander infants in some
communities are more likely to be colonised with these organisms from a young age, as a consequence of
socioeconomic disadvantage (eg crowded housing). In these children, acute otitis media often develops in the first
months of life and recurs throughout childhood.
Acute otitis media can occur in adults, but is less common than in children. Management is similar.
Diagnosis of acute otitis media

Acute otitis media is characterised by middle ear inflammation and middle ear effusion. The diagnosis is made if
there is acute onset of either of the following signs of acute otitis media on examination:
bulging of the tympanic membrane (strongly suggestive of middle ear inflammation)

otorrhoea (indicative of tympanic membrane perforation and middle ear effusion, provided acute diffuse
otitis externa has been excluded).
Although visualising the tympanic membrane is considered important to confirm the diagnosis of acute otitis
media, this may be difficult in the presence of copious otorrhoea, particularly in infants. If the tympanic membrane
cannot be visualised initially, ensure the patient receives follow-up to check progress and reassess the membrane;
review by an otolaryngologist or audiologist can aid diagnosis.
Middle ear effusion can be diagnosed by an immobile tympanic membrane on pneumatic otoscopy or a type B
tympanogram; nonpneumatic otoscopy is not usually sufficient to detect effusion.
Middle ear effusion can occur in both acute otitis media (in which the effusion is infected) and otitis media with
effusion, in which the effusion is not infected. If middle ear effusion is not accompanied by other signs or
symptoms of AOM (eg acute onset of ear pain [in young children, tugging, holding or rubbing the ear may indicate
ear pain], fever, irritability, poor feeding, bulging tympanic membrane), a diagnosis of otitis media with
effusion should be made instead.
Pain alone is not sufficient for diagnosis of acute otitis media.
Pain alone is not sufficient for diagnosis of acute otitis media.
Approach to managing acute otitis media

Adequate and regular analgesia (with paracetamol or a nonsteroidal anti-inflammatory drug [NSAID]) is the
mainstay of acute otitis media treatment, whether or not antibiotic therapy is used. For suitable analgesic regimens,
see Pharmacological management of pain in children.
Adequate and regular analgesia is the mainstay of acute otitis media treatment. For most children, antibiotic therapy can be
safely withheld.
For most children with acute otitis media, antibiotic therapy can be safely withheld. However, antibiotic therapy is
required in the following groups:
infants younger than 6 months

children younger than 2 years with bilateral infection
children who are systemically unwell (eg lethargic, pale, very irritable); fever alone is not an indication for
antibiotic therapy
children with otorrhoea
Aboriginal and Torres Strait Islander children—for treatment recommendations, see the Recommendations
for clinical care guidelines on the management of otitis media in Aboriginal and Torres Strait Islander
populations [Note 1]
children at high risk of complications (eg immunocompromised children).
For other children with acute otitis media, antibiotic therapy has a limited benefit—initial antibiotic therapy does
not improve pain at 24 hours; for every 100 children treated with antibiotics, only five children will be better at 2
to 3 days as a consequence of taking antibiotics; and antibiotics only shorten the duration of symptoms by about 12
hours. Further, antibiotic therapy can cause harm (eg diarrhoea, rash or more serious hypersensitivity reactions,
bacterial resistance).
Consequently, children not in the groups described above can be initially treated with analgesia alone. For children
younger than 2 years, analgesia alone is appropriate; however, initial antibiotic therapy may be reasonable
depending on the clinical context and likelihood of follow-up—clinical judgment is required.
Advise the patient or carer to return for follow-up if symptoms worsen, or do not improve within 48 to 72 hours;
antibiotics may be required. If the patient is unlikely to return for follow-up, a delayed prescription for antibiotic
therapy can be provided; however, it is essential that the patient is aware of the circumstances in which follow-up
and reassessment are required.
Pain is a poor indicator of response to antibiotic therapy.
Many patients have an expectation of treatment with antibiotics. For children who do not require initial antibiotic
therapy, effective communication with the patient or carer about the limited role of antibiotics in acute otitis media
is essential. The discussion should address misconceptions about the effectiveness of antibiotic therapy and the
expectation of an antibiotic prescription. Shared decision making, which involves a discussion of the evidence for
the potential benefits and harms of therapy, provides a useful template for these discussions.
Antibiotic treatment is not required for children with otitis media with effusion.
Rare suppurative complications of acute otitis media include mastoiditis and facial palsy—urgent referral to an
otolaryngologist is required.
Controlled trials showed decongestants, antihistamines and oral corticosteroids are not beneficial for acute otitis
media.
Note 1: Darwin Otitis Guidelines Group, Office for Aboriginal and Torres Strait Islander Health Otitis Media Technical Advisory Group.
Recommendations for clinical care guidelines on the management of otitis media in Aboriginal and Torres Strait Islander populations. Darwin:
Department of Health and Ageing (DOHA); 2010. [URL]
Shared decision making in acute otitis media

Shared decision making enables doctors and patients to make health decisions in partnership, informed by the best
available evidence and the patient or carer’s values and preferences.
Patients who take part in shared decision making have a more accurate understanding of the benefits and harms of
the available treatment approaches, and are more likely to choose conservative management. Further, short-term
trial data demonstrated that shared decision making reduced antibiotic prescribing in primary care.
The steps for shared decision making when deciding whether antibiotic treatment will be used for suspected acute
otitis media are outlined in Box 2.3 (below). A graphic to support shared decision making has been created by the
Australian Commission on Safety and Quality in Health Care and is available here.
Shared decision making for antibiotic treatment in acute otitis media (Box 2.3)
Printable box
To engage in shared decision making with patients and carers:
Reassure the patient or carer that acute otitis media is a self-limiting condition. Severe complications are
rare with or without antibiotics.
Ask about the patient or carer’s expectations for management of acute otitis media.
Explain that when initial antibiotic therapy is not essential (see Approach to managing acute otitis media)
there are two treatment approaches.
Analgesia alone, with follow-up if symptoms worsen, or do not improve within 48 to 72 hours. A
delayed prescription for antibiotics can be offered if the patient will not be able to return.
Analgesia with initial antibiotic therapy.
Explain that symptoms of acute otitis media usually last 2 to 3 days, whether or not antibiotics are used.
Discuss the limited benefits of antibiotic therapy, even when a bacterial cause is likely.
Initial antibiotic therapy does not improve pain at 24 hours. For every 100 children treated with
antibiotics, only five children will be better at 2 to 3 days because they took antibiotics. Antibiotics
only shorten the duration of symptoms by about 12 hours. It is not possible to know in advance
which children will benefit and which will not.
Discuss the potential harms of antibiotic therapy.
Adverse effects of antibiotics include diarrhoea, rash or more serious hypersensitivity reactions.
Antibiotics disrupt the balance of bacteria in the body (the microbiome). While the consequences of
this are not fully understood, it can cause problems ranging from yeast infections (eg thrush) to more
serious infections (eg Clostridium difficile infection).
Antibiotics can also cause bacteria in the body to become resistant to antibiotics so that future
infections are harder to treat. Multidrug-resistant bacteria (known as ‘superbugs’) can be spread
between people, affecting your family and the community.
For every 100 children treated with antibiotics, seven children will experience an antibiotic adverse
effect. It is not possible to know in advance which children will experience adverse effects and
which will not.
Ask about the preferences, values and concerns of the patient or carer, and answer any remaining
questions.
Make a joint decision about whether to use analgesia alone or combine analgesia with antibiotics [NB1]
[NB2]; if a decision is made to use antibiotic therapy, see here for treatment recommendations.
Discuss criteria for patient follow-up and reassessment.
NB1: A graphic to support shared decision making has been created by the Australian Commission on Safety and Quality in Health Care and is
available here.
NB2: Patient information on symptom management has been created by NPS MedicineWise and is available here for adults or here for children;
Antibiotic regimens for acute otitis media

If antibiotics are indicated (see Approach to managing acute otitis media), use:
amoxicillin 15 mg/kg up to 500 mg orally, 8-hourly for 5 days.
If adherence to an 8-hourly regimen is unlikely, a 12-hourly regimen can be used instead:
amoxicillin 30 mg/kg up to 1 g orally, 12-hourly for 5 days.
Do not use lower amoxicillin doses because they will not achieve adequate plasma and tissue concentrations to
treat resistant Streptococcus pneumoniae strains.
Children who have not responded adequately to amoxicillin therapy by 48 to 72 hours may have infection caused
by a beta-lactamase–producing strain of Haemophilus influenzae or Moraxella catarrhalis. Adding clavulanate to
amoxicillin provides increased activity against these pathogens. For children 2 months or older, use:
amoxicillin+clavulanate 22.5+3.2 mg/kg up to 875+125 mg orally, 12-hourly for 5 to 7

days.
For infants 1 month to younger than 2 months, use:

amoxicillin+clavulanate 15+3.75 mg/kg orally, 8-hourly for 5 to 7 days.
For children with chronic otorrhoea, combine oral antibiotics with topical ciprofloxacin. Add:
ciprofloxacin 0.3% ear drops, 5 drops instilled into the affected ear, 12-hourly until the
middle ear has been free of discharge for at least 3 days.
If a child is systemically very unwell or does not respond to therapy, arrange urgent clinical review by a specialist
or in hospital. Intravenous therapy may be necessary.
For children with delayed nonsevere hypersensitivity to penicillins, in place of amoxicillin or

amoxicillin+clavulanate, use:
1 cefuroxime (child 3 months or older) 15 mg/kg up to 500 mg orally, 12-hourly for 5 days
[Note 2]
OR

orally, 12-hourly for 5 days.
For children with immediate (nonsevere or severe) or delayed severe hypersensitivity to penicillins, use
trimethoprim+sulfamethoxazole as above.
Note 2: Cefuroxime is preferred to cefalexin and cefaclor because of its superior antipneumococcal activity.
Preventing and managing recurrent bacterial otitis media

Risk factors for recurrent bacterial otitis media include:
group child care

allergic rhinitis
adenoid disease
various structural anomalies, such as cleft palate and those associated with Down syndrome
exposure to smoke (eg cigarettes, wood fires)
socioeconomic disadvantage (eg crowded housing).
Ensure the child is up-to-date with Streptococcus pneumoniae vaccination. Antibiotic prophylaxis has limited
impact on the rate of recurrence.
If recurrent infection occurs, manage as for acute otitis media and consider referral to an otolaryngologist.
Frequent recurrences may require myringotomy and insertion of tympanostomy tubes (grommets).
Otitis media with effusion

Middle ear effusion can persist for several weeks after resolution of acute otitis media; this presentation is referred
to as otitis media with effusion. Otitis media with effusion is characterised by middle ear effusion without the
other signs or symptoms of acute otitis media (eg acute onset of ear pain, bulging tympanic membrane). Clinical
signs of middle ear effusion include:
loss of lucency of the tympanic membrane

visible grey-white or blue fluid
an immobile tympanic membrane with dilated blood vessels on pneumatic otoscopy or tympanometry.
By 3 months, 90% of effusions will have resolved spontaneously. Persistent otitis media with effusion (glue ear) is
the presence of a middle ear effusion for longer than 3 months.
Management of otitis media with effusion aims to restore hearing, if affected, and resolve and prevent recurrent
effusions. Management strategies depend on the duration of effusion and whether hearing is affected. Address risk
factors for recurrent bacterial otitis media.
Clinical care guidelines are available for the management of Aboriginal and Torres Strait Islander patients with
otitis media with effusion [Note 3].
Effusion present for less than 3 months: if the child has normal hearing and is not at risk for speech or language
problems, it is appropriate to manage the effusion with observation because the majority of effusions resolve
spontaneously. However, referral to an otolaryngologist is indicated if an effusion is associated with speech delay
or learning problems, or if there is structural damage to the tympanic membrane (eg significant retraction,
cholesteatoma). A tympanostomy tube restores hearing in the short term but long-term improvement in learning
has not been demonstrated.
Effusion present for 3 months or longer (persistent otitis media with effusion): diagnosis may be difficult;
patients can present with conductive hearing loss or, if hearing loss is undetected, behavioural problems. Referral
to an otolaryngologist is indicated for children with audiometry that shows bilateral hearing loss. A tympanostomy
tube restores hearing in the short term but long-term improvement in learning has not been demonstrated. Children
without hearing loss can be managed with a further 3 months of observation.
Some children with persistent otitis media with effusion, especially Aboriginal or Torres Strait Islander children
and children with risk factors for recurrent bacterial otitis media, are at high risk of developing chronic suppurative
otitis media.
Studies showed antihistamines, decongestants and corticosteroids (topical or oral) have no clinically significant
benefit in otitis media with effusion.
Note 3: Darwin Otitis Guidelines Group, Office for Aboriginal and Torres Strait Islander Health Otitis Media Technical Advisory Group.
Recommendations for clinical care guidelines on the management of otitis media in Aboriginal and Torres Strait Islander populations. Darwin:
Department of Health and Ageing (DOHA); 2010. [URL]
Chronic suppurative otitis media

Chronic suppurative otitis media is an infection of the middle ear with a perforated eardrum and discharge for at
least 6 weeks. Chronic suppurative otitis media can cause hearing impairment and disability. Occasionally,
especially in developing countries and Aboriginal or Torres Strait Islander people, serious complications can occur,
such as intracranial infection and acute mastoiditis.
For patients with chronic suppurative otitis media (whether or not a tympanostomy tube has been inserted),
cleaning the external ear canal by dry aural toilet is important and should be performed before instilling ear drops.
Dry aural toilet can be performed by a healthcare professional (using mechanical suction or, under direct
visualisation, cotton wool on a probe) or the patient or their carer (by dry mopping the ear with rolled tissue spears
or similar, 6-hourly until the external canal is dry).
Aminoglycoside-based ear drops have previously been used for chronic suppurative otitis media; however, due to
concerns about safety, in particular the risk of auditory and vestibular toxicity, quinolone ear drops are now
preferred.
To treat chronic suppurative otitis media, use topical antibiotic therapy alone:
ciprofloxacin 0.3% ear drops, 5 drops instilled into the affected ear, 12-hourly until the
middle ear has been free of discharge for at least 3 days.
There is inadequate evidence to support the use of topical corticosteroids in combination with topical antibiotics
for the treatment of chronic suppurative otitis media.
Persistent discharge may require prolonged courses of treatment. Referral to an otolaryngologist is recommended
for further examination and to exclude cholesteatoma or chronic osteitis.
Key references
Acute otitis media
Coxeter P, Del Mar CB, McGregor L, Beller EM, Hoffmann TC. Interventions to facilitate shared decision making to
address antibiotic use for acute respiratory infections in primary care. Cochrane Database Syst Rev 2015;
(11):CD010907.
Darwin Otitis Guidelines Group, Office for Aboriginal and Torres Strait Islander Health Otitis Media Technical Advisory
Group. Recommendations for clinical care guidelines on the management of otitis media in Aboriginal and Torres Strait
Islander populations (2010). Canberra: Australian Department of Health and Ageing (DOHA); 2010.
http://www.health.gov.au/internet/main/publishing.nsf/Content/indigenous-otitismedia-clinical-care-guidelines
Elwyn G, Frosch D, Thomson R, Joseph-Williams N, Lloyd A, Kinnersley P, et al. Shared decision making: a model for
clinical practice. J Gen Intern Med 2012;27(10):1361–7.
Gunasekera H, Miller HM, Burgess L, Chando S, Sheriff SL, Tsembis JD, et al. Agreement between diagnoses of otitis
media by audiologists and otolaryngologists in Aboriginal Australian children. Med J Aust 2018;209(1):29–35
.
Gunasekera H, O'Connor TE, Vijayasekaran S, Del Mar CB. Primary care management of otitis media among
Australian children. Med J Aust 2009;191(9 Suppl):S55–9.
Hoffmann T, Del Mar C, Coxeter P. Middle ear infection: should my child take antibiotics? [decision aid]. Canberra:
Australian Commission on Safety and Quality in Health Care (ACSQHC); Nov 2016.
https://www.safetyandquality.gov.au/our-work/information-for-consumers/our-work-information-for-consumers-specific-
health-conditions/
Hoffmann TC, Del Mar CB. Shared decision making: what do clinicians need to know and why should they bother?
Med J Aust 2014;201(9):513–4.
Lieberthal AS, Carroll AE, Chonmaitree T, Ganiats TG, Hoberman A, Jackson MA, et al. The diagnosis and
management of acute otitis media. Pediatrics 2013;131(3):e964–99.
National institute for Health and Care Excellence (NICE). Otitis media (acute): antimicrobial prescribing [NG91].
London: NICE; 2018. https://www.nice.org.uk/guidance/ng91
Ngo CC, Massa HM, Thornton RB, Cripps AW. Predominant bacteria detected from the middle ear fluid of children
experiencing otitis media: A systematic review. PLoS One 2016;11(3):e0150949. .
NPS MedicineWise. Respiratory tract infection action plan. Sydney: NPS MedicineWise; 2016.
https://www.nps.org.au/medical-info/clinical-topics/reducing-antibiotic-resistance#resources.
NPS MedicineWise. Childhood RTI Fact Sheet: What every parent should know. Sydney: NPS MedicineWise; 2017.
https://www.nps.org.au/medical-info/clinical-topics/reducing-antibiotic-resistance#resources.
Sjoukes A, Venekamp RP, , Hay AD, Little P, Schilder AG, et al. Paracetamol (acetaminophen) or non-steroidal anti-
inflammatory drugs, alone or combined, for pain relief in acute otitis media in children. Cochrane Database Syst Rev
2016;(12):CD011534. .
Thanaviratananich S, Laopaiboon M, Vatanasapt P. Once or twice daily versus three times daily amoxicillin with or
without clavulanate for the treatment of acute otitis media. Cochrane Database Syst Rev 2013;(12):CD004975.
.
Venekamp RP, Prasad V, Hay AD. Are topical antibiotics an alternative to oral antibiotics for children with acute otitis
media and ear discharge?. BMJ 2016;352:i308. .
Venekamp RP, Sanders SL, Glasziou PP, Del Mar CB, Rovers MM. Antibiotics for acute otitis media in children.
Preventing and managing recurrent bacterial otitis media
Darwin Otitis Guidelines Group, Office for Aboriginal and Torres Strait Islander Health Otitis Media Technical Advisory
Group. Recommendations for clinical care guidelines on the management of otitis media in Aboriginal and Torres Strait
Islander populations (2010). Canberra: Australian Department of Health and Ageing (DOHA); 2010.
http://www.health.gov.au/internet/main/publishing.nsf/Content/indigenous-otitismedia-clinical-care-guidelines
Otitis media with effusion
Principi N, Marchisio P, Esposito S. Otitis media with effusion: benefits and harms of strategies in use for treatment and
prevention. Expert Rev Anti Infect Ther 2016;14(4):415–423 .
Rosenfeld RM, Shin JJ, Schwartz SR, Coggins R, Gagnon L, Hackell JM, et al. Clinical Practice Guideline: Otitis media
with effusion (Update). Otolaryngol Head Neck Surg 2016;154(1 Suppl):S1–S41 .
Venekamp RP, Burton MJ, van Dongen TM, , van Zon A, Schilder AG. Antibiotics for otitis media with effusion in
children. Cochrane Database Syst Rev 2016;(6):CD009163. .
Chronic suppurative otitis media

Harris AS, Elhassan HA, Flook EP. Why are ototopical aminoglycosides still first-line therapy for chronic suppurative
otitis media? A systematic review and discussion of aminoglycosides versus quinolones. J Laryngol Otol
2016;130(1):2–7 .
Panchasara A, Singh A, Mandavia D, Jha S, Tripathi C. Efficacy and safety of ofloxacin and its combination with
dexamethasone in chronic suppurative otitis media. A randomised, double blind, parallel group, comparative study.
Acta Otorhinolaryngol Ital 2015;35(1):39–44 .
Renukananda GS, U P S, George NM. Topical vs combination ciprofloxacin in the management of discharging chronic
suppurative otitis media. J Clin Diagn Res 2014;8(6):KC01–KC04 .
Peritonsillar abscess (quinsy) and peritonsillar
cellulitis
Peritonsillar abscess (quinsy) and peritonsillar cellulitis
Peritonsillar abscess (quinsy) is a suppurative infection of the tissue between the palatine tonsil capsule and the
pharyngeal muscles. Patients can present with trismus, severe unilateral throat pain, high fever or a change in
voice. Most abscesses are polymicrobial; pathogens include Streptococcus pyogenes (group A streptococcus) and
Fusobacterium species. Peritonsillar cellulitis has a similar clinical presentation to peritonsillar abscess, without
suppuration or abscess formation.
Monitor patients for signs of airway obstruction. If present, urgent transfer to hospital with airway management is
required.
Drainage or aspiration of the abscess is the mainstay of treatment for peritonsillar abscess.
Antibiotic therapy is indicated for peritonsillar abscess and peritonsillar cellulitis. Use:
intravenous to oral switch.
For patients hypersensitive to penicillins, use:
1 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly; see below
for intravenous to oral switch
OR
2 lincomycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly; see below for
Intravenous to oral switch: for peritonsillar abscess, continue intravenous therapy for 1 to 2 days following
successful abscess drainage, then switch to oral therapy. For peritonsillar cellulitis, switch to oral therapy once the
patient improves Box 2.35 for guidance on when to switch to oral therapy).
For oral therapy for peritonsillar abscess or peritonsillar cellulitis, use:
phenoxymethylpenicillin 500 mg (child: 15 mg/kg up to 500 mg) orally, 12-hourly to

complete a total of 10 days of therapy (intravenous + oral).
A 12-hourly dosing regimen for phenoxymethylpenicillin is preferred over more frequent dosing regimens because
of improved adherence.
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly to complete a total of
10 days of therapy (intravenous + oral) [Note 1].
Oral liquid formulations of clindamycin have an unpleasant taste and are often poorly tolerated by children.
Cefalexin is a suitable alternative to clindamycin for most children with delayed nonsevere hypersensitivity to
penicillins [Note 2]. Use:
cefalexin 25 mg/kg up to 1 g orally, 12-hourly to complete a total of 10 days of therapy

(intravenous + oral).
Azithromycin is a suitable alternative to clindamycin for children with immediate (nonsevere or severe) or
delayed severe hypersensitivity to penicillins, use:
azithromycin 12 mg/kg up to 500 mg orally, daily.
Azithromycin has a long intracellular half-life. Stop azithromycin when either a total of 10 days of treatment
(intravenous + oral) has been completed, or 5 days of oral azithromycin has been taken, whichever occurs first.
Note 1: An oral liquid formulation of clindamycin is not commercially available; for formulation options for children or people with swallowing
Key references
Kara N, Spinou C. Appropriate antibiotics for peritonsillar abscess - a 9 month cohort. Otorhinolaryngol Head Neck
Surg 2010;40:20–4.
Dis 2016;16(8):e139–52.
Wiksten JE, Pitkaranta A, Blomgren K. Metronidazole in conjunction with penicillin neither prevents recurrence nor
enhances recovery from peritonsillar abscess when compared with penicillin alone: a prospective, double-blind,
randomized, placebo-controlled trial. J Antimicrob Chemother 2016;71(6):1681–7.
Pertussis
Diagnosis of pertussis
Pertussis (whooping cough) is caused by Bordetella pertussis. It classically presents with a persistent cough
(lasting longer than 2 weeks) with one or more of the following features:
paroxysms of coughing
inspiratory whoop
post-tussive vomiting.
Older children and adults may not have the classical symptoms of pertussis and may present with only a persistent
cough.
Pertussis infection is diagnosed by nucleic acid amplification testing (NAAT) (eg polymerase chain reaction
[PCR]). For both children and adults, the optimal diagnostic sample for NAAT is a nasopharyngeal swab [Note 1];
a throat swab is less sensitive. NAAT is most sensitive in the first 3 weeks of illness.
Report cases of pertussis to the local public health authority [Note 2] [Note 3].
For detailed recommendations about prevention, diagnosis and management of pertussis, see Pertussis: CDNA
National Guidelines for Public Health Units [URL].
Note 1: Use dacron or rayon tipped swabs. Do not use calcium alginate swabs.
Treatment of pertussis
The antibiotic recommendations below are used for treatment of patients with diagnosed pertussis (including
pneumonia due to Bordetella pertussis) and for antibiotic prophylaxis in selected contacts of these patients (see
Prevention of pertussis for indications for prophylaxis).
Infants younger than 6 months have the highest risk of morbidity and mortality from pertussis, and may require
hospitalisation for supportive care of complications, such as apnoea, hypoxaemia and feeding difficulties.
The evidence that antibiotics alter the clinical course of B. pertussis infection is unclear. However, antibiotics
effectively eliminate B. pertussis from the nasopharynx, so treatment of established disease minimises
transmission to susceptible contacts. In patients of any age, antibiotic treatment is recommended if the diagnosis of
pertussis is made within 3 weeks of cough or other symptom onset. Advise patients to avoid contact with others,
especially young children and infants, until antibiotic therapy has been taken for at least 5 days. After 3 weeks of
cough or other symptom onset, patients are rarely infectious and antibiotic therapy is not indicated.
For antibiotic treatment of pertussis, or for antibiotic prophylaxis in selected contacts of patients with pertussis,
use:
1 azithromycin
adult: 500 mg orally, on day 1, then 250 mg orally, daily for a further 4
days (total duration of therapy is 5 days)
child 6 months or older: 10 mg/kg up to 500 mg orally, on day 1, then

5 mg/kg up to 250 mg daily for a further 4 days (total duration of
therapy is 5 days)
neonate and child younger than 6 months: 10 mg/kg orally, daily for 5
days
OR
1 clarithromycin 500 mg (child: 7.5 mg/kg up to 500 mg) orally, 12-hourly for 7 days
OR

Azithromycin and clarithromycin are the preferred macrolides for this indication. There is no evidence to support
the use of roxithromycin for the treatment of pertussis. Erythromycin is active against B. pertussis, but is poorly
tolerated and requires more frequent dosing.
Prevention of pertussis
Identify contacts of patients diagnosed with pertussis and assess the need for antibiotic prophylaxis in
collaboration with the local public health authority [Note 4] [Note 5]. Contacts are individuals who have been
within 1 metre of an infectious pertussis case for more than 1 hour.
Contacts are individuals who have been within 1 metre of an infectious pertussis case for more than 1 hour.
Evidence to support antibiotic prophylaxis for contacts is limited. Its use is focused on preventing pertussis in
infants younger than 6 months.
In community settings, prescribe pertussis prophylaxis to the following patient groups if they are contacts of a
pertussis case:
infants younger than 6 months

women in the last month of pregnancy
individuals who may transmit pertussis to infants younger than 6 months. This includes children and adults
who:
have contact with the pertussis case in a childcare setting (need for prophylaxis varies depending on
the whether an outbreak has occurred, the age of children at the childcare setting and vaccination
status—seek advice from the local public health authority)
reside in a household with an infant less than 6 months of age; if the pertussis case is a member of the
household, all household members should receive prophylaxis
reside in a household with a woman in the last month of pregnancy; if the pertussis case is a member
of the household, all household members should receive prophylaxis.
If the need for prophylaxis is uncertain, seek advice from the local public health authority and consider the
vaccination status of contacts and the degree of contact with the pertussis case.
Healthcare settings and other circumstances where high-risk individuals have been exposed may warrant
consideration for prophylaxis (eg the contact is a grandparent who provides care for an infant younger than 6
months, but does not reside in the same household)—seek advice from the local public health authority.
If indicated, start antibiotic prophylaxis as soon as possible, using the same regimen as for treatment of pertussis.
The benefit of prophylaxis outweighs the harms of antibiotic use if prophylaxis is started within 14 days after first
contact with the pertussis case.
For detailed recommendations about pertussis prophylaxis, see Pertussis: CDNA National Guidelines for Public
Health Units [URL].
For information about vaccination against pertussis, see the Australian Immunisation Handbook [URL].
Key references
Diagnosis of pertussis
Communicable Diseases Network Australia (CDNA). Pertussis: CDNA national guidelines for public health units
[version 3.0]. Canberra: Department of Health; 2015.
http://www.health.gov.au/internet/main/publishing.nsf/Content/cdna-song-pertussis.htm
Treatment of pertussis
Altunaiji S, Kukuruzovic R, Curtis N, Massie J. Antibiotics for whooping cough (pertussis). Cochrane Database Syst
Rev 2007;(3):CD004404.
Langley JM, Halperin SA, Boucher FD, Smith B, Pediatric Investigators Collaborative Network on Infections in
Canada. Azithromycin is as effective as and better tolerated than erythromycin estolate for the treatment of pertussis.
Pediatrics 2004;114(1):e96–101.
Tiwari T, Murphy TV, Moran J, National Immunization Program CDC. Recommended antimicrobial agents for the
treatment and postexposure prophylaxis of pertussis: 2005 CDC Guidelines. MMWR Recomm Rep 2005;54(RR-14):1–
16.
Wang K, Bettiol S, Thompson MJ, Roberts NW, Perera R, Heneghan CJ, et al. Symptomatic treatment of the cough in
whooping cough. Cochrane Database Syst Rev 2014;(9):CD003257.
Prevention of pertussis
Communicable Diseases Network Australia (CDNA). Pertussis: CDNA national guidelines for public health units
http://www.health.gov.au/internet/main/publishing.nsf/Content/cdna-song-pertussis.htm
Tiwari T, Murphy TV, Moran J, National Immunization Program CDC. Recommended antimicrobial agents for the
treatment and postexposure prophylaxis of pertussis: 2005 CDC Guidelines. MMWR Recomm Rep 2005;54(RR-14):1–
16.
Retropharyngeal abscess
What is retropharyngeal abscess?
Retropharyngeal abscess is an uncommon, but potentially life-threatening condition. Symptoms of retropharyngeal
abscess may initially mimic pharyngitis but, as inflammation increases, pain, trismus, respiratory distress and
airway obstruction can develop.
Retropharyngeal abscess can be a complication of infection in the oropharynx, middle ear, prevertebral space,
nasal cavity or nasopharynx. Infection can result from local trauma from a procedure or ingestion of a foreign
body, but spontaneous infection can also occur, especially in children. If infection spreads to the lymph nodes in
the retropharyngeal space, cellulitis, phlegmon, suppuration and abscess formation can occur. The abscess may be
localised or extend inferiorly into the posterior mediastinum and prevertebral space. For management of infection
extending into the mediastinum, see Mediastinitis.
Retropharyngeal abscess is usually a polymicrobial infection; implicated organisms include Streptococcus

pyogenes (group A streptococcus), Staphylococcus aureus and anaerobes (eg Prevotella, Peptostreptococcus and
Fusobacterium species).
Management of retropharyngeal abscess

Retropharyngeal abscess is a potentially life-threatening condition. Initial management of retropharyngeal abscess
involves:
urgent transfer to hospital with airway management

referral to an otolaryngologist for early surgical drainage
intravenous antibiotic therapy.
If the abscess is small (eg less than 2 cm), surgical drainage may not be required—seek expert advice.
For empirical therapy of retropharyngeal abscess, use:
1 amoxicillin+clavulanate intravenously; see below for intravenous to oral switch
adult: 1+0.2 g 6-hourly [Note 1] [Note 2]

child younger than 3 months and less than 4 kg: 25+5 mg/kg 12-hourly
child younger than 3 months and 4 kg or more: 25+5 mg/kg 8-hourly
child 3 months or older: 25+5 mg/kg up to 1+0.2 g 6-hourly [Note 3] [Note 4]
OR (as a two-drug regimen)
1 cefazolin 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly; for adults with septic

shock or requiring intensive care support, consider dosing cefazolin 6-hourly. See below
PLUS
metronidazole 500 mg (child: 12.5 mg/kg up to 500 mg) intravenously, 12-hourly; see
below for intravenous to oral switch.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use cefazolin plus
metronidazole as above.
OR
If the patient is at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box
2.31), or is not improving despite adequate drainage, add empirical therapy for MRSA to the above regimens:
Consider replacing vancomycin with clindamycin or lincomycin (see dosages above) if local epidemiology
indicates that MRSA is likely to be susceptible to lincosamides and the patient is not severely unwell.
Modify therapy based on the results of culture and susceptibility testing. If MRSA is not identified by culture,
consider stopping additional therapy for MRSA. If MRSA is identified, modify therapy based on susceptibility
results.
Intravenous to oral switch: once the patient improves, switch to oral therapy after a minimum of 3 to 5 days
intravenous therapy, guided by the results of culture and susceptibility testing. See Box 2.35 for guidance on when
to switch to oral therapy.
If a pathogen is not identified, for oral therapy, use:

875+125 mg) orally, 12-hourly to complete a total of 10 to 14 days of therapy (intravenous
+ oral) [Note 5].
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly to complete a total of
10 to 14 days of therapy (intravenous + oral) [Note 6].
Oral liquid formulations of clindamycin have an unpleasant taste and are often poorly tolerated by children.
Trimethoprim+sulfamethoxazole is a suitable alternative for children who are hypersensitive to penicillins, use:
trimethoprim+sulfamethoxazole (child 1 month or older) 4+20 mg/kg up to 160+800 mg

orally, 12-hourly to complete a total of 10 to 14 days of therapy (intravenous + oral).
Note 1: At the time of writing, there is limited clinical evidence to determine the optimal dosage regimen of intravenous amoxicillin+clavulanate. A
reasonable alternative regimen for adults with retropharyngeal abscess is 2+0.2 g intravenously, 8-hourly.
Note 2: If the abscess has been adequately drained, consider reducing the dose of amoxicillin+clavulanate to 1+0.2 g intravenously, 8-hourly.
Note 3: At the time of writing, there is limited clinical evidence to determine the optimal dosage regimen of intravenous amoxicillin+clavulanate. For
children who weigh 40 kg or more who have a retropharyngeal abscess, a reasonable alternative regimen is 2+0.2 g intravenously, 8-hourly.
Note 4: If the abscess has been adequately drained, consider reducing the dose of amoxicillin+clavulanate to 25+5 mg/kg up to 1+0.2 g intravenously,
8-hourly.
Note 5: Amoxicillin+clavulanate may be suitable for children aged 1 month to younger than 2 months but a different dosage is required.
Note 6: An oral liquid formulation of clindamycin is not commercially available; for formulation options for children or people with swallowing
Key references
Abdel-Haq N, Quezada M, Asmar BI. Retropharyngeal abscess in children: the rising incidence of methicillin-resistant
Staphylococcus aureus. Pediatr Infect Dis J 2012;31(7):696–9.
Bolton M, Wang W, Hahn A, Ramilo O, Mejias A, Jaggi P. Predictors for successful treatment of pediatric deep neck
infections using antimicrobials alone. Pediatr Infect Dis J 2013;32(9):1034–6.
Georget E, Gauthier A, Brugel L, Verlhac S, Remus N, Epaud R, et al. Acute cervical lymphadenitis and infections of
the retropharyngeal and parapharyngeal spaces in children. BMC Ear Nose Throat Disord 2014;14:8.
Grisaru-Soen G, Komisar O, Aizenstein O, Soudack M, Schwartz D, Paret G. Retropharyngeal and parapharyngeal
abscess in children--epidemiology, clinical features and treatment. Int J Pediatr Otorhinolaryngol 2010;74(9):1016–20.
Hoffmann C, Pierrot S, Contencin P, Morisseau-Durand MP, Manach Y, Couloigner V. Retropharyngeal infections in

children. Treatment strategies and outcomes. Int J Pediatr Otorhinolaryngol 2011;75(9):1099–103.
Kirse DJ, Roberson DW. Surgical management of retropharyngeal space infections in children. Laryngoscope
2001;111(8):1413–22.
McClay JE, Murray AD, Booth T. Intravenous antibiotic therapy for deep neck abscesses defined by computed
tomography. Arch Otolaryngol Head Neck Surg 2003;129(11):1207–12.
Dis 2016;16(8):e139–52.
Nazir KA, Fozia PA, Ul Islam M, Shakil A, Patigaroo SA. Paediatric acute retropharyngeal abscesses: an experience.
Afr J Paediatr Surg 2013;10(4):327–35.
Page NC, Bauer EM, Lieu JE. Clinical features and treatment of retropharyngeal abscess in children. Otolaryngol
Head Neck Surg 2008;138(3):300–6.
Wong DK, Brown C, Mills N, Spielmann P, Neeff M. To drain or not to drain - management of pediatric deep neck
abscesses: a case-control study. Int J Pediatr Otorhinolaryngol 2012;76(12):1810–3.
Woods CR, Cash ED, Smith AM, Smith MJ, Myers JA, Espinosa CM, et al. Retropharyngeal and parapharyngeal
abscesses among children and adolescents in the United States: epidemiology and management trends, 2003-2012. J
Pediatric Infect Dis Soc 2016;5(3):259–68.
Acute rhinosinusitis
What is acute rhinosinusitis?
Rhinosinusitis refers to inflammation of the nasal mucosa and the paranasal sinuses. Although the term ‘sinusitis’
is commonly used to describe this condition, the term ‘rhinosinusitis’ is used in these guidelines because
inflammation of the paranasal sinuses (sinusitis) usually occurs concurrently with inflammation of the nasal
mucosa (rhinitis). Rhinitis can occur in isolation and is usually caused by an allergy (see Overview of rhinitis).
Rhinosinusitis is characterised by the presence of two or more of the following symptoms:
nasal blockage (congestion or obstruction)

nasal discharge (anterior or posterior nasal drip)
facial pain or pressure
reduction or loss of sense of smell.
Acute rhinosinusitis refers to rhinosinusitis that lasts less than 4 weeks.
If symptoms persist for longer than 12 weeks, the condition is termed chronic rhinosinusitis; see Chronic
rhinosinusitis for management.
For patients with symptoms lasting 4 to 12 weeks, the same assessment and management considerations apply as
for patients with acute rhinosinusitis; however, a bacterial cause may be more likely than a viral cause. Exclude
noninfective causes, and consider referral to an otolaryngologist and other management strategies recommended
for chronic rhinosinusitis.
Acute rhinosinusitis is one of the most common presentations in primary care in Australia. It is usually a self-
limiting viral infection, often called ‘the common cold’. Less than 2% of patients develop a secondary bacterial
infection. Primary bacterial infection is rare, but can occur in immunocompromised patients, or patients with
odontogenic infection, deficient mucociliary clearance mechanisms or mechanical nasal obstruction. It is important
to differentiate between viral and bacterial causes of acute rhinosinusitis (see Approach to managing acute
rhinosinusitis).
Most patients with acute rhinosinusitis can be safely managed in the community; however, patients with
complicated acute bacterial rhinosinusitis require hospitalisation for intravenous antibiotics and urgent surgical
referral. Infection is considered complicated if it spreads beyond the paranasal sinuses and nasal cavity into
adjacent spaces (eg meninges, ocular space, periorbital space), or when signs of sepsis or septic shock are present.
Clinical features of acute rhinosinusitis that indicate spreading bacterial infection are listed in Box 2.4. For
management, see Complicated acute bacterial rhinosinusitis.
Clinical features of acute rhinosinusitis that indicate spreading bacterial infection (Box 2.4)
Clinical features of bacterial infection extending beyond the paranasal sinuses and nasal cavity into adjacent
spaces (eg meninges, ocular space, periorbital space) include:
acute-onset confusion or impaired consciousness

diplopia or impaired vision
meningism (eg neck stiffness, severe headache, photophobia)
periorbital oedema or cellulitis
proptosis
signs of sepsis or septic shock (for definitions, see here for adults or here for children).
If any of these features are present, hospitalisation for intravenous antibiotics and urgent surgical referral are
required. For management, see Complicated acute bacterial rhinosinusitis.
Consider the possibility of acute fungal rhinosinusitis (eg mucormycosis, aspergillosis) in patients with immune
compromise or conditions associated with metabolic acidosis (eg diabetes). Acute fungal rhinosinusitis can present
with epistaxis, visual changes (particularly diplopia), acute-onset confusion or impaired consciousness, as well as
the usual symptoms of rhinosinusitis. If fungal infection is suspected or confirmed, seek urgent surgical and
infectious diseases advice.
Approach to managing acute rhinosinusitis
Figure 2.2 outlines the approach to assessment and management of acute rhinosinusitis.
Once complicated acute rhinosinusitis has been excluded (see What is acute rhinosinusitis?), try to differentiate
between a bacterial and viral cause of acute rhinosinusitis.
In the first 3 to 4 days of illness, acute viral rhinosinusitis and acute bacterial rhinosinusitis are indistinguishable.
The signs and symptoms of acute viral and bacterial rhinosinusitis overlap considerably, especially during the first
3 to 4 days of illness. If the patient presents in the first 3 to 4 days of illness, manage as for viral rhinosinusitis, as
this is the most likely cause of symptoms. After the first 3 to 4 days of illness, the clinical course may help to
distinguish between acute viral and bacterial rhinosinusitis.
See Table 2.6 for features of acute viral and bacterial rhinosinusitis, and Figure 2.2 for approach to assessment and
management.
Features of acute viral and bacterial rhinosinusitis (Table 2.6)
Feature Acute viral rhinosinusitis Acute bacterial rhinosinusitis

High fever (39°C or higher) present at the
Fever [NB1] Often present in the first few days of illness. onset of illness and persisting for 3 to 4
consecutive days.
Severe symptoms can occur at the onset of
illness and persist for 3 to 4 consecutive
Symptoms peak rapidly and decline by the days.
Symptom onset
third day of illness. Severe symptoms are defined as high fever
(39°C or higher) plus purulent nasal
discharge or facial pain.
Symptoms usually resolve or improve within
7 to 14 days, but bacterial infection is more
likely if:
Symptoms resolve by 7 days in 75% of
Symptom duration
patients. In 25% of patients, symptoms last symptoms persist for longer than 7 to
and improvement
longer than 7 days but reduce in severity. 10 days without improvement
symptoms worsen after initial
improvement.
NB1: Fever has a sensitivity and specificity of about 50% for predicting acute bacterial rhinosinusitis.
For patients with suspected acute viral rhinosinusitis, offer symptomatic therapy alone. Explain to the patient or
carer that viral infection is the most likely cause of the symptoms and antibiotic therapy is of no benefit. Also
explain that viral rhinosinusitis is a self-limiting condition and symptoms usually resolve within 7 days. Ask the
patient to return if they develop features indicating bacterial infection (see Table 2.6) or complicated infection (see
Box 2.4).
For patients with suspected acute bacterial rhinosinusitis, offer symptomatic therapy and discuss the limited role
of antibiotic therapy using a shared decision making approach (see Antibiotic therapy for acute bacterial
rhinosinusitis).
Approach to assessment and management of acute rhinosinusitis (Figure 2.2)
Printable figure
Symptomatic therapy for acute rhinosinusitis
Symptomatic therapy is recommended for all patients with acute rhinosinusitis.
Regular oral analgesia and saline nasal preparations improve symptoms and day-to-day functioning in patients with acute
rhinosinusitis.
Regular oral analgesia (eg paracetamol, nonsteroidal anti-inflammatory drugs [NSAIDs]) is recommended in all
patients. Pain has a significant impact on day-to-day functioning and is often the reason patients with acute
rhinosinusitis seek medical attention. For dosages, see here for adults or here for children.
Saline nasal preparations (sprays, rinses or drops) may reduce sinus symptoms and improve the patient’s quality
of life. They are particularly beneficial for patients with recurrent episodes of acute rhinosinusitis (see Recurrent
acute rhinosinusitis).
Intranasal corticosteroids moderately improve symptoms of acute rhinosinusitis. For dosages, see Intranasal
corticosteroids.
Intranasal and systemic decongestants are beneficial if congestion is the prominent symptom. They are
recommended for short-term use only (up to 5 days) in adults and children 6 years or older. See Decongestants for
further information.
Intranasal ipratropium bromide is beneficial if rhinorrhoea is the prominent symptom. For dosages, see
Ipratropium.
Oral corticosteroids should only be used for acute rhinosinusitis under specialist advice.
Antihistamines do not relieve symptoms of acute rhinosinusitis; they should only be considered if allergy is likely
to be contributing to symptoms.
Patient information on symptom management has been created by NPS MedicineWise and is available here for
adults or here for children; alternatively, see the NPS MedicineWise website.
Cigarette smoke and air pollution increase the risk of rhinosinusitis. Smoking cessation by patients, parents or
carers can help prevent future episodes of rhinosinusitis.
Antibiotic therapy for acute bacterial rhinosinusitis

Is antibiotic therapy indicated?
Antibiotic therapy is commonly inappropriately prescribed for acute rhinosinusitis. Antibiotic therapy should only
be considered if bacterial infection is likely (see Approach to managing acute rhinosinusitis). Primary bacterial
infection is rare, and secondary bacterial infection occurs in less than 2% of patients. Do not prescribe antibiotics
for acute viral rhinosinusitis.
Acute bacterial rhinosinusitis is usually a self-limiting condition. If antibiotics are prescribed, the rate of symptom
improvement is increased at days 3 and 7, but at day 10, there is no difference in improvement between patients
treated with or without antibiotics. The use of antibiotics for acute bacterial rhinosinusitis does not prevent the
occurrence of rare complications, such as complicated acute bacterial rhinosinusitis.
Acute bacterial rhinosinusitis is usually a self-limiting condition and antibiotics make little difference to the course of the illness.
The small benefit of antibiotic therapy must be balanced against the potential harms (eg diarrhoea, rash or more
serious hypersensitivity reactions, bacterial resistance). For every 100 patients treated with antibiotics for acute
bacterial rhinosinusitis, 12 patients will experience an antibiotic adverse effect.
Initially treat patients with suspected acute bacterial rhinosinusitis with symptomatic therapy alone, with follow-up
if symptoms worsen or do not improve.
Many patients have an expectation of treatment with antibiotics. Effective communication with the patient or carer
about the limited role of antibiotics in acute bacterial rhinosinusitis is essential. The discussion should address
misconceptions about the effectiveness of antibiotic therapy and the expectation of an antibiotic prescription.
Shared decision making, which involves a discussion of the evidence for the potential benefits and harms of
therapy, provides a useful template for these discussions.
If a decision is made to use antibiotic therapy, see Antibiotic regimens for acute bacterial rhinosinusitis for
treatment recommendations.
Shared decision making in acute bacterial rhinosinusitis

available evidence and the patient or carer’s values and preferences.
Patients who take part in shared decision making have a more accurate understanding of the benefits and harms of
the available treatment approaches, and are more likely to choose conservative management. Further, short-term
trial data demonstrated that shared decision making reduces antibiotic prescribing in primary care.
The steps for shared decision making when deciding whether antibiotic treatment will be used for acute bacterial
rhinosinusitis are outlined in Box 2.5. A graphic to support shared decision making discussions is available here.
Shared decision making for antibiotic therapy in acute bacterial rhinosinusitis (Box 2.5)
Printable box
Reassure the patient or carer that acute bacterial rhinosinusitis is usually self-limiting. Complications are
rare and the use of antibiotics for acute bacterial rhinosinusitis does not prevent complications.
Ask about the patient or carer’s expectations for management of acute bacterial rhinosinusitis.
Explain that there are two treatment approaches:
Symptomatic therapy alone with follow-up if symptoms do not improve in 5 days, or earlier if
symptoms worsen. A delayed prescription for antibiotic therapy can be offered if the patient will not
be able to return.
Symptomatic therapy plus an immediate prescription for antibiotic therapy.
Explain that symptoms of acute bacterial rhinosinusitis usually resolve or improve within 7 to 14 days
without antibiotic therapy. Acknowledge that symptoms impact day-to-day functioning and that this is
frustrating, but symptomatic therapy is most useful for managing this.
If antibiotics are prescribed, the rate of symptom improvement is increased at days 3 and 7, but at
day 10, there is no difference in improvement between patients treated with or without antibiotics.
this are not fully understood, it can cause problems ranging from yeast infections (eg thrush) to more
serious infections (eg Clostridium difficile infection).
Antibiotics can cause bacteria in the body to become resistant to antibiotics so that future infections
are harder to treat. Multidrug-resistant bacteria (known as ‘superbugs’) can be spread between
people, affecting other family members and the community.
For every 100 patients treated with antibiotics for acute bacterial rhinosinusitis, 12 patients will
experience an antibiotic adverse effect.
questions.
Make a joint decision about whether to use symptomatic therapy alone or combine symptomatic therapy
with antibiotic therapy [NB1] [NB2]; if a decision is made to use antibiotic therapy, see Antibiotic
regimens for acute bacterial rhinosinusitis for treatment recommendations.
Discuss criteria for patient follow-up and reassessment. Ask the patient to return in 5 days if symptoms do
not improve, or earlier if symptoms worsen (particularly fever) or if symptoms suggestive of complicated
infection occur (see Box 2.4).
NB1: A graphic to support shared decision making discussions is available here.
NB2: Patient information on symptom management has been created by NPS MedicineWise and is available here for adults or here for children;
Antibiotic regimens for acute bacterial rhinosinusitis
Only consider antibiotic therapy if a bacterial cause of acute rhinosinusitis is likely. To differentiate between acute
viral and bacterial rhinosinusitis, see Approach to managing acute rhinosinusitis. Engage in shared decision
making with the patient or carer to decide whether to use antibiotic therapy.
Acute bacterial rhinosinusitis is usually a self-limiting condition and antibiotics make little difference to the course of the illness.
The usual pathogens in acute bacterial rhinosinusitis are Streptococcus pneumoniae and Haemophilus influenzae.
Moraxella catarrhalis infection is less frequent.
For antibiotic management of acute bacterial rhinosinusitis, use:
amoxicillin 500 mg (child: 15 mg/kg up to 500 mg) orally, 8-hourly for 5 days; see Patient
review and modification of therapy.
If adherence to an 8-hourly regimen is unlikely, a 12-hourly regimen can be used instead. Use:
amoxicillin 1 g (child: 30 mg/kg up to 1 g) orally, 12-hourly for 5 days; see Patient review
and modification of therapy.
Lower amoxicillin doses should not be used because they will not achieve adequate plasma and tissue
concentrations to treat S. pneumoniae strains with intermediate susceptibility to penicillins.
cefuroxime 500 mg (child 3 months or older: 15 mg/kg up to 500 mg) orally, 12-hourly for
5 days; see Patient review and modification of therapy [Note 1].
doxycycline orally, 12-hourly for 5 days; see Patient review and modification of therapy
adult: 100 mg
OR (for children younger than 8 years or children requiring an oral liquid formulation)

orally, 12-hourly for 5 days; see Patient review and modification of therapy.
Patient review and modification of therapy
Ask the patient to return for review and reassessment of the diagnosis if symptoms do not improve in 5 days, or
earlier if symptoms worsen (particularly fever) or if symptoms of complicated infection develop (see Box 2.4). If
present, see Complicated acute bacterial rhinosinusitis for management.
If the patient is not improving and uncomplicated acute bacterial rhinosinusitis remains the likely diagnosis,
consider increasing the duration of antibiotic therapy to 10 days.
If the patient is being treated with oral amoxicillin, consider changing antibiotic therapy to
amoxicillin+clavulanate. The infection may be caused by a beta-lactamase–producing strain of H. influenzae or M.
catarrhalis and adding clavulanate provides increased activity against these pathogens. Change amoxicillin to:

875+125 mg) orally, 12-hourly for 5 days [Note 2].
Complicated acute bacterial rhinosinusitis

Acute bacterial rhinosinusitis is considered complicated if the infection spreads beyond the paranasal sinuses and
nasal cavity into adjacent spaces (eg meninges, ocular space, periorbital space), or when signs of sepsis or septic
shock are present. For clinical features that indicate spreading infection, see Box 2.4. For sepsis and septic shock
definitions, see here for adults or here for children.
In patients with immune compromise or conditions associated with metabolic acidosis (eg diabetes), consider the
possibility of acute fungal rhinosinusitis (eg mucormycosis, aspergillosis), which can have a similar presentation to
complicated acute bacterial rhinosinusitis.
Patients with complicated acute bacterial rhinosinusitis require intravenous antibiotics; patients with spreading
infection also require urgent surgical referral.
For patients with sepsis or septic shock, start antibiotic therapy for complicated acute bacterial rhinosinusitis
within 1 hour of presentation to medical care or, for ward-based patients, development of sepsis or septic shock,
immediately after appropriate samples are taken for culture. For nonantibiotic management of sepsis or septic
shock, see Early intervention for sepsis or septic shock.
For complicated acute bacterial rhinosinusitis, the choice of antibiotic depends on the duration of symptoms, the
severity of systemic features, evidence of extension (eg meningitis or brain abscess) and other complicating factors
(eg recent surgery)—seek expert advice. For initial therapy while awaiting the results of culture and susceptibility
testing and expert advice, use:
1 ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously, 12-hourly
OR
The above regimens can be used for patients with immediate nonsevere or delayed nonsevere hypersensitivity to
penicillins.
For patients at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) (see Box 2.31), add to the
above regimen:
vancomycin intravenously; see Principles of vancomycin use for dosing and principles of
If the patient has had recent neurosurgery, treat as postneurosurgical brain abscess—see Brain abscess and
subdural empyema.
For all patients, seek expert advice for ongoing management and duration of antibiotic therapy.
Recurrent acute rhinosinusitis

Acute rhinosinusitis is considered recurrent when patients have four or more distinct episodes per year without
persistent symptoms between episodes. If symptoms persist for longer than 12 weeks, the condition is termed
chronic rhinosinusitis. For management of chronic rhinosinusitis, see Chronic rhinosinusitis.
Recurrent acute rhinosinusitis is often associated with contributing factors that influence patient management (eg
nasal polyps, allergy, immune function); for details, see Chronic rhinosinusitis. Refer patients with recurrent acute
rhinosinusitis to an otolaryngologist, particularly if a structural abnormality is suspected.
Refer patients with recurrent acute rhinosinusitis to an otolaryngologist, particularly if a structural abnormality is suspected.
Recurrent acute rhinosinusitis has a significant impact on the patient’s day-to-day functioning and quality of life.
Offer symptomatic therapy to all patients; nasal saline rinses can be particularly beneficial.
Do not prescribe long-term antibiotic therapy for recurrent acute rhinosinusitis.
Both bacteria and viruses can cause recurrent acute rhinosinusitis. For each episode of acute rhinosinusitis,
distinguish between a viral and bacterial cause (see Approach to managing acute rhinosinusitis. If bacterial
infection is likely, use shared decision making to determine whether to prescribe antibiotics; the antibiotic
regimens for acute bacterial rhinosinusitis are suitable for recurrent acute bacterial rhinosinusitis (see Antibiotic
therapy for acute bacterial rhinosinusitis. Repeated courses of antibiotic therapy increase the likelihood of adverse
effects such as diarrhoea, rash or more serious hypersensitivity reactions, and bacterial resistance. Do not prescribe
long-term antibiotic therapy for recurrent acute rhinosinusitis.
Key references
What is acute rhinosinusitis?
McCullough AR, Pollack AJ, Plejdrup Hansen M, Glasziou PP, Looke DF, Britt HC, et al. Antibiotics for acute
respiratory infections in general practice: comparison of prescribing rates with guideline recommendations. Med J Aust
2017;207(2):65–9.
Meltzer EO, Hamilos DL, Hadley JA, Lanza DC, Marple BF, Nicklas RA, et al. Rhinosinusitis: Establishing definitions
for clinical research and patient care. Otolaryngol Head Neck Surg 2004;131(6 Suppl):S1–62.
Morcom S, Phillips N, Pastuszek A, Timperley D. Sinusitis. Aust Fam Physician 2016;45(6):374–7.
National Institute for Health and Care Excellence (NICE). Sinusitis (acute): antimicrobial prescribing [NG79]. London:
NICE; 2017. https://www.nice.org.uk/guidance/ng79/resources
Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Ashok Kumar K, Kramper M, et al. Clinical practice guideline
(update): adult sinusitis. Otolaryngol Head Neck Surg 2015;152(2 Suppl):S1–S39.
Approach to managing acute rhinosinusitis
Chow AW, Benninger MS, Brook I, Brozek JL, Goldstein EJ, Hicks LA, et al. IDSA clinical practice guideline for acute
bacterial rhinosinusitis in children and adults. Clin Infect Dis 2012;54(8):e72–e112.
Rosenfeld RM. Clinical practice. Acute sinusitis in adults. N Engl J Med 2016;375(10):962–70.
Wald ER, Applegate KE, Bordley C, Darrow DH, Glode MP, Marcy SM, et al. Clinical practice guideline for the
diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years. Pediatrics 2013;132(1):e262–80.
Symptomatic therapy for acute rhinosinusitis
King D, Mitchell B, Williams CP, Spurling GK. Saline nasal irrigation for acute upper respiratory tract infections.
Shaikh N, Wald ER. Decongestants, antihistamines and nasal irrigation for acute sinusitis in children. Cochrane
Venekamp RP, Thompson MJ, Hayward G, Heneghan CJ, Del Mar CB, Perera R, et al. Systemic corticosteroids for
acute sinusitis. Cochrane Database Syst Rev 2014;(3):CD008115.
Wilson JF. In the clinic. Acute sinusitis. Ann Intern Med 2010;153(5):ITC31–16.
Zalmanovici Trestioreanu A, Yaphe J. Intranasal steroids for acute sinusitis. Cochrane Database Syst Rev 2013;
(12):CD005149.
Antibiotic therapy for acute bacterial rhinosinusitis
Burgstaller JM, Steurer J, Holzmann D, Geiges G, Soyka MB. Antibiotic efficacy in patients with a moderate probability
of acute rhinosinusitis: a systematic review. Eur Arch Otorhinolaryngol 2016;273(5):1067–77.
(11):CD010907.
Falagas ME, Giannopoulou KP, Vardakas KZ, Dimopoulos G, Karageorgopoulos DE. Comparison of antibiotics with
placebo for treatment of acute sinusitis: a meta-analysis of randomised controlled trials. Lancet Infect Dis
2008;8(9):543–52.
Falagas ME, Karageorgopoulos DE, Grammatikos AP, Matthaiou DK. Effectiveness and safety of short vs. long
duration of antibiotic therapy for acute bacterial sinusitis: a meta-analysis of randomized trials. Br J Clin Pharmacol
2009;67(2):161–71.
Med J Aust 2014;201(9):513–4.
Lemiengre MB, van Driel ML, Merenstein D, Young J, De Sutter AI. Antibiotics for clinically diagnosed acute
rhinosinusitis in adults. Cochrane Database Syst Rev 2012;(10):CD006089.
McCullough AR, Pollack AJ, Plejdrup Hansen M, Glasziou PP, Looke DF, Britt HC, et al. Antibiotics for acute
respiratory infections in general practice: comparison of prescribing rates with guideline recommendations. Med J Aust
2017;207(2):65–9.
Dis 2016;16(8):e139–52.
Rosenfeld RM. Clinical practice. Acute sinusitis in adults. N Engl J Med 2016;375(10):962–70.
Wald ER, Applegate KE, Bordley C, Darrow DH, Glode MP, Marcy SM, et al. Clinical practice guideline for the
diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years. Pediatrics 2013;132(1):e262–80.
Complicated acute bacterial rhinosinusitis
Recurrent acute rhinosinusitis
Kaper NM, Breukel L, Venekamp RP, Grolman W, van der Heijden GJ. Absence of evidence for enhanced benefit of
antibiotic therapy on recurrent acute rhinosinusitis episodes: a systematic review of the evidence base. Otolaryngol
Head Neck Surg 2013;149(5):664–7.
Sore throat
Assessment of sore throat
Overview
Sore throat is often referred to as pharyngitis (inflammation of the pharynx) or tonsillitis (inflammation of the palatine tonsils), but it
can be a symptom of many other conditions.
Patient assessment is essential to ensure appropriate patient management—see Figure 2.3 for an outline of the approach to assessment
and management of sore throat.
Approach to assessing and managing sore throat (Figure 2.3)
Printable figure
NB1: Aboriginal and Torres Strait Islander people living in urban settings and, potentially, immigrants from developing countries may also be at high risk.
Assess the patient’s need for hospitalisation

Most patients with sore throat can be safely managed in the community. However, patients with airway obstruction or a deep neck
space infection require urgent transfer to hospital with airway management. Clinical features of airway obstruction or a deep neck
space infection are listed in Table 2.7. In patients with these features, differential diagnoses include:
acute epiglottitis
peritonsillar abscess (quinsy) and peritonsillar cellulitis
retropharyngeal abscess
pharyngeal diphtheria
severe Epstein–Barr virus (EBV) infection
spreading odontogenic infections (including Ludwig angina)
septic jugular thrombophlebitis (Lemierre syndrome).
Patients with dysphagia causing dehydration or severe throat pain may also require hospital assessment or admission.
Consider differential diagnoses

A summary of causes of sore throat is provided in Table 2.7.
Viral pharyngitis and tonsillitis are the most common causes of sore throat in patients of all ages and are self-limiting. Viral infection
is strongly suggested by the presence of any one of the following clinical features: cough, hoarse voice, conjunctivitis, nasal
congestion, anterior stomatitis, viral exanthema, diarrhoea, the absence of fever. To increase confidence in the diagnosis and
management approach, consider nucleic acid amplification testing (eg polymerase chain reaction [PCR]) to detect respiratory viruses.
Streptococcus pyogenes (group A streptococcus) causes approximately 10% of sore throats in adults and 20% of sore throats in
children, and is usually self-limiting. Streptococcal pharyngitis and tonsillitis are hard to diagnose based on clinical features alone.
The clinical features traditionally associated with streptococcal infection are fever (above 38°C), tender cervical lymphadenopathy,
tonsillar exudate, and absence of cough, rhinorrhoea or nasal congestion. However, even the presence of all four of these features is
predictive of streptococcal infection in fewer than 50% of patients. These clinical features are even less predictive in children than in
adults.
Throat swab culture for S. pyogenes can confirm the diagnosis; however, S. pyogenes is part of the normal throat flora and a positive
culture result may not indicate current infection. If possible, collect a throat swab for culture if antibiotic therapy is being considered
and base any decision to use or continue antibiotic therapy on culture results.
Causes of sore throat (Table 2.7)
Condition Details
Conditions associated with airway
obstruction or deep neck space
infection:
Urgent transfer to hospital with airway management is required.
Acute epiglottitis
Clinical features include:
Peritonsillar abscess (quinsy) and
peritonsillar cellulitis muffled voice
stridor
Retropharyngeal abscess trismus
drooling
Pharyngeal diphtheria neck swelling
torticollis
severe Epstein–Barr virus (EBV)
severe neck pain
infection
unilateral throat pain
severe croup or bacterial tracheitis respiratory distress
signs of airway compromise
spreading odontogenic infections signs of sepsis or septic shock (for definitions, see here for adults or here for children).
(including Ludwig angina)
Septic jugular thrombophlebitis

(Lemierre syndrome)
The most common causes of sore throat in patients of all ages.
Viral pharyngitis and tonsillitis Clinical features include cough, hoarse voice, conjunctivitis, nasal congestion, anterior
stomatitis, viral exanthema, diarrhoea and the absence of fever.
More common in school-aged children and adolescents, but can occur in younger children
and adults.
Streptococcal pharyngitis and
Clinical features include fever (above 38°C), tender cervical lymphadenopathy, tonsillar
tonsillitis
exudate, and absence of cough, rhinorrhoea or nasal congestion.
Collect a throat swab for culture if antibiotic therapy is being considered.

More common in children between 5 and 15 years old.
Caused by Streptococcus pyogenes, so manage with the antibiotic regimens for streptococcal
pharyngitis and tonsillitis.
Scarlet fever
Clinical features include a sudden high fever (above 38.5°C) followed by a distinctive rash
(red initially, becoming dry and rough with a sandpaper feel), facial flushing with circumoral
pallor and tongue discolouration (white initially, becoming red and bumpy [strawberry
tongue]).
Common in adolescents and young adults.
Epstein–Barr virus (EBV) Clinical features include severe sore throat, fever, nausea, lymphadenopathy, splenomegaly,
infection (glandular fever, infectious hepatomegaly, rash and fatigue.
mononucleosis)
If suspected, consider performing an infectious mononucleosis (IM) test or EBV serology.
More common in children younger than 5 years but can occur in older children and
adolescents.
Primary oral mucocutaneous herpes Clinical features include fever, intraoral or hypopharyngeal lesions, aphthous tonsil ulcers
(herpes gingivostomatitis) and cervical lymphadenopathy.
If suspected, consider collecting a throat swab for herpes simplex virus (HSV) type–specific
nucleic acid amplification testing (eg polymerase chain reaction [PCR]).
Common in children.
Usually caused by coxsackieviruses.

Hand, foot and mouth disease
Clinical features include vesicular or ulcerative mucosal eruptions in the mouth and throat,
loss of appetite, and rash or skin lesions.
Common in children.
Usually caused by coxsackieviruses.

Herpangina
Clinical features include high fever (above 38.5°C), vesicular or ulcerative mucosal
eruptions in the mouth and throat, cervical lymphadenopathy, headache, abdominal pain,
vomiting and loss of appetite.
Sexually transmitted infections: Occur in sexually active patients.
Neisseria gonorrhoeae infection These infections are usually asymptomatic, but patients can present with pharyngeal
Syphilis (see Early syphilis) symptoms.
An uncommon cause of pharyngitis; more common in patients aged 10 to 24 years.
Arcanobacterium haemolyticum Clinical features are similar to streptococcal pharyngitis and tonsillitis. Consider diagnosis in
(formerly Corynebacterium patients who do not respond to empirical antibiotic therapy for streptococcal infection. A
haemolyticum) pharyngitis and rash, similar to scarlet fever, may occur and can be misattributed to penicillin
tonsillitis hypersensitivity.
Can be identified on throat swab culture.

Noninfective causes of sore throat include postnasal drip due to allergic rhinitis and
Noninfective causes
rhinosinusitis, cigarette smoke, dry air, snoring, tracheal intubation and medications.
Approach to managing sore throat

Figure 2.3 outlines the approach to assessment and management of sore throat.
For patients with viral pharyngitis or tonsillitis, use symptomatic therapy. Explain to the patient or carer that this is a self-limiting
condition and symptoms usually resolve within 7 days. Antibiotic therapy is of no benefit.
For patients with streptococcal pharyngitis and tonsillitis, use symptomatic therapy. Antibiotic therapy is only indicated in selected
patients (see Is antibiotic therapy indicated?).
Ask all patients to return if symptoms worsen or do not improve (particularly fever) within a reasonable timeframe (eg 3 to 7 days), or
if new symptoms develop (eg vomiting, dehydration, rigors).
For sore throat caused by other conditions listed in Table 2.7, the appropriate management will depend on the condition. Patients with
airway obstruction or a deep neck space infection require urgent transfer to hospital with airway management.
Symptomatic therapy for sore throat

Symptomatic therapy is recommended for all patients with sore throat.
Symptomatic therapy includes:
paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs) to relieve pain and fever (for dosages, see here for adults or
here for children)
medicated lozenges containing an antiseptic, anti-inflammatory or anaesthetic drug to relieve throat pain in adults and
adolescents.
Patient information on symptom management has been created by NPS MedicineWise and is available here for adults or here for
children; alternatively, see the NPS MedicineWise website.
Cigarette smoke and air pollution increase the risk of sore throat. Smoking cessation by patients, parents or carers can help prevent
recurrent sore throat.
For patients with severe symptoms of pharyngitis (eg severe throat pain, dysphagia, drooling), consider using a corticosteroid to
reduce the intensity and duration of pain. Typical regimens are:
dexamethasone 10 mg (child: 0.6 mg/kg up to 10 mg) orally, as a single dose

OR
prednisolone 60 mg (child: 1 mg/kg up to 60 mg) orally, daily for 1 or 2 days.
Antibiotic therapy for streptococcal pharyngitis and tonsillitis

Is antibiotic therapy indicated?
Empirical antibiotic therapy should only be considered if streptococcal pharyngitis and tonsillitis are the likely cause of sore throat
(see Assessment of sore throat). Use symptomatic therapy to treat throat pain and fever in all patients.
Do not prescribe antibiotics for viral pharyngitis and tonsillitis.
Streptococcal pharyngitis and tonsillitis are usually self-limiting. Antibiotics shorten the duration of symptoms by less than 1 day, but
at day 7 there is no difference in improvement between patients treated with and without antibiotics. This small benefit of antibiotic
therapy must be balanced against the potential harms (eg diarrhoea, rash or more serious hypersensitivity reactions, bacterial
resistance).
Empirical antibiotic therapy is recommended for the following high-risk patient groups to prevent nonsuppurative complications of
Streptococcus pyogenes infection (eg acute rheumatic fever, poststreptococcal glomerulonephritis):
patients aged 2 to 25 years from populations with a high incidence of acute rheumatic fever (eg Aboriginal and Torres Strait
Islander Australians living in rural or remote settings, Maori and Pacific Islander people) [Note 1]
patients of any age with existing rheumatic heart disease
patients with scarlet fever (see Table 2.7 for symptoms).
Empirical antibiotic therapy is also recommended for patients with severe symptoms of pharyngitis (eg patients requiring
hospitalisation, patients with severe throat pain or dysphagia) to reduce the severity and duration of symptoms.
If possible, collect a throat swab for culture to confirm S. pyogenes infection before starting antibiotic therapy, and base any decision
to use or continue antibiotic therapy on culture results.
Antibiotic therapy can be considered for patients with confirmed S. pyogenes on throat swab culture who have ongoing symptoms of
streptococcal pharyngitis and tonsillitis.
Initially treat all other patients with suspected streptococcal pharyngitis and tonsillitis with symptomatic therapy alone, with follow-
up if symptoms worsen or do not improve.
Many patients have an expectation of treatment with antibiotics. Effective communication with the patient or carer about the limited
role of antibiotics in streptococcal pharyngitis and tonsillitis is essential. The discussion should address misconceptions about the
effectiveness of antibiotic therapy and the expectation of an antibiotic prescription. Shared decision making, which involves a
discussion of the evidence for the potential benefits and harms of therapy, provides a useful template for these discussions.
If a decision is made to use antibiotic therapy, see Antibiotic regimens for streptococcal pharyngitis and tonsillitis for treatment
recommendations.
Note 1: Aboriginal and Torres Strait Islander people living in urban settings and, potentially, immigrants from developing countries
may also be at high risk.
Shared decision making in sore throat

Shared decision making enables doctors and patients to make health decisions in partnership, informed by the best available evidence
and the patient or carer’s values and preferences.
Patients who take part in shared decision making have a more accurate understanding of the benefits and harms of the available
treatment approaches, and are more likely to choose conservative management. Further, short-term trial data demonstrated that shared
decision making reduces antibiotic prescribing in primary care.
The steps for shared decision making when deciding whether antibiotic treatment will be used for streptococcal pharyngitis or
tonsillitis are outlined in Box 2.6. A graphic to support shared decision making discussions has been created by the Australian
Commission on Safety and Quality in Health Care and is available here.
Shared decision making for antibiotic treatment in suspected streptococcal pharyngitis or tonsillitis when risk
of nonsuppurative complications is not high (Box 2.6)
Printable box
Reassure the patient or carer that streptococcal pharyngitis and tonsillitis are usually self-limiting. Except in high-risk patient
groups, complications are rare (see Is antibiotic therapy indicated?).
Ask about the patient or carer’s expectations for management of streptococcal pharyngitis and tonsillitis.
Explain that there are two treatment approaches:
Symptomatic therapy alone with follow-up if symptoms worsen or do not improve within a reasonable timeframe (eg 3
to 7 days). A delayed prescription for antibiotic therapy can be offered if the patient will not be able to return.
Symptomatic therapy plus an immediate prescription for antibiotic therapy.
Explain that symptoms of streptococcal pharyngitis and tonsillitis usually last 7 days, whether or not antibiotics are used.
Antibiotics only shorten the duration of symptoms by less than 1 day.
Antibiotics can prevent complications such as rheumatic fever, but these are rare in patients who are not in a high-risk
group.
Antibiotics disrupt the balance of bacteria in the body (the microbiome). While the consequences of this are not fully
understood, it can cause problems ranging from yeast infections (eg thrush) to more serious infections (eg Clostridium
difficile infection).
Antibiotics can cause bacteria in the body to become resistant to antibiotics so that future infections are harder to treat.
Multidrug-resistant bacteria (known as ‘superbugs’) can be spread between people, affecting other family members and
the community.
Ask about the preferences, values and concerns of the patient or carer, and answer any remaining questions.
Make a joint decision about whether to use symptomatic therapy alone or combine symptomatic therapy with antibiotic
therapy [NB1] [NB2]; if a decision is made to use antibiotic therapy, see Antibiotic regimens for streptococcal pharyngitis
and tonsillitis for treatment recommendations.
Discuss criteria for patient follow-up and reassessment. Ask the patient to return if symptoms worsen or do not improve
(particularly fever) within a reasonable timeframe (eg 3 to 7 days), or if new symptoms develop (eg vomiting, dehydration,
rigors).
NB1: A graphic to support shared decision making discussions has been created by the Australian Commission on Safety and Quality in Health Care and is available here.
NB2: Patient information on symptom management has been created by NPS MedicineWise and is available here for adults or here for children; alternatively, see the NPS
MedicineWise website.
Antibiotic regimens for streptococcal pharyngitis and tonsillitis

If possible, collect a throat swab for culture to confirm S. pyogenes infection before starting antibiotic therapy, and base any decision
to use or continue antibiotic therapy on culture results.
If antibiotic therapy for streptococcal pharyngitis and tonsillitis is indicated (see Is antibiotic therapy indicated?), use:
phenoxymethylpenicillin 500 mg (child: 15 mg/kg up to 500 mg) orally, 12-hourly for 10 days; see below
for further advice on duration of therapy.
S. pyogenes remains highly susceptible to phenoxymethylpenicillin. A 12-hourly dosing regimen for phenoxymethylpenicillin is
effective for the treatment of streptococcal pharyngitis and tonsillitis, and is preferred over more frequent dosing regimens because of
improved adherence.
Do not use amoxicillin for streptococcal pharyngitis and tonsillitis.
Amoxicillin should not be used for streptococcal pharyngitis and tonsillitis. Amoxicillin exposes the patient to unnecessary broader-
spectrum treatment and can cause a rash if the patient has undiagnosed Epstein–Barr virus (EBV) infection.
Intramuscular benzathine benzylpenicillin can be used if patient adherence to the 10-day oral phenoxymethylpenicillin regimen is
unlikely, oral therapy is not tolerated, or a single-dose treatment is preferred. Use:
benzathine benzylpenicillin intramuscularly, as a single dose [Note 2]

adult or child 20 kg or more: 1.2 million units (2.3 mL)
child 6 kg or less: 0.3 million units (0.6 mL)
child 6 kg to less than 12 kg: 0.45 million units (0.9 mL)
child 16 kg to less than 20 kg: 0.9 million units (1.7 mL).
Benzathine benzylpenicillin is long acting and provides adequate concentrations of benzylpenicillin for up to 4 weeks, so only a
single dose is required. Do not confuse benzathine benzylpenicillin with benzylpenicillin, which is short acting.
If oral therapy is not possible initially and benzathine benzylpenicillin is not available, use:
procaine benzylpenicillin 1.5 g (child: 50 mg/kg up to 1.5 g) intramuscularly, daily; switch to oral
phenoxymethylpenicillin (see above) when tolerated to complete a total of 10 days of therapy
(intramuscular + oral).
For patients with delayed nonsevere hypersensitivity to penicillins, cefalexin can be used in most cases [Note 3]. Use:
cefalexin 1 g (child: 25 mg/kg up to 1 g) orally, 12-hourly for 10 days; see below for further advice on
Duration of therapy: symptoms of streptococcal pharyngitis and tonsillitis usually last 7 days. However, a 10-day treatment duration
is recommended for phenoxymethylpenicillin and cefalexin to eradicate S. pyogenes from the pharynx and prevent nonsuppurative
complications. Azithromycin has a long intracellular half-life, so 5 days of therapy is sufficient.
Ask the patient to return if symptoms worsen or do not improve (particularly fever) within a reasonable timeframe (eg 3 to 7 days), or
if new symptoms develop (eg vomiting, dehydration, rigors).
If a rash develops after starting antibiotic therapy, assess the patient for antimicrobial hypersensitivity, but also consider if an
alternative diagnosis could explain the rash, such as a viral exanthem, Epstein–Barr virus (EBV) infection, or Arcanobacterium
haemolyticum (formerly Corynebacterium haemolyticum) pharyngitis. For management of A. haemolyticum pharyngitis, see
Antibiotic therapy for Arcanobacterium haemolyticum pharyngitis.
Note 2: All benzathine benzylpenicillin preparations (benzathine benzylpenicillin 900 mg/2.3 mL [equivalent to 1.2 million units]; benzathine benzylpenicillin tetrahydrate
1 200 000 units/2.3 mL [equivalent to 1016.6 mg benzathine benzylpenicillin tetrahydrate]; benzathine benzylpenicillin tetrahydrate 600 000 units/1.17 mL [equivalent to
517 mg benzathine benzylpenicillin tetrahydrate]) contain the same concentration of benzathine benzylpenicillin.
Note 3: It is safe to use cefalexin in patients who had a delayed nonsevere reaction to a penicillin in the distant past. It is also safe to use cefalexin in patients who have had a
delayed nonsevere reaction recently, unless the reaction involved amoxicillin or ampicillin, because cross-reactivity between these drugs is possible. For patients who have had
a recent delayed nonsevere reaction to amoxicillin or ampicillin, use the drug recommended for patients with immediate (nonsevere or severe) or delayed severe
hypersensitivity.
Antibiotic therapy for Arcanobacterium haemolyticum pharyngitis and tonsillitis

If Arcanobacterium haemolyticum (formerly Corynebacterium haemolyticum) is identified on throat swab culture and the patient
remains symptomatic, consider treatment with erythromycin. The dosage and duration of treatment are not well established; a
reasonable regimen is:
erythromycin (base) 500 mg (child 20 to 34 kg: 250 mg; 35 kg and over: 500 mg) orally, 6-hourly for 10
days.
If an oral liquid formulation of erythromycin is required for children, a reasonable regimen is:
erythromycin (ethyl succinate) (child 1 month or older) 20 mg/kg up to 800 mg orally, 6-hourly for 10
days.
Recurrent pharyngitis and tonsillitis

In patients with recurrent pharyngitis and tonsillitis, ensure that noninfective causes of sore throat have been addressed; these include
postnasal drip due to allergic rhinitis and rhinosinusitis, cigarette smoking (including parent or carer smoking), dry air, snoring, and
medications.
Long-term antibiotic therapy is not recommended to prevent recurrent streptococcal pharyngitis and tonsillitis because of conflicting
evidence about efficacy and concern about the development of antibiotic resistance. Antibiotics also have poor penetration into the
debris in tonsillar crypts.
Consider referral to an otolaryngologist for patients with recurrent pharyngitis or tonsillitis.
Key references
Assessment of sore throat
Kronman MP, Zhou C, Mangione-Smith R. Bacterial prevalence and antimicrobial prescribing trends for acute respiratory tract infections.
Pediatrics 2014;134(4):e956–65.
Renner B, Mueller CA, Shephard A. Environmental and non-infectious factors in the aetiology of pharyngitis (sore throat). Inflamm Res
2012;61(10):1041–52.
RHDAustralia (ARF/RHD writing group), National Heart Foundation of Australia, Cardiac Society of Australia and New Zealand. Australian
guideline for prevention, diagnosis and management of acute rheumatic fever and rheumatic heart disease. Darwin: Menzies School of
Health Research; 2012. https://www.rhdaustralia.org.au/arf-rhd-guideline
Shulman ST, Bisno AL, Clegg HW, Gerber MA, Kaplan EL, Lee G, et al. Clinical practice guideline for the diagnosis and management of
group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis 2012;55(10):e86–102.
Approach to managing sore throat
National Institute for Health and Care Excellence (NICE). Sore throat (acute): antimicrobial prescribing [NG84]. London: NICE; 2018.
https://www.nice.org.uk/guidance/ng84
Symptomatic therapy for sore throat
Hayward G, Thompson MJ, Perera R, Glasziou PP, Del Mar CB, Heneghan CJ. Corticosteroids as standalone or add-on treatment for
sore throat. Cochrane Database Syst Rev 2012;(10):CD008268.
Sadeghirad B, Siemieniuk RAC, Brignardello-Petersen R, Papola D, Lytvyn L, Vandvik PO, et al. Corticosteroids for treatment of sore
throat: systematic review and meta-analysis of randomised trials. BMJ 2017;358:j3887.
Antibiotic therapy for streptococcal pharyngitis and tonsillitis
Altamimi S, Khalil A, Khalaiwi KA, Milner RA, Pusic MV, Al Othman MA. Short-term late-generation antibiotics versus longer term penicillin
for acute streptococcal pharyngitis in children. Cochrane Database Syst Rev 2012;(8):CD004872.
Chiappini E, Regoli M, Bonsignori F, Sollai S, Parretti A, Galli L, et al. Analysis of different recommendations from international guidelines
for the management of acute pharyngitis in adults and children. Clin Ther 2011;33(1):48–58.
Coxeter P, Del Mar CB, McGregor L, Beller EM, Hoffmann TC. Interventions to facilitate shared decision making to address antibiotic use
for acute respiratory infections in primary care. Cochrane Database Syst Rev 2015;(11):CD010907.
Elwyn G, Frosch D, Thomson R, Joseph-Williams N, Lloyd A, Kinnersley P, et al. Shared decision making: a model for clinical practice. J
Gen Intern Med 2012;27(10):1361–67.
Gerber MA, Tanz RR. New approaches to the treatment of group A streptococcal pharyngitis. Curr Opin Pediatr 2001;13(1):51–55.
Hoffmann TC, Del Mar CB. Shared decision making: what do clinicians need to know and why should they bother? Med J Aust
2014;201(9):513–14.
Kaplan EL, Gooch IW, Notario GF, Craft JC. Macrolide therapy of group A streptococcal pharyngitis: 10 days of macrolide therapy
(clarithromycin) is more effective in streptococcal eradication than 5 days (azithromycin). Clin Infect Dis 2001;32(12):1798–802.
Radetsky M. Hostage to history: The duration of antimicrobial treatment for acute streptococcal pharyngitis. Pediatr Infect Dis J
2017;36(5):507–12.
RHDAustralia (ARF/RHD writing group), National Heart Foundation of Australia, Cardiac Society of Australia and New Zealand. Australian
guideline for prevention, diagnosis and management of acute rheumatic fever and rheumatic heart disease. Darwin: Menzies School of
Health Research; 2012. https://www.rhdaustralia.org.au/arf-rhd-guideline
Shulman ST, Bisno AL, Clegg HW, Gerber MA, Kaplan EL, Lee G, et al. Clinical practice guideline for the diagnosis and management of
group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis 2012;55(10):e86–102.
Spinks A, Glasziou PP, Del Mar CB. Antibiotics for sore throat. Cochrane Database Syst Rev 2013;(11):CD000023.
van Driel ML, De Sutter AI, Habraken H, Thorning S, Christiaens T. Different antibiotic treatments for group A streptococcal pharyngitis.
Antibiotic therapy for Arcanobacterium haemolyticum pharyngitis and tonsillitis
Miller RA, Brancato F, Holmes KK. Corynebacterium hemolyticum as a cause of pharyngitis and scarlatiniform rash in young adults. Ann
Intern Med 1986;105(6):867–72.
Recurrent pharyngitis and tonsillitis
Ng GJ, Tan S, Vu AN, Del Mar CB, van Driel ML. Antibiotics for preventing recurrent sore throat. Cochrane Database Syst Rev 2015;
(7):CD008911.
Stoodley P, Debeer D, Longwell M, Nistico L, Hall-Stoodley L, Wenig B, et al. Tonsillolith: not just a stone but a living biofilm. Otolaryngol
Head Neck Surg 2009;141(3):316–21.
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature, interpreted and distilled by
Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Blepharitis
Clinical features of blepharitis
Blepharitis is a chronic inflammatory condition of the eyelid margins (see Figure 2.4). The pathophysiology is not
fully understood, but it involves staphylococcal enzymes and toxins, and immune-mediated damage. Blepharitis is
often associated with other conditions such as seborrhoeic dermatitis, acne, rosacea and dry eyes. While it can be
categorised into anterior or posterior blepharitis, there is considerable overlap of symptoms, and they often co-
exist.
Anterior blepharitis is an inflammation of the anterior eyelid margin involving the eyelid skin and eyelashes. It
presents with symptoms of burning and grittiness in both eyes. Examination of the eyelids shows crusting, scaling
and redness of the eyelid margin.
Posterior blepharitis is caused by dysfunction of the meibomian glands, which are sebaceous glands at the rim of
the eyelid (see Figure 2.4). It is commonly associated with rosacea. Signs include redness of the eyelid margin
with blocked meibomian glands and a frothy discharge along the eyelid margins (although these are difficult to see
macroscopically). There may be associated chalazia.
Diagram of the eye (Figure 2.4)
Management of blepharitis
Eyelid hygiene is the mainstay of therapy and controls symptoms and signs of blepharitis if performed daily.
Eyelid hygiene involves:
warm compresses applied to the eyelids (with eyes closed) daily for 2 to 5 minutes to soften the crusts,
followed by
gentle scrubbing of the lashes with either sodium bicarbonate solution (1 teaspoon in 500 mL freshly boiled
and cooled water), baby shampoo solution (5 drops in 100 mL freshly boiled and cooled water) or
proprietary eyelid solutions or wipes.
The efficacy of topical antibiotics is uncertain. However, in cases of anterior blepharitis, if symptoms are not
controlled despite adequate eyelid hygiene, consider adding:
chloramphenicol 1% eye ointment topically, applied to the eyelid margin of both eyes,
twice daily for 1 to 2 weeks.
Systemic antibiotics are used mainly for their anti-inflammatory effect if symptoms of posterior blepharitis
(particularly if associated with rosacea) are not controlled despite adequate eyelid hygiene. Use:
doxycycline
adult: 100 mg orally, daily, reduced to 50 mg orally, daily after clinical improvement
(usually after 2 to 4 weeks), for a minimum of 8 weeks
child 8 years or older and less than 26 kg: 50 mg orally, daily, reduced to 25 mg orally,
daily after clinical improvement (usually after 2 to 4 weeks), for a minimum of 8 weeks
child 8 years or older and 26 to 35 kg: 75 mg orally, daily, reduced to 50 mg orally, daily
after clinical improvement (usually after 2 to 4 weeks), for a minimum of 8 weeks
child 8 years or older and more than 35 kg: 100 mg orally, daily, reduced to 50 mg orally,
daily after clinical improvement (usually after 2 to 4 weeks), for a minimum of 8 weeks.
For pregnant or breastfeeding women, use:
1 erythromycin (base) 500 mg orally, daily for a minimum of 8 weeks. If the 500 mg dose is
not tolerated, reduce to 250 mg
OR
1 erythromycin (ethyl succinate) 800 mg orally, daily for a minimum of 8 weeks. If the 800
mg dose is not tolerated, reduce to 400 mg.
For children younger than 8 years, use:
erythromycin (ethyl succinate) (child 1 month or older) 20 mg/kg up to 800 mg orally,

daily as a single dose, or in two divided doses to improve tolerability, for a minimum of 8
weeks. If this dose is not tolerated, reduce to 10 mg/kg up to 400 mg daily.
Review after 8 weeks—maintenance therapy may be required to control symptoms.
Unlike in adults, cutaneous symptoms of rosacea are often absent in children with posterior blepharitis—seek
expert advice from an ophthalmologist because corneal complications can occur even in the absence of acute
symptoms.
Key references
American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern Guidelines
Blepharitis San Francisco, CA: American Academy of Ophthalmology; 2013.
Copeland RA, Afshari NA, editors. Copeland and Afshari's principles and practice of cornea. New Delhi, India: Jaypee-
Highlights Medical Publishers, Inc; 2013.
Denniston A, Murray P, editors. Oxford handbook of ophthalmology. 3rd ed. Oxford: Oxford University Press; 2014.
Frucht-Pery J, Sagi E, Hemo I, Ever-Hadani P. Efficacy of doxycycline and tetracycline in ocular rosacea. Am J
Ophthalmol 1993;116(1):88–92.
Chalazion (meibomian cyst) and hordeolum (stye)
Chalazion (meibomian cyst) and hordeolum (stye)
A chalazion (meibomian cyst) is a focal inflammatory lesion on the eyelid caused by obstruction of the
meibomian glands, which are sebaceous glands at the margin of the eyelids (see Figure 2.4). Chalazia are
usually associated with blepharitis. The lesions are generally not tender unless there is acute inflammation.
They can be managed conservatively with repeated warm compresses, and usually resolve within 1 month.
Hordeolum presents as a tender, inflamed mass at the eyelid margin; it may be external (stye) or internal, and
is usually caused by staphylococci. An external hordeolum arises from obstruction and secondary infection of
the glands of Zeiss or Moll. Internal hordeolum is an acute infection of a meibomian gland. Hordeola usually
discharge spontaneously following management with warm compresses.
Topical antibiotics are not indicated for chalazia and hordeolum.
Warm compresses are the mainstay of treatment for chalazion and hordeolum; topical antibiotics are not indicated.
Oral antistaphylococcal antibiotic therapy is indicated if there is accompanying cellulitis—see drug regimens
for periorbital cellulitis. Incision and drainage may be necessary for persistent lesions.
Periorbital (preseptal) and orbital (postseptal)
cellulitis
Periorbital (preseptal) cellulitis: clinical features
Distinguishing between periorbital and orbital cellulitis is important because orbital cellulitis can lead to loss of
vision.
Periorbital (preseptal) cellulitis is a soft tissue infection of the eyelids, anterior to the orbital septum (the
anatomical structure separating the eyelids from the orbit—see Figure 2.4). It is usually caused by spread of
organisms from infection of contiguous structures (eg sinusitis, hordeolum, dacryocystitis) or eyelid trauma.
Children under 4 years of age have an incomplete orbital septum so are at increased risk of orbital cellulitis from
retrograde spread of infection from the preseptal to orbital space.
In periorbital cellulitis, swelling and erythema of periorbital soft tissue are present, but the inflammation does not
extend posterior to the orbital septum into the orbit. Vision and eye movements are normal and the patient is
systemically well.
Common pathogens are Staphylococcus aureus and Streptococcus species, or, in patients who are not fully
vaccinated, Haemophilus influenzae type b (Hib). Staphylococcal infection is more likely in patients with a local
lesion such as a hordeolum, dacryocystitis or a wound. Herpes simplex virus and herpes zoster virus are other
causes.
Periorbital (preseptal) cellulitis: management

Approach to management of periorbital (preseptal) cellulitis
Investigate and manage patients who are systemically unwell (eg fever, malaise) as for orbital cellulitis.
Investigate and manage patients who are systemically unwell (eg fever, malaise) as for orbital cellulitis.
Most patients with periorbital (preseptal) cellulitis can be treated with oral antibiotics; patients with more severe
symptoms may require intravenous antibiotics. Review within 48 hours is essential to ensure the patient’s
condition is improving. If symptoms and signs have not improved after 48 hours, consider switching to broad-
spectrum intravenous therapy—see orbital cellulitis.
If the infection has not improved after 48 hours, consider switching to broad-spectrum intravenous therapy for orbital cellulitis.
Antibiotic choice for periorbital (preseptal) cellulitis depends on a number of factors. Modified empirical regimens
are included below for patients with:
penicillin hypersensitivity
concurrent sinusitis
risk factors for Haemophilus influenzae type b (Hib) infection (eg children younger than 5 years who are not
fully vaccinated)
an increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection.
Oral therapy for periorbital (preseptal) cellulitis
For empirical therapy of periorbital cellulitis, use:
1 flucloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 days
OR
1 dicloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 days.
[Note 1]. Use:
If the patient has concurrent sinusitis or risk factors for H. influenzae type b infection (eg children younger than 5
years who are not fully vaccinated), use:
1 amoxicillin+clavulanate
adult: 875+125 mg orally, 12-hourly for 7 days

child 2 months or older: 22.5+3.2 mg/kg up to 875+125 mg orally, 12-hourly for 7 days
infant 1 month to younger than 2 months: 15+3.75 mg/kg orally, 8-hourly for 7 days.
OR
2 cefuroxime 500 mg (child 3 months or older: 15 mg/kg up to 500 mg) orally, 12-hourly
for 7 days.
In confirmed cases of H. influenzae type b infection, clearance antibiotics with or without immunisation may be
required for the patient and close contacts; see Clearance antibiotics for invasive meningococcal or Hib disease.
For patients at increased risk of MRSA infection (see Box 2.31), add one of the following drugs:

160+800 mg) orally, 12-hourly for 7 days
OR
2 clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly for 7 days.
For periorbital cellulitis without systemic features, 7 days of antibiotic treatment is usually sufficient. Extend
therapy if the infection has not resolved completely by the end of the treatment course.
Intravenous therapy for periorbital (preseptal) cellulitis
For empirical therapy of periorbital cellulitis in patients who require intravenous therapy (including children with
more severe symptoms), use:
flucloxacillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly for 7 days.
cefazolin 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly for 7 days.
1 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly for 7 days
OR
lincomycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly for 7 days.
2
If the patient has concurrent sinusitis or risk factors for H. influenzae type b infection (eg children younger than 5
years who are not fully vaccinated), use:
1 ceftriaxone 1 g (child 1 month or older: 50 mg/kg up to 1 g) intravenously, daily for 7

days
OR
In confirmed cases of H. influenzae type b infection, clearance antibiotics with or without immunisation may be
required for the patient and close contacts; see Clearance antibiotics for invasive meningococcal or Hib disease.
For patients at increased risk of MRSA infection (see Box 2.31), add:
use. Treat for 7 days.
In some regions, based on local MRSA susceptibility patterns, clindamycin or lincomycin may be a suitable
alternative to vancomycin:
1 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly for 7 days
OR
2 lincomycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly for 7 days.
For periorbital cellulitis without systemic features, 7 days of antibiotic treatment is usually sufficient. Extend
therapy if the infection has not resolved completely by the end of the treatment course.
Orbital (postseptal) cellulitis: clinical features

Orbital (postseptal) cellulitis is less common but much more serious than periorbital (preseptal) cellulitis. It usually
arises from infection of the paranasal sinuses, but can also be caused by endogenous spread in
immunocompromised patients. Children under 4 years of age have an incomplete orbital septum so are at increased
risk of orbital cellulitis from retrograde spread of infection from the preseptal to orbital space.
Pathogens include Staphylococcus aureus, Streptococcus species, Haemophilus influenzae type b (in patients who
are not fully vaccinated) and anaerobic bacteria. Orbital cellulitis can be caused by fungi in immunocompromised
patients or those with diabetes.
Clinical symptoms of orbital cellulitis are more pronounced than in periorbital cellulitis; patients may have
reduced vision, limited or painful eye movements, diplopia, proptosis or chemosis. The patient may or may not be
systemically unwell.
Orbital (postseptal) cellulitis: management

Approach to management of orbital (postseptal) cellulitis
If orbital cellulitis is suspected, collect blood samples for culture. A CT scan of the orbits and sinuses should be
performed in all cases of suspected orbital cellulitis, because a delay in diagnosis can result in visual compromise
or spread to the cranial fossa. If there is intracranial extension, consider brain abscess, which requires empirical
antibiotic therapy with activity against anaerobes—see Brain abscess.
Urgent surgical drainage of the sinuses or of an orbital, subperiosteal or intracranial abscess may be required to
prevent loss of vision.
Admit the patient to hospital and undertake 4-hourly eye observations (visual acuities and pupil reactions). Patients
with orbital cellulitis are rarely suitable for community-based parenteral antimicrobial therapy.
Use intravenous therapy initially, then switch to oral therapy when the infection is improving (see Guidance for
antimicrobial intravenous to oral switch). Modify therapy based on the results of culture and susceptibility testing,
if possible.
The total duration of therapy (intravenous + oral) is 10 to 14 days.
Intravenous therapy for orbital (postseptal) cellulitis
Suitable intravenous empirical regimens for orbital cellulitis are shown below.
Use:
1 cefotaxime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly. Switch to oral therapy

when the patient is improving
OR THE COMBINATION OF
1 ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously, daily. Switch

to oral therapy when the patient is improving
PLUS
flucloxacillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly. Switch to oral

therapy when the patient is improving.


PLUS
use. Switch to oral therapy when the patient is improving.
use. Switch to oral therapy when the patient is improving
PLUS
ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 12-hourly. Switch to

oral therapy when the patient is improving [Note 2].
For patients at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31),
use:

OR

use. Switch to oral therapy when the patient is improving.
choice.
Oral therapy for orbital (postseptal) cellulitis
Switch to oral therapy when the patient is clinically improving. Select oral antibiotic therapy according to the
results of culture and susceptibility testing, if possible. If culture and susceptibility test results are not available,
use:
amoxicillin+clavulanate
adult and child 2 months or older: 875+125 mg (child 2 months or older: 22.5+3.2 mg/kg
up to 875+125 mg) orally, 12-hourly for a total duration of 10 to 14 days (intravenous +
oral)
infant 1 month to younger than 2 months: 15+3.75 mg/kg orally, 8-hourly for a total
duration of 10 to 14 days (intravenous + oral).
For patients with delayed nonsevere hypersensitivity to penicillins, cefalexin can be used in most cases [Note 3];
use:
cefalexin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly, for a total duration of
10 to 14 days (intravenous + oral).
For patients with immediate (nonsevere or severe) or delayed severe hypersensitivity to penicillins, and patients
at increased risk of MRSA infection (see Box 2.31), use:
1 clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly, for a total duration
of 10 to 14 days (intravenous + oral)
PLUS
ciprofloxacin 750 mg (child: 20 mg/kg up to 750 mg) orally, 12-hourly, for a total duration
of 10 to 14 days (intravenous + oral) [Note 4] [Note 5]
OR (as a single preparation)

160+800 mg) orally, 12-hourly, for a total duration of 10 to 14 days (intravenous + oral).
choice.
Key references
Dis 2016;16(8):e139–e52.
Epiphora
Epiphora
Epiphora (watery eye) has a number of causes, and management depends on the patient’s age and associated
history. Lacrimal punctal stenosis and nasolacrimal duct obstruction are common causes. In children under 2
years, congenital nasolacrimal duct obstruction usually responds to removal of mucoid discharge and
massaging of the lacrimal sac. If the obstruction does not resolve by 12 to 18 months of age, probing under
general anaesthesia may be required. In adults, punctal stenosis or nasolacrimal duct obstruction may require
surgical management. Antibiotic therapy is not indicated in patients with discharge unless signs of
conjunctivitis or dacryocystitis are present.
Key references
Royal Children's Hospital (Melbourne). Nasolacrimal duct obstruction sticky and-or watery eye [pre-referral
guideline]. Melbourne: Royal Children's Hospital. Last Updated: 2011.
Dacryocystitis
Dacryocystitis
Dacryocystitis is an infection of the lacrimal sac, usually associated with obstruction of the nasolacrimal duct
(see Figure 2.4). It can be acute or chronic.
Acute dacryocystitis is characterised by pain, redness and swelling. It is usually caused by Staphylococcus
aureus, Streptococcus pyogenes (group A streptococcus) or Gram-negative bacteria. It may be associated with
periorbital (preseptal) cellulitis. Systemic antibiotic therapy is required and choice is directed by results of
Gram stain and culture.
For initial empirical therapy of acute dacryocystitis, use:
cefalexin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly.
Cefalexin can be used in most patients with delayed nonsevere penicillin hypersensitivity [Note 1]. For
patients with immediate (nonsevere or severe) or delayed severe hypersensitivity to penicillins or those at
increased risk of infection with methicillin-resistant Staphylococcus aureus (MRSA) (see Box 2.31) or if
MRSA is isolated from culture, seek expert advice.
If the patient is in significant pain, refer to an ophthalmologist because surgical drainage may be indicated.
Chronic dacryocystitis is characterised by recurring episodes of epiphora or mucopurulent discharge, which

may be associated with a nontender mass (or a mucocoele). Pressure over the lacrimal sac may express
mucopurulent material from the punctum. There is no role for antibiotics in cases of chronic dacryocystitis
and surgical management is usually required. Acute dacryocystitis may be superimposed on chronic
dacryocystitis, and should be treated as for acute dacryocystitis above.
Consider using a topical antibiotic if associated bacterial conjunctivitis is present.
Note 1: It is safe to use cefalexin in patients who had a delayed nonsevere reaction to a penicillin in the distant past. It is also safe to use
cefalexin in patients who have had a delayed nonsevere reaction recently, unless the reaction involved amoxicillin or ampicillin, because cross-
reactivity between these drugs is possible. For patients who have had a recent delayed nonsevere reaction to amoxicillin or ampicillin, seek
expert advice.
Key references
Denniston A, Murray P, editors. Oxford handbook of ophthalmology. 3rd ed. Oxford: Oxford University Press;
2014.
Sainju R, Franzco AA, Shrestha MK, Ruit S. Microbiology of dacryocystitis among adults population in southern
Australia. Nepal Med Coll J 2005;7(1):18–20.
Conjunctivitis
Introduction to conjunctivitis
Conjunctivitis is inflammation of the conjunctiva. It is a very common clinical presentation. There are numerous
causes, including viral and bacterial infections, and allergy. Symptoms and signs can help to differentiate between
the aetiologies and avoid unnecessary use of antibiotics (see Table 2.8).
Symptoms and signs can help to differentiate between viral, bacterial and allergic conjunctivitis and avoid unnecessary use of
antibiotics.
Comparative features of allergic, viral and bacterial conjunctivitis (Table 2.8)
Allergic Viral Bacterial [NB1]

Age Children or adults More common in adults More common in children
Local response to an allergen,
including:
Can be primary or secondary
Frequently associated with a
seasonal (typically (eg to nasolacrimal duct
spring and autumn) viral upper respiratory tract
obstruction).
perennial infection and preauricular
Aetiology
contact hypersensitivity lymphadenopathy. Pathogens include
reactions (eg Staphylococcus aureus,
Most commonly caused by
preservatives in eye Streptococcus pneumonia,
adenovirus.
drops, contact lens Haemophilus influenzae.
solutions).
Symptoms are initially

Symptoms have a rapid onset.
In seasonal and perennial unilateral but often become
Usually unilateral but may be
conjunctivitis, symptoms are bilateral within days.
bilateral.
usually bilateral.
Common symptoms:
Common symptoms:
Clinical features Common symptoms:
conjunctival injection
conjunctival injection
itch (red eye)
(red eye)
watery or mucoid watery or mucoid
purulent discharge
discharge. discharge
crusting of the eyelids.
irritation.
NB1: Excluding chlamydial conjunctivitis and gonococcal conjunctivitis
Prompt referral to an ophthalmologist is required for conjunctivitis that is associated with severe or worsening
symptoms (eg significant pain, reduced vision or photophobia) to exclude more serious diagnoses such as keratitis.
Pain, reduced vision or photophobia require prompt referral to an ophthalmologist.
Children aged 2 to 12 months with sticky eyes often have blocked lacrimal (tear) ducts rather than conjunctivitis,
and the accumulated material is mucus from the tear film rather than pus. If the conjunctiva is not inflamed, treat as
for Epiphora.
Allergic conjunctivitis
One of the most common causes of noninfective conjunctivitis is allergic conjunctivitis. This results from a local
response to an allergen, and includes seasonal (typically in spring and autumn) and perennial conjunctivitis, and
contact hypersensitivity reactions (eg to preservatives in eye drops and contact lens solutions). The primary
diagnostic symptom is itch with watery eyes. In seasonal and perennial conjunctivitis, symptoms are usually
bilateral. For the management of allergic conjunctivitis, see Treatment of allergic conjunctivitis.
Viral conjunctivitis
Viral conjunctivitis is most commonly caused by adenovirus and is frequently associated with a viral upper
respiratory tract infection and preauricular lymphadenopathy. Diagnosis is clinical. Symptoms of conjunctival
injection (red eye), watery discharge and irritation are initially unilateral but often become bilateral.
Symptomatic treatment is recommended, including cold compresses several times a day and lubricant eye drops.
Inform patients of hygiene measures to reduce the spread of infection. Avoid the use of topical corticosteroids
without advice from an ophthalmologist.
There is no role for topical antibiotics such as chloramphenicol.
There is no role for topical chloramphenicol in viral conjunctivitis.
Ocular infection with herpes simplex virus (see Herpes simplex keratitis) and herpes zoster virus (see Herpes
zoster ophthalmicus) can also cause conjunctivitis. Seek expert advice from an ophthalmologist.
Bacterial conjunctivitis
Bacterial conjunctivitis can be primary or secondary (eg to nasolacrimal duct obstruction). Cases typically present
with conjunctival injection (red eye), purulent discharge and crusting of the eyelids.
Common pathogens include Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae
(especially in children younger than 5 years who are not fully vaccinated, often causing ‘conjunctivitis–otitis
syndrome’). For information on conjunctivitis caused by Chlamydia trachomatis or Neisseria gonorrhoeae, see
Chlamydial conjunctivitis or Gonococcal conjunctivitis. Conjunctivitis caused by Neisseria meningitidis can
precede or accompany systemic disease; treatment is as for invasive meningococcal disease—see Neisseria
meningitidis (meningococcal) meningitis.
Many cases of bacterial conjunctivitis resolve within 7 days without treatment.
Systematic reviews have found that topical antibiotics confer modest benefits in improving symptom resolution in
bacterial conjunctivitis. However, most cases resolve within 7 days without treatment. In patients who present with
marked symptoms (eg purulent discharge), it is reasonable to prescribe topical antibiotic therapy. All neonates and
young infants require treatment. Use:
1 chloramphenicol 0.5% eye drops, 1 drop into the affected eye, four times a day for up to 7
days [Note 1]
OR
2 framycetin 0.5% eye drops, 1 drop into the affected eye, four times a day, for up to 7 days.
Both chloramphenicol and framycetin can cause contact hypersensitivity reactions, which may be severe.
Aminoglycoside (eg gentamicin, tobramycin) and quinolone (eg ciprofloxacin, ofloxacin) eye drops are not
recommended for empirical treatment.
Aminoglycoside and quinolone eye drops are not recommended for empirical treatment of bacterial conjunctivitis.
If conjunctivitis persists, perform bacterial and viral conjunctival swabs to identify atypical or resistant organisms,
or consider referral to an ophthalmologist to exclude alternative diagnoses.
Note 1: Chloramphenicol eye ointment can be used instead of chloramphenicol eye drops if the patient prefers.
Chlamydial conjunctivitis
Acute chlamydial conjunctivitis
Chlamydia trachomatis conjunctivitis (adult inclusion conjunctivitis) usually presents as an acute or subacute
unilateral conjunctivitis with mucopurulent discharge, or as a chronic conjunctivitis. It should be considered as a
differential diagnosis of bacterial or viral conjunctivitis.
Chlamydial conjunctivitis usually occurs in neonates, and in adults with exposure to sexually transmitted
infections. Infection in a neonate, infant or child may reflect mother-to-child transmission, accidental transmission
or sexual abuse (see also STIs in infants and children).
Conjunctival swabs for nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]) are
recommended in all neonates, and in patients with persistent conjunctivitis when C. trachomatis is suspected.
Systemic treatment is necessary. There is no evidence that concomitant topical therapy improves outcomes. For
adults and children older than 1 month, use:
azithromycin 1 g (child: 20 mg/kg up to 1 g) orally, as a single dose.
For neonates, use:
azithromycin 20 mg/kg orally, daily for 3 days.
Approximately 50% of neonates with chlamydial conjunctivitis have associated chlamydial pneumonia (see
Pneumonia caused by Mycoplasma pneumoniae or Chlamydophila (Chlamydia) species).
Treat the mother of the infected neonate for C. trachomatis infection—for treatment regimens, management of
sexual contacts and other information, see Approach to Chlamydia trachomatis infection.
Refer patients with chlamydial conjunctivitis who have pain, photophobia or reduced vision to an ophthalmologist
because corneal complications can occur.
Trachoma
Trachoma is a form of chronic C. trachomatis conjunctivitis caused by repeated infections with C. trachomatis
serotypes A, B, Ba or C. It is the leading cause of preventable infectious blindness in the world, especially in
developing countries, and is still common in remote Aboriginal and Torres Strait Islander communities in
Australia. Without treatment, recurrent infection can lead to scarring of the eyelids, corneal ulceration, corneal
scarring and loss of vision. Suspect trachoma in all cases of conjunctivitis in endemic areas. Treatment is with
azithromycin (see Acute chlamydial conjunctivitis above for dosage).
In areas where trachoma is prevalent, regular face washing and treatment of household contacts is recommended.
Community-wide treatment may be required in areas where prevalence is high. For further information on public
health management of trachoma, see the Communicable Diseases Network Australia National guidelines for the
public health management of trachoma [URL].
Gonococcal conjunctivitis
Introduction
Conjunctivitis caused by Neisseria gonorrhoeae usually presents with an acute onset of copious, purulent
discharge. Request culture, Gram stain and nucleic acid amplification testing (NAAT) (eg polymerase chain
reaction [PCR]) on conjunctival swabs to confirm the diagnosis.
Gonococcal conjunctivitis is an ophthalmic emergency—seek advice from an ophthalmologist urgently.
Gonococcal conjunctivitis can cause ulceration and perforation of the cornea so is an ophthalmic emergency; all
cases should be treated in consultation with an ophthalmologist. If gonococcal conjunctivitis is suspected
clinically, take conjunctival swabs for microbiological testing, then start empirical antimicrobial therapy
immediately. Refer immediately to an ophthalmologist if corneal opacity develops.
Infection in a neonate, infant or child may reflect mother-to-child transmission, accidental transmission or sexual
abuse (see also STIs in infants and children).
Management of gonococcal conjunctivitis in adults and children 1 month and older
Gonococcal conjunctivitis requires systemic treatment; topical antimicrobial therapy is not adequate.
For adults and children older than 1 month, use:
1 ceftriaxone 1 g (child 1 month or older: 50 mg/kg up to 1 g) intramuscularly or

intravenously, as a single dose [Note 2]
OR
1 cefotaxime 1 g (child: 50 mg/kg up to 1 g) intramuscularly or intravenously, as a single

dose [Note 3]
azithromycin 1 g (child: 20 mg/kg up to 1 g) orally, as a single dose.
Azithromycin is used concomitantly with ceftriaxone to delay cephalosporin resistance in N. gonorrhoeae, and
because co-infection with Chlamydia trachomatis is possible.
For patients with immediate nonsevere or delayed nonsevere penicillin hypersensitivity, use one of the regimens
above. For patients with immediate severe or delayed severe hypersensitivity to penicillins, seek expert advice.
Immediately refer to an ophthalmologist if corneal opacity develops.
Evaluate the patient for other sites of infection, as well as other sexually transmitted infections. For further
information, including management of sexual contacts see Approach to Neisseria gonorrhoeae infection.
Note 2: Intramuscular injection of ceftriaxone is painful; consider reconstituting with lidocaine 1%. Split large intramuscular doses into two
injections.
Note 3: Intramuscular injection of cefotaxime is painful; consider reconstituting with lidocaine 0.5%. Split large intramuscular doses into two
injections.
Management of gonococcal conjunctivitis in neonates
Gonococcal conjunctivitis in neonates usually presents in the first 2 to 5 days of life, and sometimes at birth, with
acute, severe, hyperpurulent conjunctivitis. It is highly contagious and can lead rapidly to perforation of the cornea
and blindness. Request culture, Gram stain and nucleic acid amplification testing (eg polymerase chain reaction
[PCR]) on conjunctival swabs, and start empirical treatment.
Gonococcal conjunctivitis requires systemic treatment; topical antimicrobial therapy is not adequate. Use:
1 cefotaxime 100 mg/kg intramuscularly or intravenously, as a single dose
OR
2 ceftriaxone 25 to 50 mg/kg up to 125 mg intramuscularly or intravenously, as a single

dose [Note 4]
Azithromycin is used concomitantly with ceftriaxone to delay cephalosporin resistance in N. gonorrhoeae, and
because co-infection with C. trachomatis is possible.
Irrigate the eye with saline several times daily until purulence subsides. Immediately refer to an ophthalmologist if
corneal opacity develops.
Treat the mother of the neonate for N. gonorrhoeae infection—for treatment regimens, management of sexual
contacts and other information, see Approach to Neisseria gonorrhoeae infection.
Note 4: See Broad-spectrum cephalosporins: cefotaxime and ceftriaxone for a warning on the use of ceftriaxone with calcium-containing intravenous
solutions in neonates.
Key references
Bacterial conjunctivitis
German EJ, Hurst MA, Wood D. Reliability of drop size from multi-dose eye drop bottles: is it cause for concern? Eye
(Lond) 1999;13 (Pt 1):93–100.
Hutnik C, Mohammad-Shahi MH. Bacterial conjunctivitis. Clin Ophthalmol 2010;4:1451–7. .
Jefferis J, Perera R, Everitt H, van Weert H, Rietveld R, Glasziou P, et al. Acute infective conjunctivitis in primary care:
who needs antibiotics? An individual patient data meta-analysis. Br J Gen Pract 2011;61(590):e542–8.
Sheikh A, Hurwitz B, van Schayck CP, McLean S, Nurmatov U. Antibiotics versus placebo for acute bacterial
conjunctivitis. Cochrane Database Syst Rev 2012;(9):CD001211.
Touitou E, Barry BW. Enhancement in drug delivery. Boca Raton: CRC Press; 2006.
Chlamydial conjunctivitis
Bowling B, Kanski JJ. Kanski's clinical ophthalmology Edinburgh: Elsevier; 2015.
Gonococcal conjunctivitis
Haimovici R, Roussel TJ. Treatment of gonococcal conjunctivitis with single-dose intramuscular ceftriaxone. Am J
Ophthalmol 1989;107(5):511–4.
Mak DB, Smith DW, Harnett GB, Plant AJ. A large outbreak of conjunctivitis caused by a single genotype of Neisseria
gonorrhoeae distinct from those causing genital tract infections. Epidemiol Infect 2001;126(3):373–8.
Corneal abrasion and foreign bodies
Corneal abrasion and foreign bodies
Chloramphenicol eye drops or ointment have been used as prophylaxis in corneal abrasions, and following
removal of corneal foreign bodies, despite no proven benefit. Consider:
chloramphenicol 0.5% eye drops, 1 drop into the affected eye, four times daily until
healed [Note 1].
Note 1: Chloramphenicol eye ointment can be used instead of chloramphenicol eye drops if the patient prefers.
Keratitis
Introduction to keratitis
Infectious keratitis is a sight-threatening emergency. Urgent referral to an ophthalmologist is essential.
Infectious keratitis is a sight-threatening condition involving infection of the cornea. Causes include bacteria such
as Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae and Pseudomonas aeruginosa,
and viruses such as herpes simplex virus (HSV). Keratitis caused by fungi, mycobacteria or Acanthamoeba is rarer
and more difficult to treat. Urgent consultation with an ophthalmologist is essential in all cases.
Bacterial keratitis
Contact lens wearers and patients with a compromised ocular surface (eg after trauma) are at increased risk of
bacterial keratitis. Symptoms include pain, photophobia and reduced vision. A white spot is usually seen on the
cornea. Immediate referral for consideration of a corneal scrape for microbiological testing and initiation of topical
treatment is essential.
If referral is delayed, start topical treatment in consultation with an ophthalmologist. Use:
1 ciprofloxacin 0.3% eye drops, 1 drop into the affected eye, every hour (including
overnight)
OR
1 ofloxacin 0.3% eye drops, 1 drop into the affected eye, every hour (including overnight)
OR (if available)
1 cefazolin 5% plus gentamicin 0.9% eye drops, 1 drop into the affected eye every hour
(including overnight) [Note 1].
Continue treatment until specialist consultation. Modify therapy based on the results of culture and susceptibility
testing.
Oral or intravenous antibiotic therapy does not have a role in the management of bacterial keratitis unless there is
spread to the sclera.
Note 1: Cefazolin plus gentamicin eye drops require extemporaneous preparation. Combinations of other cephalosporins and aminoglycosides are
also used.
Herpes simplex keratitis

Ocular manifestations of herpes simplex virus (HSV) vary and include blepharitis (inflammation of the eyelid
margins), conjunctivitis, keratitis, iritis and retinitis. Herpes simplex keratitis is the most common manifestation
and can be classified as epithelial keratitis (ie dendritic or geographic ulcer), stromal keratitis or endotheliitis; all
can result in corneal scarring and loss of vision.
Prompt referral to an ophthalmologist is recommended for patients with suspected herpes simplex keratitis.
Fluorescein staining of the cornea facilitates a presumptive clinical diagnosis of herpes simplex epithelial keratitis;
antigen detection or nucleic acid amplification testing (eg polymerase chain reaction [PCR]) enables rapid
confirmation. Differentiation between types of keratitis is difficult and requires slit lamp examination, so prompt
referral to an ophthalmologist for assessment is recommended.
To treat dendritic ulcer in adults, use:
aciclovir 3% eye ointment topically into the affected eye, 5 times daily for 10 to 14 days,
or for at least 3 days after healing, whichever is shorter.
If the eye ointment is not available, use oral antiviral therapy. The following dosage regimens have been used for
immunocompetent adults with dendritic ulcer:
1 valaciclovir 500 mg orally, 12-hourly for 7 to 10 days
OR
2 aciclovir 400 mg orally, 5 times daily for 7 to 10 days.
Other forms of herpes simplex keratitis (geographic ulcer; stromal keratitis; endothelial keratitis and associated
uveitis) should be diagnosed and managed in conjunction with an ophthalmologist.
For recurrent herpes simplex keratitis, consider long-term suppressive oral antiviral therapy—seek
ophthalmologist advice.
In neonates, herpes simplex infection is always treated with intravenous therapy—see Neonatal herpes simplex
infection. Seek expert advice for management in children.
Herpes zoster ophthalmicus

Antiviral therapy reduces pain and ocular complications in patients with herpes zoster ophthalmicus. Start
treatment as soon as the diagnosis is suspected, ideally within 72 hours of the onset of rash; however, treatment
can be started beyond 72 hours if there are active vesicles present, or in immunocompromised or elderly patients to
reduce the risk of ocular complications. Symptoms of concern include a red eye, visual loss and photophobia.
Corneal ulcers in herpes zoster ophthalmicus have prolonged healing times, and may be complicated by corneal
perforation. Consult an ophthalmologist in all cases of herpes zoster ophthalmicus.
Consult an ophthalmologist in all cases of herpes zoster ophthalmicus.
Use oral antiviral therapy for immunocompetent patients. Intravenous aciclovir should be used for
immunocompromised patients with herpes zoster ophthalmicus, or for nonresponding or fulminant infection.
Topical aciclovir has no role in the initial treatment of herpes zoster ophthalmicus.
Topical aciclovir has no role in the initial treatment of herpes zoster ophthalmicus.
When oral therapy is appropriate for herpes zoster ophthalmicus, use:
1 valaciclovir 1 g (child over 2 years: 20 mg/kg up to 1 g) orally, 8-hourly for 7 days
OR
2 famciclovir 500 mg orally, 8-hourly for 7 days
OR
2 aciclovir 800 mg (child: 20 mg/kg up to 800 mg) orally, 5 times daily for 7 days.
In children—valaciclovir is not licensed in Australia for use in children younger than 12 years; however, it is
licensed internationally for use in younger children (over 2 years).
In pregnancy—there are more safety data to support the use of aciclovir in pregnancy compared with valaciclovir
or famciclovir. However, there is some evidence and clinical experience that valaciclovir (a prodrug of aciclovir) is
safe in pregnancy, and some prescribers prefer it because the 8-hourly dosing regimen is easier for patients to
follow.
Use intravenous aciclovir for immunocompromised patients with herpes zoster ophthalmicus, or for
nonresponding or fulminant infection:
2] [Note 3].
Patients with undiagnosed HIV infection may present initially with herpes zoster infection. In patients who need to
be started on therapy for HIV, see Shingles in adults with HIV infection for advice on starting antiretroviral
therapy. In patients with HIV infection taking antiretroviral therapy, check the potential for drug interactions when
prescribing other drugs (see Antiretroviral drug interactions).
Key references
Introduction to keratitis
Green M, Apel A, Stapleton F. A longitudinal study of trends in keratitis in Australia. Cornea 2008;27(1):33–9.
Bacterial keratitis
Allan BD, Dart JK. Strategies for the management of microbial keratitis. Br J Ophthalmol 1995;79(8):777–86.
Constantinou M, Daniell M, Snibson GR, Vu HT, Taylor HR. Clinical efficacy of moxifloxacin in the treatment of
bacterial keratitis: a randomized clinical trial. Ophthalmology 2007;114(9):1622–9.
McDonald EM, Ram FS, Patel DV, McGhee CN. Topical antibiotics for the management of bacterial keratitis: an
evidence-based review of high quality randomised controlled trials. Br J Ophthalmol 2014;98(11):1470–7.
Willcox MD. Review of resistance of ocular isolates of Pseudomonas aeruginosa and staphylococci from keratitis to
ciprofloxacin, gentamicin and cephalosporins. Clin Exp Optom 2011;94(2):161–8.
Herpes simplex keratitis
Bowling B, Kanski JJ. Kanski's clinical ophthalmology. Edinburgh: Elsevier; 2015.
White ML, Chodosh J. Herpes simplex virus keratitis: A treatment guideline - 2014. San Francisco, CA: American
Academy of Ophthalmology; 2014. https://www.aao.org/clinical-statement/herpes-simplex-virus-keratitis-treatment-
guideline.
Herpes zoster ophthalmicus
American Academy of Ophthalmology. Herpes zoster ophthalmicus [clinical education online excerpt]. San Francisco,
CA: American Academy of Ophthalmology; Accessed Dec 2018. https://www.aao.org/focalpointssnippetdetail.aspx?
id=8367b620-245c-4ebf-89e7-eca0c8d35aa3
Bagheri N, Wajda B, Calvo C, Durrani A, editors. The Wills Eye Manual - office and emergency room diagnosis and
treatment of eye disease. 7th ed. Philadelphia: Wolters Kluwer; 2016.
Tyring S, Engst R, Corriveau C, Robillard N, Trottier S, Van Slycken S, et al. Famciclovir for ophthalmic zoster: a
randomised aciclovir controlled study. Br J Ophthalmol 2001;85(5):576–81.
Wehrhahn MC, Dwyer DE. Herpes zoster: epidemiology, clinical features, treatment and prevention. Aust Prescr
2012;35:143–7. https://www.nps.org.au/australian-prescriber/articles/herpes-zoster-epidemiology-clinical-features-
treatment-and-prevention
Endophthalmitis
Clinical features of endophthalmitis
Endophthalmitis is an inflammatory condition of the intraocular cavity (the aqueous or vitreous humour; see
Figure 2.4), usually caused by infection. It is classified as exogenous or endogenous endophthalmitis.
Exogenous endophthalmitis is a sight-threatening but uncommon complication following an intraocular

procedure or surgery (eg cataract surgery, intravitreal injections for age-related macular degeneration or diabetic
retinopathy), or following a penetrating eye injury. It is usually acute, presenting 3 to 5 days after the procedure or
injury with acute onset of pain, redness, floaters, photophobia and blurred vision. The most common bacterial
pathogens are staphylococci, streptococci and Gram-negative bacilli. Less commonly, a chronic endophthalmitis
can present 6 weeks or more following surgery, caused by organisms such as Cutibacterium acnes (formerly
Propionibacterium acnes).
Endogenous endophthalmitis is the result of haematogenous spread of bacterial or fungal (including Candida
species) infections. Risk factors and sources include a history of injecting drugs, indwelling catheters, pneumonia,
endocarditis and liver abscess. Presentation is often less acute than exogenous endophthalmitis, and both eyes may
be affected.
Management of endophthalmitis
For information about pre-emptive treatment following a penetrating eye injury, see Pre-emptive treatment
following a penetrating eye injury.
Urgently refer all cases of endophthalmitis to an ophthalmologist so that they can obtain a vitreous sample for
culture and administer intravitreal antibiotics. Delayed treatment results in loss of vision.
All cases of endophthalmitis require urgent same-day management by an ophthalmologist with intravitreal antibiotic injections.
Intravitreal antibiotics are the mainstay of treatment for all cases of endophthalmitis, administered by an
ophthalmologist. Use:
ceftazidime 2 mg/0.1 mL or 2.25 mg/0.1 mL by intravitreal injection
PLUS
vancomycin 1 mg/0.1 mL by intravitreal injection.
For exogenous endophthalmitis, if there is likely to be a significant delay in transferring the patient to an
emergency department or specialised unit for intravitreal treatment, start therapy with moxifloxacin or
ciprofloxacin in consultation with an ophthalmologist; use:
1 moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally [Note 1] [Note 2]
OR
2 ciprofloxacin 750 mg (child: 20 mg/kg up to 750 mg) orally [Note 3] [Note 4].
Moxifloxacin has better intraocular penetration than ciprofloxacin; however, ciprofloxacin can be used if
moxifloxacin is not available. Urgent transfer of the patient for intravitreal treatment is the first priority; do not
delay patient transfer to start oral antibiotics.
In cases of endogenous endophthalmitis, identify and treat the primary infection with systemic antibiotics, which
are used in addition to intravitreal therapy for endophthalmitis. Collect blood and other relevant samples for
culture and susceptibility testing. Choose initial systemic antibiotic therapy based on the likely source of infection
(eg endocarditis) and the intraocular penetration of the drug(s). Intraocular penetration is limited by the blood–
retina barrier and blood–aqueous barrier, though inflammation can increase penetration. Seek advice from an
Choose initial systemic antibiotic therapy for endogenous endophthalmitis based on the likely source of infection and the
intraocular penetration of the drug(s)—seek expert advice.
If the source of infection is not apparent, and if advice from an infectious diseases physician or clinical
microbiologist is not immediately available, start empirical therapy with:
ceftazidime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly
PLUS
use.
If fungal infection is suspected (eg signs of fungal infection on ophthalmological examination, there is a history of
injecting drugs, or the patient is not responding to antibiotic therapy), seek advice from an infectious diseases
physician or clinical microbiologist regarding choice of antifungal therapy. Intravitreal and systemic antifungal
therapy may be required.
Modify treatment according to clinical response and the results of culture and susceptibility testing, if possible.
Patients presenting with visual symptoms after elective intraocular surgery
Do not prescribe topical antibiotics to patients presenting with pain, photophobia and reduced vision after elective
intraocular surgery; refer to an ophthalmologist to exclude endophthalmitis and ongoing postoperative uveitis.
Note 1: Moxifloxacin is not licensed for use in children on the basis of animal studies that showed an adverse effect on cartilage development with
quinolone use; however, there are few data from human trials to support this finding. Moxifloxacin can be used in children when it is the drug of
choice.
Note 2: An oral liquid formulation of moxifloxacin is not commercially available; for formulation options for children or people with swallowing
choice.
Key references
Durand ML. Bacterial and Fungal Endophthalmitis. Clin Microbiol Rev 2017;30(3):597–613.
Endophthalmitis Vitrectomy Study Group Results of the Endophthalmitis Vitrectomy Study. A randomized trial of
immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch
Ophthalmol 1995;113(12):1479–96 .
Ferencz JR, Assia EI, Diamantstein L, Rubinstein E. Vancomycin concentration in the vitreous after intravenous and
intravitreal administration for postoperative endophthalmitis. Arch Ophthalmol 1999;117(8):1023–7.
Han DP, Wisniewski SR, Wilson LA, Barza M, Vine AK, Doft BH, et al. Spectrum and susceptibilities of microbiologic
isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol 1996;122(1):1–17.8659579 .
Morlet N, Graham GG, Gatus B, McLachlan AJ, Salonikas C, Naidoo D, et al. Pharmacokinetics of ciprofloxacin in the
human eye: a clinical study and population pharmacokinetic analysis. Antimicrob Agents Chemother 2000;44(6):1674–
9.
Febrile neutropenia
Approach to managing patients with febrile neutropenia
In patients with febrile neutropenia, rapid initiation of broad-spectrum antimicrobials is essential. Consider
infection in any unwell patient with neutropenia (neutrophils less than 0.5 × 109/L, or less than 1 × 109/L with a
predicted decline to less than 0.5 × 109/L), because fever may not be present, particularly if the patient is elderly or
taking corticosteroids.
If febrile neutropenia is suspected in a patient in a general practice or outpatient setting, transfer the patient to
hospital urgently.
For the greatest survival benefit, give antibiotics as early as possible. Start antibiotics within 1 hour of the patient
presenting to medical care or, for a ward-based patient, developing febrile neutropenia; if there are signs of sepsis
or septic shock (see here for definitions in adults and here for definitions in children), start antibiotics within 30
minutes. See Early intervention for sepsis or septic shock for nonantibiotic management of sepsis or septic shock.
Obtain blood samples for culture before administering antibiotics. In adults, collect two sets of samples (ie four
bottles) from separate sites (a peripheral site and the access device, for patients with a central venous access
device). A single, smaller-volume sample is appropriate for young children.
Consider removing intravascular devices—seek expert haematology or oncology advice.
Choice of empirical therapy for patients with febrile neutropenia

Detailed advice on the choice of antimicrobial regimen for febrile neutropenia is included in the Australian
consensus guidelines [Note 1].
When possible, the choice of antimicrobials for treatment of febrile neutropenia should be based on local
protocols, or clinical microbiology or infectious diseases advice. Empirical antibiotic regimens based on local
epidemiology can improve outcomes because survival is increased when appropriate antibiotics are given early;
this is particularly important for patients with sepsis, septic shock or requiring intensive care support.
If the patient has been screened for faecal carriage of multidrug-resistant Gram-negative bacteria, treatment should
be guided by the results of susceptibility testing.
In the absence of local protocols and immediately available clinical microbiology or infectious diseases advice, the
empirical regimens in this topic can be used; however, seek advice and modify therapy as soon possible.
The empirical regimens in this topic include activity against Pseudomonas aeruginosa, which (although a
pathogen in only a minority of cases) is associated with high rates of morbidity and mortality. Meta-analyses show
that the antipseudomonal drugs piperacillin+tazobactam, cefepime and ceftazidime are suitable for empirical
therapy in the majority of patients.
However, if the patient is colonised, or has recently been infected, with a multidrug-resistant Gram-negative
bacterium, use the empirical regimens with activity against multidrug-resistant Gram-negative bacteria. These
regimens are not indicated on the basis of other risk factors for resistant infection.
Regimens with activity against multidrug-resistant Gram negative bacteria are not indicated for patients with risk factors for
resistant infection, except if known to be colonised or recently infected with a resistant bacterium.
Despite Gram-positive bacteria being the most common cause of febrile neutropenia, vancomycin is not routinely
recommended in these guidelines because controlled trials have not demonstrated a significant benefit from its
inclusion in the empirical regimen.
Early antifungal therapy may be required for patients suspected to have fungal infection, including unstable
patients at high risk of fungal infection. The choice of treatment depends on the prophylactic antifungal regimen
used—seek expert advice.
Modify therapy as soon as additional information is available (eg source of infection; results of Gram stain, culture
or susceptibility testing; expert advice). Evaluate appropriateness of antimicrobial therapy daily, with consideration
given to the patient’s clinical status and the principles of antimicrobial stewardship.
Data to inform the appropriate duration of therapy are limited. The duration is influenced by the response to
antimicrobial therapy, isolation of a pathogen and the rate of neutrophil recovery—seek expert advice [Note 2].
Trial data indicate that a subgroup of low-risk patients with febrile neutropenia can complete treatment at home
with oral therapy—seek expert advice and refer to the Australian consensus guidelines [Note 3].
Note 1: Tam CS, O’Reilly M, Andresen D, Lingaratnam S, Kelly A, Burbury K, et al. Use of empiric
antimicrobial therapy in neutropenic fever. Australian Consensus Guidelines 2011 Steering Committee. Intern
Med J 2011;41(1b):90-101. [URL]
Note 2: Specific advice on the duration of therapy (including conversion to oral therapy) is included in the
Australian consensus guidelines: Tam CS, O’Reilly M, Andresen D, Lingaratnam S, Kelly A, Burbury K, et al.
Use of empiric antimicrobial therapy in neutropenic fever. Australian Consensus Guidelines 2011 Steering
Committee. Intern Med J 2011;41(1b):90-101. [URL]
Note 3: Tam CS, O’Reilly M, Andresen D, Lingaratnam S, Kelly A, Burbury K, et al. Use of empiric
antimicrobial therapy in neutropenic fever. Australian Consensus Guidelines 2011 Steering Committee. Intern
Med J 2011;41(1b):90-101. [URL]
Worth LJ, Lingaratnam S, Taylor A, Hayward AM, Morrissey S, Cooney J, et al. Use of risk stratification to
guide ambulatory management of neutropenic fever. Australian Consensus Guidelines 2011 Steering Committee.
Intern Med J 2011;41(1b):82-9. [URL]
Febrile neutropenia: empirical therapy without activity against

multidrug-resistant Gram-negative bacteria
Patients without septic shock and not requiring intensive care support
The following empirical regimens are intended for initial therapy only. Modify therapy as soon as additional
information or expert advice is available. Evaluate appropriateness of antimicrobial therapy daily, with
consideration given to the patient’s clinical status and the principles of antimicrobial stewardship.
For patients without septic shock and not requiring intensive care support (including patients with risk factors for
infection with a multidrug-resistant Gram-negative bacterium, except if known to be colonised or recently infected
with a resistant bacterium), use:

hourly
OR
1 cefepime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly [Note 4]
OR
1 ceftazidime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly [Note 4] [Note 5].
Add vancomycin to the above regimens if the patient has sepsis.
Consider adding vancomycin to the above regimens if the patient has:
an increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31)
an intravascular catheter-related infection in a unit with a significant incidence of MRSA infection.
The role of empirical vancomycin for patients with severe mucositis is uncertain and should be considered on an
individual basis—seek expert advice.
If vancomycin is indicated, use:
use.
If vancomycin is included in the empirical regimen, review its use after 48 to 72 hours. If culture and susceptibility
results are not available by 72 hours and empirical intravenous therapy is still required, it is not necessary to
continue treatment with vancomycin empirically provided that the patient is clinically improving.
patients at high risk of fungal infection.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use cefepime or
ceftazidime, with or without vancomycin, as above.
Note 4: Compared to piperacillin+tazobactam, ceftazidime and cefepime have inferior activity against anaerobic
bacteria. If infection with anaerobic bacteria is suspected (eg patients with enterocolitis), consider using
piperacillin+tazobactam instead, or adding metronidazole to ceftazidime or cefepime.
Note 5: Compared to piperacillin+tazobactam and cefepime, ceftazidime has inferior activity against Gram-
positive bacteria. If infection with a Gram-positive bacterium is suspected (eg patients with mucositis), consider
using piperacillin+tazobactam or cefepime instead.
Patients with septic shock or requiring intensive care support

For patients with septic shock or requiring intensive care support (including patients with risk factors for
infection with a multidrug-resistant Gram-negative bacterium, except if known to be colonised or recently infected
with a resistant bacterium), the combination of an antipseudomonal beta lactam, gentamicin, and vancomycin is
recommended. Use:

adults without known or likely pre-existing kidney impairment: 7 mg/kg, for the first
dose. See Principles of aminoglycoside use for subsequent dosing [Note 7] [Note 8]
adults with known or likely pre-existing kidney impairment: 4 to 5 mg/kg, for the first
child younger than 10 years: 7.5 mg/kg, for the first dose. See Principles of
aminoglycoside use for subsequent dosing [Note 9]
child 10 years or older: 7 mg/kg, for the first dose. See Principles of aminoglycoside use
for subsequent dosing [Note 9]
PLUS

PLUS any of the following

hourly [Note 10]
OR
1 cefepime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly [Note 11] [Note 12]
OR
1 ceftazidime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly [Note 12] [Note 13]

[Note 14].
Prioritise administration of piperacillin+tazobactam, cefepime or ceftazidime, and gentamicin, because

vancomycin requires slow infusion.
Early antifungal therapy is required for patients suspected to have fungal infection. The choice of treatment
depends on the prophylactic antifungal regimen used—seek expert advice.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use a cefepime- or
ceftazidime-based regimen, as above.
If the results of susceptibility testing are not available by 72 hours and empirical intravenous therapy is still
required, seek expert advice; empirical gentamicin dosing should not continue beyond 48 hours, and vancomycin
may not be required if the patient is clinically improving.
calculate the dose.
function.
Note 10: For patients with septic shock or requiring intensive care support, there is a theoretical benefit from
administering the intermittent dose of piperacillin+tazobactam as an extended infusion over 3 to 4 hours, or as a
continuous infusion. However, at the time of writing, randomised controlled trials to evaluate the benefit of this
approach are ongoing and there are inadequate data to recommend this approach. If extended or continuous
infusion is used, unless switching from intermittent bolus dosing, give a loading dose equivalent to the normal
intermittent bolus dose before starting the infusion, so that the target drug concentration is reached earlier.
administering the intermittent dose of cefepime as an extended infusion over 3 to 4 hours, or as a continuous
infusion. However, at the time of writing, randomised controlled trials to evaluate the benefit of this approach are
ongoing and there are inadequate data to recommend this approach. If extended or continuous infusion is used,
unless switching from intermittent bolus dosing, give a loading dose equivalent to the normal intermittent bolus
dose before starting the infusion, so that the target drug concentration is reached earlier.
Note 12: Compared to piperacillin+tazobactam, ceftazidime and cefepime have inferior activity against
anaerobic bacteria. If infection with anaerobic bacteria is suspected (eg patients with enterocolitis), consider
using piperacillin+tazobactam instead, or adding metronidazole to ceftazidime or cefepime.
administering the intermittent dose of ceftazidime as an extended infusion over 3 to 4 hours or as a continuous
Note 14: Compared to piperacillin+tazobactam and cefepime, ceftazidime has inferior activity against Gram-
positive bacteria. If infection with a Gram-positive bacterium is suspected (eg patients with mucositis), consider
using piperacillin+tazobactam or cefepime instead.
Febrile neutropenia: empirical therapy with activity against multidrug-

resistant Gram-negative bacteria
A broader-spectrum regimen is appropriate for patients colonised, or recently infected, with a multidrug-resistant
Gram-negative bacterium (particularly if the patient has sepsis or septic shock, or requires intensive care support),
but is not indicated on the basis of other risk factors for resistant infection.
Broader-spectrum therapy is not indicated for patients with risk factors for infection with a multidrug-resistant Gram-negative
bacterium, except if known to be colonised or recently infected with a resistant bacterium.
If broader-spectrum therapy is indicated, for isolates susceptible to carbapenems, use:
meropenem 1 g (child: 20 mg/kg up to 1 g) intravenously, 8-hourly [Note 15] [Note 16]

[Note 17].
For isolates not susceptible to carbapenems, seek expert advice.
Add vancomycin to meropenem if the patient has sepsis or septic shock, or requires intensive care support.
Consider adding vancomycin to meropenem if the patient has:
an increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31)
an intravascular catheter-related infection in a unit with a significant incidence of MRSA infection.
The role of empirical vancomycin for patients with severe mucositis is uncertain and should be considered on an
individual basis—seek expert advice.
If vancomycin is indicated, use:
patients at high risk of fungal infection.
administering the intermittent dose of meropenem as an extended infusion over 3 to 4 hours, or as a continuous
At room temperature, meropenem is not stable in solution for 24 hours. If continuous infusion is used, administer
the 24-hour dose as 3 × 8-hour infusions.
Note 16: A meropenem dosage of 2 g (child: 40 mg/kg up to 2 g) intravenously, 8-hourly is required if

neurological infection is suspected. Some centres use this dosage for children who are very unwell; however, no
data are available to support the use of this dosage for children who do not have central nervous system
infection.
Note 17: In patients with penicillin hypersensitivity, the rate of immune-mediated cross-reactivity with
carbapenems is approximately 1%; therefore, meropenem can be considered in supervised settings. However, in
patients with a history of a severe cutaneous adverse reaction (eg drug rash with eosinophilia and systemic
symptoms [DRESS], Stevens–Johnson syndrome / toxic epidermal necrolysis [SJS/TEN], acute generalised
exanthematous pustulosis [AGEP]), consider meropenem only in a critical situation when there are limited
treatment options.
Key references
Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C, et al. European guidelines for empirical
antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th
European Conference on Infections in Leukemia. Haematologica 2013;98(12):1826–35 .
Garcia-Vidal C, Cardozo-Espinola C, Puerta-Alcalde P, Marco F, Tellez A, Agüero D, et al. Risk factors for mortality in
patients with acute leukemia and bloodstream infections in the era of multiresistance. PLoS One 2018;13(6):e0199531.
.
Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M, et al. Management of febrile

neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol 2016;27(suppl 5):v111–v118 .
Morrissey CO, Gilroy NM, Macesic N, Walker P, Ananda-Rajah M, May M, et al. Consensus guidelines for the use of
empiric and diagnostic-driven antifungal treatment strategies in haematological malignancy, 2014. Intern Med J
2014;44(12b):1298–314 .
Poon LM, Jin J, Chee YL, Ding Y, Lee YM, Chng WJ, et al. Risk factors for adverse outcomes and multidrug-resistant
Gram-negative bacteraemia in haematology patients with febrile neutropenia in a Singaporean university hospital.
Singapore Med J 2012;53(11):720–5 .
Tam CS, O'Reilly M, Andresen D, Lingaratnam S, Kelly A, Burbury K, et al. Use of empiric antimicrobial therapy in
neutropenic fever. Australian Consensus Guidelines 2011 Steering Committee. Intern Med J 2011;41(1b):90–101.
Worth LJ, Lingaratnam S, Taylor A, Hayward AM, Morrissey S, Cooney J, et al. Use of risk stratification to guide
ambulatory management of neutropenic fever. Australian Consensus Guidelines 2011 Steering Committee. Intern Med
J 2011;41(1b):82–9.
Principles of sexually transmitted infection
management
Investigations for STIs
Along with clinical review, microbiological testing is integral to the diagnosis of sexually transmitted
infections (STIs). Nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]) is the
preferred test for the diagnosis of many STIs because it is highly sensitive. Nucleic acid amplification testing
can occasionally produce false-positive results, usually due to cross-contamination, or the test being repeated
too soon after treatment (nucleic acid amplification testing does not differentiate between living and dead
organisms). Therefore, confirm an unexpected positive result with another sample or testing method,
particularly when a positive result has serious implications. More information on diagnostic tests for specific
infections is included in the relevant topics.
Concurrent STIs are not uncommon, particularly in populations with a higher prevalence of STIs, such as
men who have sex with men (MSM). Concurrent STIs are often asymptomatic infections of the rectum or
pharynx. For patients with a suspected STI, consider testing for Chlamydia trachomatis, Neisseria
gonorrhoeae, HIV and syphilis, and for patients who are not fully vaccinated, consider testing for hepatitis A
and B. Immune compromise due to HIV infection often leads to severe cases of genital herpes, warts and
molluscum contagiosum; test for HIV in these situations. Seroconversion for HIV and syphilis may not occur
for up to 6 weeks after exposure.
Contact tracing for STIs

Contact tracing (partner notification) is integral to the management of sexually transmitted infections (STIs).
The aims of contact tracing are to:
limit disease transmission

identify contacts (including those who are asymptomatic) requiring treatment to minimise the risk of
complications
prevent reinfection of the index patient by an untreated sexual partner.
Contact tracing is a priority when the contact is likely to benefit from being tested, treated or counselled
about prevention. Generally, contact tracing is required for:
hepatitis A and B (see Viral hepatitis)

HIV
Chlamydia trachomatis infection
Neisseria gonorrhoeae infection
trichomoniasis
chancroid
donovanosis
lymphogranuloma venereum
syphilis.
Formal contact tracing is not required for genital herpes or genital warts; however, give reassurance,
education and support to patients and their sexual partners.
Addressing contact tracing is the responsibility of the diagnosing clinician. The index patient should notify
his or her sexual contacts either directly, or via contact tracing websites such as Let Them Know and The
Drama Downunder. Alternatively, the diagnosing clinician or a health agency can notify sexual contacts of
the index patient, though the index patient must provide consent and the identity of the index case should
remain confidential.
Presumptive treatment (treating the contact before infection is confirmed) is sometimes required—this is
discussed in the relevant topics.
Refer to the Australasian Contact Tracing Manual for more information on contact tracing and presumptive
treatment [URL].
STI counselling
The management of a sexually transmitted infection (STI) provides an opportunity to discuss the prevention
of future infections. If relevant, recommend:
the use of condoms

HIV pre-exposure prophylaxis (PrEP)
vaccination against human papillomavirus (HPV), hepatitis A and hepatitis B—for vaccination
recommendations, see the Australian Immunisation Handbook [URL].
If appropriate, also offer advice on contraception; see Hormonal contraception and the Contraception
Choices website.
STIs in infants and children

If a sexually transmitted infection (STI) is identified in an infant or child, confirm the diagnosis with another
sample or testing method. Most STI tests can produce false-positive results and these are proportionally more
likely in low prevalence groups such as children.
If an STI is confirmed, seek expert advice. These guidelines contain limited advice on the management of
STIs in infants and children. See:
prevention of mother-to-child transmission of HIV (see Neonatal antiretroviral prophylaxis)

treatment of congenital syphilis in neonates
treatment of neonatal herpes simplex infection
treatment of gonococcal arthritis and disseminated gonococcal infection in children (see Directed
therapy for native bone or joint infection caused by other pathogens)
treatment of Chlamydia trachomatis pneumonia in infants aged 2 weeks to 5 months (see Pneumonia
caused by Mycoplasma pneumoniae or Chlamydophila (Chlamydia) species)
treatment of chlamydial conjunctivitis and gonococcal conjunctivitis.
Identification of an STI in an infant or a child may reflect mother-to-child transmission, accidental

transmission or sexual abuse. If sexual abuse is suspected, immediately refer patients for paediatric and
forensic expert advice. Hospital paediatric services can often provide initial phone advice and directions for
follow up and care. In some jurisdictions, it is mandatory to report STI diagnoses in infants and children to
state authorities.
Further reading
Australasian Sexual Health Alliance (ASHA). Australian STI management guidelines for use in primary care.
Sydney: Australasian Sexual Health Alliance (ASHA); updated 2018. [URL]
Melbourne Sexual Health Centre [website]. Melbourne: Melbourne Sexual Health Centre; 2018. [URL]
Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases
treatment guidelines, 2015. MMWR Recomm Rep 2015;64(RR-03):1–137. [URL]
Key references
Australasian Sexual Health Alliance (ASHA). Australian STI management guidelines for use in primary care.
Sydney: Australasian Sexual Health Alliance (ASHA). 2018. www.sti.guidelines.org.au/.
Workowski KA, Bolan GA. Centers for Disease Control and Prevention, Sexually transmitted diseases treatment
guidelines, 2015. MMWR Recomm Rep 2015;64(RR-03):1–137 .
Post–sexual assault antimicrobial prophylaxis
Post–sexual assault antimicrobial prophylaxis
Discuss cases of sexual assault with the relevant sexual assault referral service to guide appropriate
management. For cases involving infants and children, seek paediatric and forensic expert advice—see also
STIs in infants and children.
Investigations for sexually transmitted infections, pregnancy and forensic purposes should be performed on a
case-by-case basis. The collection of samples for forensic evidence should be undertaken by an experienced
professional, and should follow established local protocols.
Offer baseline and follow-up screening to people who have been sexually assaulted. Screen for the following
sexually transmitted pathogens: Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum
(syphilis), Trichomonas vaginalis, hepatitis B virus (HBV) and HIV. Do not screen for herpes simplex virus
(HSV), Mycoplasma or Ureaplasma species. For more information about testing recommendations and
management of adults who have been sexually assaulted, see the Australian STI Management Guidelines for
Use in Primary Care [URL].
Presumptive antimicrobial therapy for people who have been sexually assaulted is generally not required. The
identification of a sexually transmitted pathogen following sexual assault usually indicates a pre-existing
infection. If a pathogen is identified, treat the infection—as relevant, see:
Hepatitis B
HIV
Trichomoniasis
Syphilis.
For information about postexposure prophylaxis against HIV and hepatitis B virus following sexual assault,
see Postexposure prophylaxis against bloodborne viruses.
Offer emergency contraception to women of reproductive age presenting within 5 days of a sexual assault—
see Emergency (postcoital) contraception.
Key references
Australasian Sexual Health Alliance (ASHA) Australian STI management guidelines for use in primary care
Sydney: ASHA; 2018. www.sti.guidelines.org.au/.
Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment
guidelines, 2015. MMWR Recomm Rep 2015;64(RR-03):1–137.
Approach to Chlamydia trachomatis infection
Approach to Chlamydia trachomatis infection
Chlamydia trachomatis can cause the following syndromes:
cervicitis
epididymo-orchitis
pelvic inflammatory disease
infective proctitis
urethritis
conjunctivitis.
Asymptomatic chlamydial infection occurs frequently in both males and females and is generally identified by
nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]). In women, untreated chlamydial
infection can cause infertility and ectopic pregnancy.
Undertake contact tracing for patients with C. trachomatis infection (see Contact tracing for STIs). Test sexual
contacts, and then offer them presumptive treatment with the regimen in Treatment of asymptomatic Chlamydia
trachomatis infection.
For general principles of sexually transmitted infection (STI) management, including investigations and
counselling, and considerations for neonates, infants or children in whom an STI is identified, see Principles of
sexually transmitted infection management.
Treatment of asymptomatic Chlamydia trachomatis infection

To treat asymptomatic chlamydial infection, use:
1 doxycycline 100 mg orally, 12-hourly for 7 days
OR for pregnant women or patients likely to be nonadherent to doxycycline
2 azithromycin 1 g orally, as a single dose.
Perform a test of cure at least 3 weeks after starting treatment for patients who are pregnant, or those with an
anorectal infection or pelvic inflammatory disease (PID).
Key references
Australasian Sexual Health Alliance (ASHA) Australian STI management guidelines for use in primary care Sydney:
ASHA; 2018. www.sti.guidelines.org.au/.
Batteiger BE. Azithromycin efficacy in asymptomatic rectal chlamydial infection in men who have sex with men: A
more definitive answer soon? Sex Transm Dis 2017;44(7):403–5.
Borel N, Leonard C, Slade J, Schoborg RV. Chlamydial antibiotic resistance and treatment failure in veterinary and
human medicine. Curr Clin Microbiol Rep 2016;3:10–8.
Geisler WM, Uniyal A, Lee JY, Lensing SY, Johnson S, Perry RC, et al. Azithromycin versus doxycycline for urogenital
Chlamydia trachomatis infection. N Engl J Med 2015;373(26):2512–21.
Kong FY, Tabrizi SN, Law M, Vodstrcil LA, Chen M, Fairley CK, et al. Azithromycin versus doxycycline for the
treatment of genital chlamydia infection: a meta-analysis of randomized controlled trials. Clin Infect Dis
2014;59(2):193–205.
Lanjouw E, Ouburg S, de Vries HJ, Stary A, Radcliffe K, Unemo M. 2015 European guideline on the management of
Chlamydia trachomatis infections. Int J STD AIDS 2016;27(5):333–48.
Nwokolo NC, Dragovic B, Patel S, Tong CY, Barker G, Radcliffe K. 2015 UK national guideline for the management of
infection with Chlamydia trachomatis. Int J STD AIDS 2016;27(4):251–67.
Sena AC, Lensing S, Rompalo A, Taylor SN, Martin DH, Lopez LM, et al. Chlamydia trachomatis, Mycoplasma
genitalium, and Trichomonas vaginalis infections in men with nongonococcal urethritis: predictors and persistence after
therapy. J Infect Dis 2012;206(3):357–65.
World Health Organization (WHO). WHO Guidelines for the Treatment of Chlamydia trachomatis. Geneva,
Switzerland: WHO Press; 2016.
Approach to Mycoplasma genitalium infection
Approach to Mycoplasma genitalium infection
Mycoplasma genitalium is associated with the following syndromes:
cervicitis
urethritis.
M. genitalium infection is generally identified by nucleic acid amplification testing (NAAT) (eg polymerase chain
reaction [PCR]). Other Mycoplasma and Ureaplasma species are often co-reported with M. genitalium nucleic acid
amplification test results but do not require treatment [Note 1].
Screening for and treatment of asymptomatic M. genitalium infection is only recommended for ongoing sexual
partners of patients with a confirmed, symptomatic M. genitalium infection because the harm–benefit profile of
antibiotic therapy is unclear. Do not otherwise screen for or treat M. genitalium in asymptomatic individuals.
Note 1: U. urealyticum, U. parvum and M. hominis are part of the normal genital flora. Treatment is not required if these organisms are identified from
an endocervical or urethral swab.
Treatment of asymptomatic Mycoplasma genitalium infection

If available, request Mycoplasma genitalium susceptibility testing before starting therapy.
If treatment of asymptomatic M. genitalium infection is indicated, use:
doxycycline 100 mg orally, 12-hourly for 7 days
FOLLOWED BY EITHER
azithromycin 1 g orally on the first day, then 500 mg daily for 3 days
OR if macrolide resistance is confirmed or suspected
moxifloxacin 400 mg orally, daily for 7 days.
Doxycycline has poor efficacy against M. genitalium, with microbiological cure rates of approximately 30%.
However, initial pretreatment with doxycycline may reduce bacterial load and increase the likelihood of cure by
the second antibiotic. Macrolide resistance among M. genitalium is common, and the rate of quinolone resistance
in Australia is approximately 10 to 15%.
In 2018, a large Australian metropolitan sexual health centre identified M. genitalium azithromycin resistance in:
80% of M. genitalium infections in men who have sex with men (MSM)
50% of M. genitalium infections in women and heterosexual men.
Therefore, in the above regimen, follow doxycycline with moxifloxacin for:
patients with a confirmed macrolide-resistant infection, or

men who have sex with men (if assays to detect macrolide resistance are unavailable).
For all other patients, give the azithromycin regimen above.
Perform a test of cure at least 4 weeks after starting therapy.

If infection persists after completion of the azithromycin regimen, use the moxifloxacin regimen above.
If infection persists after completion of the moxifloxacin regimen, seek expert advice—treatment options include
pristinamycin.
Key references
Bissessor M, Tabrizi SN, Twin J, Abdo H, Fairley CK, Chen MY, et al. Macrolide resistance and azithromycin failure in
a Mycoplasma genitalium-infected cohort and response of azithromycin failures to alternative antibiotic regimens. Clin
Infect Dis 2015;60(8):1228–36.
Bjornelius E, Magnusson C, Jensen JS. Mycoplasma genitalium macrolide resistance in Stockholm, Sweden. Sex
Transm Infect 2017;93(3):167–8.
Couldwell DL, Tagg KA, Jeoffreys NJ, Gilbert GL. Failure of moxifloxacin treatment in Mycoplasma genitalium
infections due to macrolide and fluoroquinolone resistance. Int J STD AIDS 2013;24(10):822–8.
Guschin A, Ryzhikh P, Rumyantseva T, Gomberg M, Unemo M. Treatment efficacy, treatment failures and selection of
macrolide resistance in patients with high load of Mycoplasma genitalium during treatment of male urethritis with
josamycin. BMC Infect Dis 2015;15:40.
Horner P, Ingle SM, Garrett F, Blee K, Kong F, Muir P, et al. Which azithromycin regimen should be used for treating
Mycoplasma genitalium? A meta-analysis. Sex Transm Infect 2018;94(1):14–20.
Jensen JS, Bradshaw C. Management of Mycoplasma genitalium infections - can we hit a moving target? BMC Infect
Dis 2015;15:343.
Lau A, Bradshaw CS, Lewis D, Fairley CK, Chen MY, Kong FY, et al. The efficacy of azithromycin for the treatment of
genital Mycoplasma genitalium: A systematic review and meta-analysis. Clin Infect Dis 2015;61(9):1389–99.
Lis R, Rowhani-Rahbar A, Manhart LE. Mycoplasma genitalium infection and female reproductive tract disease: a
meta-analysis. Clin Infect Dis 2015;61(3):418–26.
Manhart LE, Jensen JS, Bradshaw CS, Golden MR, Martin DH. Efficacy of antimicrobial therapy for Mycoplasma
genitalium infections. Clin Infect Dis 2015;61 Suppl 8:S802–17.
Murray GL, Bradshaw CS, Bissessor M, Danielewski J, Garland SM, Jensen JS, et al. Increasing macrolide and
fluoroquinolone resistance in Mycoplasma genitalium. Emerg Infect Dis 2017;23(5):809–12.
Read TRH, Fairley CK, Murray GL, Jensen JS, Danielewski J, Worthington K, et al. Outcomes of resistance-guided
sequential treatment of Mycoplasma genitalium infections: a prospective evaluation. Clin Infect Dis 2019;68(4):554–60
.
Read TR, Fairley CK, Tabrizi SN, Bissessor M, Vodstrcil L, Chow EP, et al. Azithromycin 1.5g over 5 days compared to
1g single dose in urethral Mycoplasma genitalium: Impact on treatment outcome and resistance. Clin Infect Dis
2017;64(3):250–6.
Read TRH, Jensen JS, Fairley CK, Grant M, Danielewski JA, Su J, et al. Use of pristinamycin for macrolide-resistant
Mycoplasma genitalium infection. Emerg Infect Dis 2018;24(2):328–35.
Approach to Neisseria gonorrhoeae infection
Approach to Neisseria gonorrhoeae infection
Neisseria gonorrhoeae infection is more common among:
men who have sex with men

people who have recently had sex with a new partner in a country with a high prevalence of gonorrhoea (eg
developing countries)
remote Aboriginal and Torres Strait Islander populations.
In women, untreated gonococcal infection can lead to serious complications including infertility.
N. gonorrhoeae can cause the following syndromes:
cervicitis
epididymo-orchitis
infective proctitis
urethritis
conjunctivitis
disseminated gonococcal infection—see Directed therapy for native bone or joint infection caused by other
pathogens for treatment
septic arthritis.
The majority of N. gonorrhoeae cases are asymptomatic infections of the pharynx, rectum or cervix. Gonococcal
infection is generally identified by nucleic acid amplification testing (NAAT) (eg polymerase chain reaction
[PCR]). Take a sample for culture and susceptibility testing before starting antibiotic therapy because antimicrobial
resistance is emerging and most nucleic acid amplification tests do not detect resistance. Combination therapy with
azithromycin and ceftriaxone is recommended to delay cephalosporin resistance in N. gonorrhoeae.
Take a sample for culture and susceptibility testing.
Perform investigations for other sexually transmitted infections (STIs) (including HIV, syphilis and Chlamydia
trachomatis)—see also Investigations for STIs.
Undertake contact tracing for patients with N. gonorrhoeae infection (see Contact tracing for STIs). Test sexual
contacts, and then offer them presumptive treatment with the ceftriaxone and azithromycin regimen for anorectal
or genital gonococcal infection in Treatment of asymptomatic Neisseria gonorrhoeae infection.
For general principles of STI management, including advice on counselling, and considerations for neonates,
infants or children in whom an STI is identified, see Principles of sexually transmitted infection management.
Treatment of asymptomatic Neisseria gonorrhoeae infection

Due to the changing pattern of antimicrobial resistance in strains of Neisseria gonorrhoeae, refer to the Australian
STI Management Guidelines for Use in Primary Care [URL] for current information about antibiotic therapy
before prescribing.
To treat asymptomatic anorectal or genital gonococcal infection, use:
ceftriaxone 500 mg in 2 mL of 1% lidocaine intramuscularly, or 500 mg intravenously, as

a single dose [Note 1]
PLUS
azithromycin 1 g orally, as a single dose.
To treat pharyngeal gonococcal infection, a reasonable regimen is:

PLUS
azithromycin 2 g orally with food, as a single dose.
If susceptibility to penicillin is confirmed, or in areas where penicillin-resistant N. gonorrhoeae is less common

(mainly in some remote areas of northern and central Australia), to treat asymptomatic genital gonococcal
infection, use:
amoxicillin 3 g orally, as a single dose
PLUS
probenecid 1 g orally, as a single dose
PLUS
Do not use the amoxicillin-based regimen for patients who have a pharyngeal or anorectal infection; use
ceftriaxone plus azithromycin (as above).
Quinolone resistance is widespread—do not use ciprofloxacin unless a susceptible infection is identified.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use ceftriaxone plus
azithromycin (as above).
Perform a test of cure at least 2 weeks after treatment completion if using nucleic acid amplification
testing (NAAT). If using culture, test of cure may be performed 1 week after treatment completion.
Note 1: If using a 1 g vial of ceftriaxone for intramuscular injection, add 3.5 mL of 1% lidocaine and administer
2 mL of the reconstituted solution.
Key references
Bignell C, Unemo M. 2012 European guideline on the diagnosis and treatment of gonorrhoea in adults. Int J STD AIDS
2013;24(2):85–92. .
Chen MY, Stevens K, Tideman R, Zaia A, Tomita T, Fairley CK, et al. Failure of 500 mg of ceftriaxone to eradicate
pharyngeal gonorrhoea, Australia. J Antimicrob Chemother 2013;68(6):1445–7.
Fifer H, Natarajan U, Jones L, Alexander S, Hughes G, Golparian D, et al. Failure of dual antimicrobial therapy in
treatment of gonorrhea. N Engl J Med 2016;374(25):2504–6.
Golparian D, Ohlsson A, Janson H, Lidbrink P, Richtner T, Ekelund O, et al. Four treatment failures of pharyngeal
gonorrhoea with ceftriaxone (500 mg) or cefotaxime (500 mg), Sweden, 2013 and 2014. Euro Surveill 2014;19(30).
Lahra MM, Enriquez RP. Australian Gonococcal Surveillance Programme annual report, 2015. Commun Dis Intell Q
Rep 2017;41(1):E.
Read PJ, Limnios EA, McNulty A, Whiley D, Lahra MM. One confirmed and one suspected case of pharyngeal
gonorrhoea treatment failure following 500 mg ceftriaxone in Sydney, Australia. Sex Health 2013;10(5):460–2.
Tapsall J, Read P, Carmody C, Bourne C, Ray S, Limnios A, et al. Two cases of failed ceftriaxone treatment in
pharyngeal gonorrhoea verified by molecular microbiological methods. J Med Microbiol 2009;58(Pt 5):683–7.
Unemo M, Golparian D, Potocnik M, Jeverica S. Treatment failure of pharyngeal gonorrhoea with internationally
recommended first-line ceftriaxone verified in Slovenia, September 2011. Euro Surveill 2012;17(25).
Unemo M, Golparian D, Hestner A. Ceftriaxone treatment failure of pharyngeal gonorrhoea verified by international
recommendations, Sweden, July 2010. Euro Surveill 2011;16(6).
Approach to trichomoniasis
Assessment of trichomoniasis
Trichomoniasis is caused by Trichomonas vaginalis. Classical symptoms in women are vulval itch, inflamed
vagina and cervix, and a vaginal discharge that may be yellow-green and frothy with an offensive fishy odour and
pH greater than 4.5. However, 10 to 50% of cases in women are asymptomatic. In men, infection is usually
asymptomatic, but urethritis or dysuria occasionally occurs.
The diagnosis of trichomoniasis is confirmed by nucleic acid amplification testing (NAAT) (eg polymerase chain
reaction [PCR]). Nucleic acid amplification testing is significantly more sensitive than microscopy or culture.
Screen patients for other sexually transmitted infections; see also Investigations for STIs.
Treatment of trichomoniasis
To treat trichomoniasis, use:
1 metronidazole 2 g orally, as a single dose
OR
1 tinidazole 2 g orally, as a single dose.
A longer course of metronidazole is necessary for patients with recurrent infection. Use:
metronidazole 400 mg orally, 12-hourly for 5 days.
Metronidazole resistance in trichomoniasis can occur; if symptoms persist despite treatment, seek expert advice.
Consider single-dose treatment with metronidazole (as above) for symptomatic pregnant patients because
trichomoniasis in pregnancy is associated with adverse pregnancy outcomes (eg premature rupture of membranes,
preterm delivery, low birth weight). Despite this, treatment does not necessarily result in a reduction in perinatal
morbidity. The safety of tinidazole in pregnant women has not been well evaluated.
Undertake contact tracing; investigate and presumptively treat sexual partners for Trichomonas vaginalis with the
single-dose regimen above; see also Contact tracing for STIs.
Key references
Australasian Sexual Health Alliance (ASHA) Australian STI management guidelines for use in primary care. Sydney:
Cervicitis
Cervicitis
Cervicitis is characterised by a mucopurulent cervical discharge and contact bleeding (eg postcoital bleeding)
from a friable cervix. However, these features are not sensitive or specific for infection. Before starting
antimicrobial therapy, undertake nucleic acid amplification testing (NAAT) (eg polymerase chain reaction
[PCR]) for Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Trichomonas vaginalis
and, if cervical ulcers are present, herpes simplex virus. If an organism is identified, treat as for the relevant
infection:

Mycoplasma genitalium infection
trichomoniasis
herpes simplex virus.
Key references
Australasian Sexual Health Alliance (ASHA) Australian STI management guidelines for use in primary care.
Sydney: ASHA; 2018. www.sti.guidelines.org.au/.
Jensen JS, Bradshaw C. Management of Mycoplasma genitalium infections - can we hit a moving target? BMC
Infect Dis 2015;15:343.
Lis R, Rowhani-Rahbar A, Manhart LE. Mycoplasma genitalium infection and female reproductive tract disease:
a meta-analysis. Clin Infect Dis 2015;61(3):418–26.
Lusk MJ, Garden FL, Rawlinson WD, Naing ZW, Cumming RG, Konecny P. Cervicitis aetiology and case
definition: a study in Australian women attending sexually transmitted infection clinics. Sex Transm Infect
2016;92(3):175–81.
Lusk MJ, Garden FL, Cumming RG, Rawlinson WD, Naing ZW, Konecny P. Cervicitis: a prospective
observational study of empiric azithromycin treatment in women with cervicitis and non-specific cervicitis. Int J
STD AIDS 2017;28(2):120–6.
Epididymo-orchitis
Aetiology and assessment of epididymo-orchitis
Epididymo-orchitis most commonly occurs as a complication of a urethral infection caused by Chlamydia
trachomatis or Neisseria gonorrhoeae in men who are sexually active, or a urinary tract infection caused by
enteric Gram-negative bacteria. Men who engage in insertive anal sex are at risk of infection with sexually
acquired enteric pathogens in addition to other sexually transmitted pathogens. In a significant number of cases, no
pathogen is identified.
Epididymo-orchitis can also occur secondary to a number of systemic bacterial infections (eg extrapulmonary
tuberculosis, syphilis, brucellosis, melioidosis), viral infections (eg mumps) and non-infective conditions.
Epididymo-orchitis can also develop after urinary tract instrumentation.
Acute scrotal pain or inflammation can be a urological emergency. Exclude alternative diagnoses (eg Fournier
gangrene [see Necrotising skin and soft tissue infections], testicular torsion, testicular abscess).
To determine the cause of epididymo-orchitis, collect a midstream urine sample for microscopy and culture, and
susceptibility testing as required.
For men who are sexually active, or if urethral discharge is present, collect a first-void urine sample for nucleic
acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]) for C. trachomatis and N. gonorrhoeae.
A urethral swab for Gram stain, culture, and susceptibility testing of N. gonorrhoeae should also be obtained if
urethral discharge is present.
Differentiating the cause of infection (ie a sexually transmitted or urinary tract pathogen) depends on clinical
judgment and patient history. If the diagnosis is uncertain, or urethral discharge is present, use the empirical
regimen for epididymo-orchitis suspected to be caused by a sexually transmitted pathogen until the results of
investigations are available.
Epididymo-orchitis suspected to be caused by a sexually transmitted

pathogen
For empirical therapy of epididymo-orchitis suspected to be caused by a sexually transmitted pathogen, use:

PLUS EITHER
OR for patients likely to be nonadherent to doxycycline
2 azithromycin 1 g orally, as a single dose, repeated 1 week later.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use the regimen
above.
Modify therapy based on the results of investigations and clinical response. If pain and swelling have not
substantially reduced, oral therapy may need to be continued for up to 3 weeks. For men who engage in insertive
anal sex, if response to treatment is poor, alternative antibiotic therapy may be required to treat enteric organisms
Perform contact tracing and investigate sexual contacts for Chlamydia trachomatis and Neisseria gonorrhoeae. If a
pathogen is identified in the index case, presumptively treat contacts for that pathogen (see Approach
to Chlamydia trachomatis infection or Approach to Neisseria gonorrhoeae infection). If a pathogen is identified in
a sexual contact, treat the infection and undertake contact tracing for that individual. See also Contact tracing for
STIs.
Note 1: If using a 1 g vial of ceftriaxone for intramuscular injection, add 3.5 mL of 1% lidocaine and administer 2 mL of the reconstituted solution.
Epididymo-orchitis suspected to be caused by a urinary tract pathogen

Epididymo-orchitis in males who are not sexually active is likely to be caused by an organism from the urinary
tract.
For adults, treat epididymo-orchitis suspected to be caused by an organism from the urinary tract, as for acute
bacterial prostatitis for 14 days.
For prepubertal boys with epididymo-orchitis suspected to be caused by an organism from the urinary tract,
perform urinalysis; more than 80% of cases in these patients are not bacterial and do not require antibiotic therapy.
If urinalysis is negative for leucocyte esterase and nitrite, treat the child symptomatically (see Pain in
children for the approach to pain management in children and suitable regimens of paracetamol or nonsteroidal
anti-inflammatory drugs). If the urinalysis is positive for leucocyte esterase or nitrite, take a midstream urine
sample for culture and treat as for a urinary tract infection for 14 days—see Approach to managing urinary tract
infection in children.
Key references
Aetiology and assessment of epididymo-orchitis
Cristoforo TA. Evaluating the necessity of antibiotics in the treatment of acute epididymitis in pediatric patients: A
literature review of retrospective studies and data analysis. Pediatr Emerg Care 2017.
Gkentzis A, Lee L. The aetiology and current management of prepubertal epididymitis. Ann R Coll Surg Engl
2014;96(3):181–3.
Ito S, Tsuchiya T, Yasuda M, Yokoi S, Nakano M, Deguchi T. Prevalence of genital mycoplasmas and ureaplasmas in
men younger than 40 years-of-age with acute epididymitis. Int J Urol 2012;19(3):234–8.
Lampejo T, Abdulcadir M, Day S. Retrospective review of the management of epididymo-orchitis in a London-based

level 3 sexual health clinic: an audit of clinical practice. Int J STD AIDS 2017;28(10):1038–40.
Pilatz A, Hossain H, Kaiser R, Mankertz A, Schuttler CG, Domann E, et al. Acute epididymitis revisited: impact of
molecular diagnostics on etiology and contemporary guideline recommendations. Eur Urol 2015;68(3):428–35.
Taylor SN. Epididymitis. Clin Infect Dis 2015;61 Suppl 8:S770–3.
Workowski KA, Bola GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment
Epididymo-orchitis suspected to be caused by a sexually transmitted pathogen
Rep 2017;41(1):E.
Street EJ, Justice ED, Kopa Z, Portman MD, Ross JD, Skerlev M, et al. The 2016 European guideline on the
management of epididymo-orchitis. Int J STD AIDS 2017;28(8):744–9.
Wi T, Lahra MM, Ndowa F, Bala M, Dillon JR, Ramon-Pardo P, et al. Antimicrobial resistance in Neisseria
gonorrhoeae: Global surveillance and a call for international collaborative action. PLoS Med 2017;14(7):e1002344.
Epididymo-orchitis suspected to be caused by a urinary tract pathogen
Cristoforo TA. Evaluating the necessity of antibiotics in the treatment of acute epididymitis in pediatric patients: A
literature review of retrospective studies and data analysis. Pediatr Emerg Care 2017.
Gkentzis A, Lee L. The aetiology and current management of prepubertal epididymitis. Ann R Coll Surg Engl
2014;96(3):181–3.
Genital itch
Genital itch
Genital itch is more commonly caused by dermatoses (such as dermatitis and psoriasis) than infection, and
candidal infection should not be assumed. See Genital dermatitis.
Genital itch may also be caused by pubic lice (Phthirus pubis) or scabies (Sarcoptes scabiei).
Genital ulcer disease, including genital herpes
Aetiology and assessment of genital ulcer disease
Herpes simplex virus (HSV) is the most common cause of genital ulcer disease in Australia.
Syphilis is an increasingly frequent cause of genital ulcer disease, particularly in men who have sex with men
(MSM).
Other differential diagnoses to consider include: chemical burns or dermatitis from topical treatments, skin
infections caused by Gram-positive bacteria, aphthous ulcers, malignancies and autoimmune conditions. In men
who have sex with men, also consider lymphogranuloma venereum (Chlamydia trachomatis L1–L3 serovars).
Chancroid and donovanosis are very rare causes of genital ulcer disease in Australia.
Genital herpes
Assessment of genital herpes
Genital herpes is a sexually transmitted infection (STI) caused by either herpes simplex virus (HSV) 1 or 2. HSV–
1 is a common cause of initial infection, while recurrent genital herpes is usually caused by HSV–2. Nonclassical
presentations of genital herpes are common, so consider herpes simplex virus in the diagnosis of an acutely painful
genital lesion. The majority of patients with herpes simplex virus are undiagnosed.
Herpes simplex virus can also be transmitted via autoinoculation (typically HSV–1) or from contact with oral or
other herpes simplex virus lesions. Mother-to-child transmission can occur in neonates (see Neonatal herpes
simplex infection). For children with suspected anogenital herpes, seek expert advice—see also STIs in infants and
children.
Before starting antiviral therapy, collect a swab from the base of a lesion or deroofed vesicle for HSV type–specific
nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]). Screen patients for other STIs
(see Investigations for STIs). Contact tracing is not required.
For general principles of STI management, see also Principles of sexually transmitted infection management.
Patients with undiagnosed HIV infection may present initially with severe genital herpes. In patients who need to
be started on therapy for HIV, see Genital herpes in adults with HIV infection for advice on starting antiretroviral
therapy.
Antiviral therapy for genital herpes
Approach to therapy
Antiviral therapy for herpes simplex virus is not curative, but it shortens an acute episode if started within 72 hours
of symptom onset. Evidence comparing valaciclovir or famciclovir with aciclovir suggests that these drugs are
therapeutically equivalent, so consider differences in dosing schedules, tablet burden and cost when selecting
therapy.
Although there are more safety data to support the use of aciclovir in pregnancy compared with valaciclovir or
famciclovir, there is some evidence and clinical experience that valaciclovir, a prodrug of aciclovir, is safe in
pregnancy.
Patients with immune compromise (eg patients with advanced HIV infection) can have prolonged, widespread and
more painful episodes of genital or perianal herpes. If patients with immune compromise do not respond to the
relevant antiviral regimen below, seek expert advice. Antiviral resistance is a rare possibility in
immunocompromised patients who do not respond to therapy.
Initial therapy (first clinical episode)
If genital herpes is suspected, take a swab of the lesion for testing, then immediately start treatment;
microbiological confirmation is not required to start therapy.
For initial genital herpes infection, use:

1 aciclovir 400 mg orally, 8-hourly for 10 days. If clinical response is rapid, stop therapy
after 5 days
OR
1 famciclovir 250 mg orally, 8-hourly for 10 days. If clinical response is rapid, stop therapy
after 5 days
OR
1 valaciclovir 500 mg orally, 12-hourly for 10 days. If clinical response is rapid, stop
therapy after 5 days.
For the management of neonates born to a mother with an active or recent first herpes simplex virus infection, see
Neonatal herpes simplex infection.
Episodic therapy
Recurrences of herpes simplex virus can be treated with episodic therapy. Start antivirals at the onset of prodromal
symptoms or lesions. Short courses of therapy are effective because viral replication in recurrent infection is short-
lived. Use:
1 aciclovir 800 mg orally, 8-hourly for 2 days
OR
1 famciclovir 1 g orally, 12-hourly for 1 day
OR
1 valaciclovir 500 mg orally, 12-hourly for 3 days.
Suppressive therapy
Suppressive therapy reduces viral shedding, which decreases recurrences by 70 to 80% and halves the rate of
transmission. Suppressive therapy is beneficial for patients experiencing several recurrences per year, or during a
period of time when a recurrence would be particularly inconvenient. Use:
1 aciclovir 400 mg orally, 12-hourly
OR
1 famciclovir 250 mg orally, 12-hourly
OR
1 valaciclovir 500 mg orally, once daily.
Treatment may be continuous, or interrupted at intervals to determine the natural history of disease and restarted in
the event of frequent recurrences. Advise patients that recurrences may occur after stopping therapy; ensure
patients planning to interrupt suppressive therapy can start episodic therapy if required. Long-term suppressive
antiviral therapy is considered safe.
For patients with recurrences despite suppressive therapy, reassess the patient to confirm the diagnosis—if
confirmed, a reasonable regimen to use is:
valaciclovir 500 mg orally, 12-hourly.
Frequent, severe recurrences in immunocompromised patients may be due to resistant herpes simplex virus—seek
expert advice.
Suppressive therapy for women with recurrent genital herpes during late pregnancy reduces the chance of
recurrence of herpes simplex virus at delivery and increases the likelihood of a vaginal delivery. After 36 weeks’
gestation, it is reasonable to increase the dosing frequency; use:
1 aciclovir 400 mg orally, 8-hourly, until delivery
OR
2 valaciclovir 500 mg orally, 12-hourly, until delivery.
Suppressive therapy may not always protect against herpes simplex virus transmission to neonates; see Neonatal
herpes simplex infection.
Chancroid
Chancroid (soft chancre) is caused by Haemophilus ducreyi and is often associated with suppurative
lymphadenitis. It is very rare in Australia.
Seek expert advice on diagnosis and management. Haemophilus ducreyi is fastidious and difficult to culture, and
diagnosis is usually made either clinically or by nucleic acid amplification testing (NAAT) (eg polymerase chain
reaction [PCR]).
Use:
1 azithromycin 1 g orally, as a single dose
OR
1 ceftriaxone 500 mg in 2 mL of 1% lidocaine intramuscularly, or 500 mg intravenously, as

OR
1 ciprofloxacin 500 mg orally, 12-hourly for 3 days.
Donovanosis
Donovanosis (granuloma inguinale) is caused by Klebsiella granulomatis. It is a chronic, progressively destructive
infection, presenting initially as raised, beefy nodules or sores. Donovanosis remains endemic in some countries
(eg Papua New Guinea, India, southern Africa) but is rare in Australia. Microscopy of scrapings, snip or punch
biopsy, or nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]) can confirm the
diagnosis. Seek expert advice.
For treatment, use:
1 azithromycin 1 g orally, once weekly for at least 4 weeks (by directly observed therapy)
until healing occurs
OR
1 azithromycin 500 mg orally, daily for 7 days
OR
2 doxycycline 100 mg orally, 12-hourly for at least 4 weeks until healing occurs.
Key references
Genital herpes
Conant MA, Schacker TW, Murphy RL, Gold J, Crutchfield LT, Crooks RJ. Valaciclovir versus aciclovir for herpes
simplex virus infection in HIV-infected individuals: two randomized trials. Int J STD AIDS 2002;13(1):12–21.
Heslop R, Roberts H, Flower D, Jordan V. Interventions for men and women with their first episode of genital herpes.
Le Cleach L, Trinquart L, Do G, Maruani A, Lebrun-Vignes B, Ravaud P, et al. Oral antiviral therapy for prevention of
genital herpes outbreaks in immunocompetent and nonpregnant patients. Cochrane Database Syst Rev 2014;
(8):CD009036.
Patel R, Kennedy OJ, Clarke E, Geretti A, Nilsen A, Lautenschlager S, et al. European guidelines for the management
of genital herpes. Int J STD AIDS 2017;28(14):1366–79 .
Warren T, Harris J, Brennan CA. Efficacy and safety of valacyclovir for the suppression and episodic treatment of
herpes simplex virus in patients with HIV. Clin Infect Dis 2004;39 Suppl 5:S258–66.
World Health Organization (WHO). WHO Guidelines for the Treatment of Genital Herpes Simplex Virus. Geneva,
Genital warts (human papillomavirus infection)
Overview of HPV infection
Human papillomavirus (HPV) infection in the genital tract is usually asymptomatic and transient. HPV genotypes
that cause genital infection are detected by DNA testing and are divided into high-risk (oncogenic) and low-risk
genotypes.
The low-risk HPV types 6 and 11 cause more than 90% of genital warts (condylomata acuminata) and have not
been directly associated with cancer.
Persistent infection with high-risk genotypes can lead to intraepithelial neoplasia and in some cases, anogenital
cancers.
Treatment of genital warts

Treatment of genital warts is not essential; however, warts can be extensive and painful, and most patients prefer
treatment. Warts are uncommon in populations that have been vaccinated against human papillomavirus (HPV);
consider alternative diagnoses of normal anatomical variants such as pearly penile papules, Fordyce spots, Tyson
glands or vestibular papillae [Note 1].
Inform patients that human papillomavirus infection is transmitted by genital-to-genital contact, and that HPV
types that cause genital warts have not been directly associated with cancer.
Screen patients with suspected genital warts for other sexually transmitted pathogens—see Investigations for STIs.
The period of infectivity and latency of human papillomavirus is not known, so it may not be possible to determine
which sexual contact the virus was acquired from. Contact tracing is not usually required, but recommend HPV
vaccination to sexual partners who are not fully vaccinated.
Most human papillomavirus infections are transient, but can be reactivated after years of dormancy by skin trauma
(eg from scratching or shaving) or immune compromise.
Topical preparations and cryotherapy are effective treatments for genital warts. Cryotherapy often needs to be
repeated at intervals of 1 to 2 weeks. Cryotherapy is most useful when treating a small number of easily accessed
lesions. Cryotherapy can also be used as an adjunct to topical preparations for refractory lesions.
Topical preparations are less painful than cryotherapy, and ideal for numerous or bulky lesions. Use:
1 imiquimod 5% cream topically, 3 times weekly on alternate days at bedtime until warts
resolve (usually 8 to 16 weeks)
OR
1 podophyllotoxin 0.5% paint topically, twice daily for 3 days followed by a 4-day break;
repeat weekly for 4 to 6 cycles until warts resolve.
Imiquimod can cause local inflammatory effects (eg burning, itch or erythema). Reducing the frequency of
application can help manage these adverse effects.
For general principles of sexually transmitted infection (STI) management, including counselling, and
considerations for neonates, infants or children in whom an STI is identified, see Principles of sexually transmitted
infection management.
Note 1: See the STI Atlas website for images to assist with differential diagnoses.
Key references
Ali H, Donovan B, Wand H, Read TRH, Regan DG, Grulich AE, et al. Genital warts in young Australians five years into
national human papillomavirus vaccination programme: national surveillance data. BMJ 2013;346.
Grillo-Ardila CF, Angel-Muller E, Salazar-Diaz LC, Gaitan HG, Ruiz-Parra AI, Lethaby A. Imiquimod for anogenital
warts in non-immunocompromised adults. Cochrane Database Syst Rev 2014;(11):CD010389.
Komericki P, Akkilic-Materna M, Strimitzer T, Aberer W. Efficacy and safety of imiquimod versus podophyllotoxin in the
treatment of anogenital warts. Sex Transm Dis 2011;38(3):216–8.
Yan J, Chen SL, Wang HN, Wu TX. Meta-analysis of 5% imiquimod and 0.5% podophyllotoxin in the treatment of
condylomata acuminata. Dermatology 2006;213(3):218–23.
Pelvic actinomycosis
Pelvic actinomycosis
Pelvic actinomycosis is very rare. It causes a chronic polymicrobial inflammatory mass that can mimic pelvic
malignancy. It usually occurs after prolonged intrauterine contraceptive device (IUD) use. Symptoms of
pelvic actinomycosis are nonspecific and include pelvic pain, abnormal cervical discharge, abnormal bleeding
(either intermenstrual or postcoital) and weight loss.
Female genital tract colonisation with Actinomyces species is not uncommon, and antibiotic treatment or
removal of intrauterine contraceptive device (if present) is not required unless there are symptoms of pelvic
actinomycosis.
Investigate symptomatic patients by collecting an endocervical swab for Gram stain and culture (including
Actinomyces species). Radiological investigations may be indicated depending on the clinical presentation.
Treat according to the results of investigations—seek expert advice. Antibiotic therapy for at least 6 months
and removal of the intrauterine contraceptive device can lead to complete resolution, but surgical intervention
may also be necessary.
Key references
Valour F, Senechal A, Dupieux C, Lustig S, Breton P, et al. Actinomycosis: etiology, clinical features, diagnosis,
treatment, and management. Infect Drug Resist 2014;7:183–97 .
Pelvic inflammatory disease and postprocedural
pelvic infection
Aetiology and assessment of pelvic inflammatory disease and
postprocedural pelvic infection
Pelvic inflammatory disease (PID) is an infection of the female upper genital tract and may involve the uterus,
fallopian tubes, ovaries and, occasionally, adjacent pelvic structures. Pelvic inflammatory disease includes
endometritis, salpingitis, tubo-ovarian abscess, pelvic cellulitis and pelvic peritonitis. Exclude ectopic pregnancy
and other abdominal emergencies (eg appendicitis) before considering the diagnosis of pelvic inflammatory
disease.
Pelvic inflammatory disease is usually polymicrobial, caused by sexually transmitted pathogens and vaginal flora.
Chlamydia trachomatis is the most commonly identified sexually transmitted pathogen, followed by Neisseria
gonorrhoeae and Mycoplasma genitalium. In most cases of pelvic inflammatory disease, no pathogen is identified.
Postprocedural pelvic infection follows a gynaecological procedure and involves similar parts of the female upper
genital tract to pelvic inflammatory disease. Postprocedural pelvic infection is polymicrobial and usually caused by
vaginal flora.
Investigate suspected cases of pelvic inflammatory disease or postprocedural pelvic infection with an endocervical
swab for:
nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]) for C. trachomatis, N.
gonorrhoeae, and M. genitalium
Gram stain and culture of N. gonorrhoeae for susceptibility testing.
If speculum examination is not possible, a first-void urine sample or patient-collected vaginal swab can be used.
Collect blood samples for culture and susceptibility testing for patients in hospital.
Choice of empirical therapy for pelvic inflammatory disease and

For treatment of intra-amniotic infection (chorioamnionitis), see Intra-amniotic infection (chorioamnionitis).
For treatment of postpartum endometritis, see Postpartum endometritis.
For treatment of pelvic infection following pregnancy termination, see Septic abortion.
For treatment of pelvic infection following other gynaecological procedures (including insertion of an intrauterine
contraceptive device [IUD]), see Treatment of postprocedural pelvic infection. However, if the patient is at risk of
a sexually transmitted infection (STI) (eg the patient was not investigated for STIs before the procedure), see
Treatment of pelvic inflammatory disease.
For treatment of pelvic inflammatory disease (PID), use the relevant empirical regimen for pelvic inflammatory
disease.
Initial intravenous therapy (see Empirical therapy for severe PID or Empirical therapy for severe postprocedural
pelvic infection) is usually required for patients with any of the following features:
pregnancy
inability to tolerate oral therapy
severe pain
fever (38°C or higher)
systemic features (eg tachycardia, vomiting)
sepsis or septic shock
suspicion of tubo-ovarian abscess.
Oral therapy is appropriate for patients who do not have any of the above features—see Empirical therapy for
nonsevere PID or Empirical therapy for nonsevere postprocedural pelvic infection.
Treatment of pelvic inflammatory disease
Approach to managing PID
Prompt treatment of pelvic inflammatory disease (PID) reduces the risk of tubal damage and, consequently,
infertility, ectopic pregnancy and chronic pelvic pain.
To determine the appropriate empirical regimen for pelvic inflammatory disease, see Choice of empirical therapy
for pelvic inflammatory disease and postprocedural pelvic infection.
For additional considerations for patients with an intrauterine contraceptive device, see Considerations for patients
with intrauterine contraceptive devices.
counselling, and considerations for children in whom an STI is identified, see Principles of sexually transmitted
Empirical therapy for nonsevere PID

Pelvic inflammatory disease (PID) is considered nonsevere if the patient does not have severe pain, fever (38°C or
higher), systemic features (eg tachycardia, vomiting), sepsis or septic shock, or suspected tubo-ovarian abscess.
For empirical therapy of nonsevere pelvic inflammatory disease, as a three-drug regimen, use:

PLUS
metronidazole 400 mg orally, 12-hourly for 14 days
PLUS EITHER
OR for patients who are pregnant, breastfeeding [Note 2] or likely to be nonadherent to doxycycline
2 azithromycin 1 g orally, as a single dose, repeated 1 week later.
above.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, use doxycycline and
metronidazole (as above) and if Neisseria gonorrhoeae is identified, seek expert advice.
Assess the response to therapy within 72 hours and if the patient has not improved, re-evaluate the diagnosis and
consider switching to intravenous antibiotic therapy—see Empirical therapy for severe PID. If Mycoplasma
genitalium is detected, see PID caused by M. genitalium.
Perform a test of cure 1 month after starting treatment for pelvic inflammatory disease if a sexually transmitted
pathogen was detected.
See Management of sexual contacts for information on contact tracing and presumptive treatment.
Note 1: If using a 1 g vial of ceftriaxone for intramuscular injection, add 3.5 mL of 1% lidocaine and administer
2 mL of the reconstituted solution.
Note 2: Low levels of doxycycline are excreted in breast milk and pose a theoretical risk of enamel hypoplasia
and staining of developing teeth in breastfed infants. A short single course (7 to 10 days) of doxycycline is
considered safe in breastfeeding.
Empirical therapy for severe PID
Initial antibiotic therapy for severe PID

Pelvic inflammatory disease (PID) is considered severe if the patient has severe pain, fever (38°C or higher),
systemic features (eg tachycardia, vomiting), sepsis or septic shock (see Early recognition of sepsis or septic shock
in adults for definitions), or suspected tubo-ovarian abscess.
For patients with sepsis or septic shock, start antibiotic therapy within 1 hour of presentation to medical care or,
for ward-based patients, development of sepsis or septic shock, immediately after appropriate samples are taken
for culture. For nonantibiotic management of sepsis or septic shock, see Early intervention for sepsis or septic
shock.
For empirical therapy of severe pelvic inflammatory disease, as a three-drug regimen, use:
care support, use 1 g intravenously, 12-hourly. See Modification and duration of therapy
for severe PID
OR
care support, use 2 g intravenously, 6-hourly. See Modification and duration of therapy for
severe PID
azithromycin 500 mg intravenously, daily; see Modification and duration of therapy for
severe PID
PLUS
metronidazole 500 mg intravenously, 12-hourly; see Modification and duration of therapy

for severe PID.
above.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, as a three-drug regimen, use:

aminoglycoside use for subsequent dosing [Note 4] [Note 5] and see Modification and
duration of therapy for severe PID
duration of therapy for severe PID
and see Modification and duration of therapy for severe PID
PLUS
azithromycin 500 mg intravenously, daily; see Modification and duration of therapy for
severe PID
PLUS EITHER
1 clindamycin 600 mg intravenously, 8-hourly; see Modification and duration of therapy for
severe PID
OR
2 lincomycin 600 mg intravenously, 8-hourly; see Modification and duration of therapy for
severe PID.
calculate the dose.
function.
Modification and duration of therapy for severe PID
Modify therapy based on the results of investigations, if available. If the results of susceptibility testing are not
available by 72 hours and empirical intravenous therapy is still required, stop the gentamicin-containing regimen
and seek expert advice. If M. genitalium is detected, see PID caused by M. genitalium.
Switch to oral therapy once the patient is clinically stable (see Guidance for antimicrobial intravenous to oral
switch). Use oral metronidazole plus doxycycline (as for nonsevere PID) to complete a total treatment duration
of 2 weeks (intravenous + oral).
Perform a test of cure 1 month after starting treatment for pelvic inflammatory disease if a sexually transmitted
pathogen was detected.
See Management of sexual contacts for information on contact tracing and presumptive treatment.
PID caused by M. genitalium

M. genitalium infection often fails to respond to azithromycin or doxycycline. Given the potential severe
complications of pelvic inflammatory disease, if a nucleic acid amplification test (NAAT) identifies M. genitalium
during treatment, and symptoms persist on empirical therapy, stop the empirical regimen and switch to:
Perform a test of cure 1 month after starting treatment for M. genitalium infection. See also Approach
to Mycoplasma genitalium infection.
Management of sexual contacts
Perform contact tracing and investigate sexual contacts for Chlamydia trachomatis and Neisseria gonorrhoeae.
Testing for M. genitalium is only necessary for ongoing sexual partners. While awaiting test results,
presumptively treat current sexual partners with:
If N. gonorrhoeae is identified in the index case, presumptively treat sexual contacts—see Approach to Neisseria
gonorrhoeae infection. If N. gonorrhoeae is identified in a sexual contact, see Approach to Neisseria gonorrhoeae
infection for additional treatment (if necessary), information on additional testing (including test of cure) and
contact tracing.
If C. trachomatis is identified in the index case, further treatment of sexual contacts is not required. If
C. trachomatis is identified in a sexual contact, further treatment of the contact is not required;
however, undertake contact tracing for that individual—see Approach to Chlamydia trachomatis infection.
If M. genitalium is identified in the index case, further treatment of sexual contacts is not required. If
M. genitalium is identified in a sexual contact, further treatment of the contact is not required; however, perform a
test of cure at least 3 weeks after presumptive treatment with azithromycin.
Seek expert advice for results that are difficult to interpret (eg an unexpected negative result).
See also Contact tracing for STIs.
Treatment of postprocedural pelvic infection

Approach to managing postprocedural pelvic infection
To determine the appropriate empirical regimen, see Choice of empirical therapy for pelvic inflammatory
disease and postprocedural pelvic infection. If the patient is at risk of a sexually transmitted infection (STI) (eg the
patient was not investigated for STIs before the procedure), see Treatment of pelvic inflammatory disease.
For additional considerations for patients with an intrauterine contraceptive device, see Considerations for patients
with intrauterine contraceptive devices.
Empirical therapy for nonsevere postprocedural pelvic infection
Postprocedural pelvic infection is considered nonsevere if the patient does not have severe pain, fever (38°C or
higher), systemic features (eg tachycardia, vomiting), sepsis or septic shock, or suspected tubo-ovarian abscess.
For empirical therapy of nonsevere postprocedural pelvic infection, use:
amoxicillin+clavulanate 875+125 mg orally, 12-hourly for 14 days.
For patients with hypersensitivity to penicillins, use:
trimethoprim+sulfamethoxazole 160+800 mg orally, 12-hourly for 14 days
PLUS
Assess the response to therapy within 72 hours and if the patient has not improved, re-evaluate the diagnosis and
consider switching to intravenous therapy—see Empirical therapy for severe postprocedural pelvic
infection below.
Empirical therapy for severe postprocedural pelvic infection
Initial antibiotic therapy for severe postprocedural pelvic infection
Postprocedural pelvic infection is considered severe if the patient has severe pain, fever (38°C or higher), systemic
features (eg tachycardia, vomiting), sepsis or septic shock (see Early recognition of sepsis or septic shock in
adults for definitions), or suspected tubo-ovarian abscess.
Give patients with sepsis or septic shock appropriate broad-spectrum antibiotics within 1 hour of presentation to
medical care or, for ward-based patients, development of sepsis or septic shock, immediately after appropriate
samples are taken for culture. For nonantibiotic management of sepsis or septic shock, see Early intervention for
sepsis or septic shock.
Rarely, patients who are critically ill may have infection caused by Streptococcus pyogenes (group A
streptococcus) or Clostridium species; see Streptococcus pyogenes bloodstream infections, including toxic shock
syndrome and Clostridial necrotising skin and soft tissue infection.
For empirical therapy of patients with severe postprocedural pelvic infection, as a three-drug regimen, use:

duration of therapy for severe postprocedural pelvic infection
and see Modification and duration of therapy for severe postprocedural pelvic infection
PLUS

for severe postprocedural pelvic infection
PLUS EITHER
1 amoxicillin 2 g intravenously, 6-hourly; see Modification and duration of therapy for

severe postprocedural pelvic infection
OR
1 ampicillin 2 g intravenously, 6-hourly; see Modification and duration of therapy for severe
postprocedural pelvic infection.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, as a two-drug
regimen, use:
care support, use 1 g intravenously, 12-hourly. See Modification and duration of therapy
for severe postprocedural pelvic infection
OR
care support, use 2 g intravenously, 6-hourly. See Modification and duration of therapy for

for severe postprocedural pelvic infection.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, as a two-drug regimen, use:

and see Modification and duration of therapy for severe postprocedural pelvic infection
PLUS EITHER
OR
severe postprocedural pelvic infection.
calculate the dose.
function.
Modification and duration of therapy for severe postprocedural pelvic infection
Modify therapy based on the results of investigations, if available. If the results of susceptibility testing are not
and use the ceftriaxone or cefotaxime-containing regimen as above.
Switch to oral therapy once the patient is clinically stable (see Guidance for antimicrobial intravenous to oral
switch). Use oral amoxicillin+clavulanate (as for nonsevere postprocedural pelvic infection) to complete a total
treatment duration (intravenous + oral) of at least 2 weeks.
Considerations for patients with infection and an intrauterine

contraceptive device
Screen patients for sexually transmitted infections before the insertion of an intrauterine contraceptive device
(IUD) to avoid introducing pathogens into the upper genital tract during insertion.
For patients with a long-term indwelling intrauterine contraceptive device presenting with symptoms of pelvic
inflammatory disease (PID), consider pelvic actinomycosis.
If a patient with an intrauterine contraceptive device is diagnosed with pelvic inflammatory disease or
postprocedural pelvic infection, treat the infection (see Choice of empirical therapy for pelvic inflammatory
disease and postprocedural pelvic infection). Removal of the intrauterine contraceptive device is not required
unless the infection is severe or there is no clinical improvement within 48 to 72 hours of starting therapy. If the
intrauterine contraceptive device is removed, a new device can be inserted once the infection has resolved.
Key references
Australasian Sexual Health Alliance (ASHA). Australian STI management guidelines for use in primary care. Sydney:
ASHA. 2018. www.sti.guidelines.org.au/ .
Brunham RC, Gottlieb SL, Paavonen J. Pelvic inflammatory disease. N Engl J Med 2015;372(21):2039–2048 .
Chappell CA, Wiesenfeld HC. Pathogenesis, diagnosis, and management of severe pelvic inflammatory disease and
tuboovarian abscess. Clin Obstet Gynecol 2012;55(4):893–903 .
Goller JL, De Livera AM, Fairley CK, Guy RJ, Bradshaw CS, Chen MY, Hocking JS. Characteristics of pelvic
inflammatory disease where no sexually transmitted infection is identified: a cross-sectional analysis of routinely
collected sexual health clinic data. Sex Transm Infect 2017;93(1):68–70 .
Jensen JS, Bradshaw C. Management of Mycoplasma genitalium infections - can we hit a moving target?. BMC Infect
Dis 2015;15:343. .
Jensen JS, Cusini M, Gomberg M, Moi H. 2016 European guideline on Mycoplasma genitalium infections. J Eur Acad
Dermatol Venereol 2016;30(10):1650–1656 .
Latimer RL, Read TRH, Vodstrcil LA, Goller JL, Ong JJ, Fairley CK, et al. Clinical Features and Therapeutic Response
in Women Meeting Criteria for Presumptive Treatment for Pelvic Inflammatory Disease Associated With Mycoplasma
genitalium. Sex Transm Dis 2019;46(2):73–79 .
Lis R, Rowhani-Rahbar A, Manhart LE. Mycoplasma genitalium infection and female reproductive tract disease: a
meta-analysis. Clin Infect Dis 2015;61(3):418–426 .
Martínez F, López-Arregui E. Infection risk and intrauterine devices. Acta Obstet Gynecol Scand 2009;88(3):246–250
.
Ross J, Guaschino S, Cusini M, Jensen J. 2017 European guideline for the management of pelvic inflammatory
disease. Int J STD AIDS 2018;29(2):108–114 .
Savaris RF, Fuhrich DG, Duarte RV, Franik S, Ross J. Antibiotic therapy for pelvic inflammatory disease. Cochrane
Database Syst Rev 2017;4:CD010285. .
Tepper NK, Steenland MW, Gaffield ME, Marchbanks PA, Curtis KM. Retention of intrauterine devices in women who
acquire pelvic inflammatory disease: a systematic review. Contraception 2013;87(5):655–660 .
Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep
2015;64(RR-03):1–137 .
Infective proctitis
Aetiology and assessment of infective proctitis
Infective proctitis caused by a sexually transmitted infection (STI) usually occurs within a few days to weeks
following receptive anal sex in both women and men. Patients may present with anal pain, discharge, discomfort,
bleeding or tenesmus. These symptoms can be difficult to differentiate from acute infectious diarrhoea or
noninfective causes such as inflammatory bowel disease (discharge may be difficult to distinguish from diarrhoea,
particularly in cases of proctitis caused by lymphogranuloma venereum [LGV]). If diarrhoea is present, perform
stool culture in addition to other investigations. For the management of proctitis caused by inflammatory bowel
disease, see Ulcerative colitis: induction therapy for active proctitis or distal colitis.
Sexually transmitted pathogens commonly involved in infective proctitis are Neisseria gonorrhoeae, Chlamydia
trachomatis (including the LGV serovar, which causes severe inflammation) and herpes simplex virus.
Mycoplasma genitalium is commonly identified in anorectal swabs from men who have sex with men (MSM) but
studies have not confirmed its pathogenicity.
For cases of suspected proctitis, take anorectal swabs for:
nucleic acid amplification test (NAAT) (eg polymerase chain reaction [PCR]) for N. gonorrhoeae, C.
trachomatis and herpes simplex virus
culture of N. gonorrhoeae for susceptibility testing.
Syphilis often causes anal lesions in men who have sex with men. Perform serological testing for syphilis and
HIV in men who have sex with men presenting with proctitis; see also Investigations for STIs.
In cases of painful proctitis, lubrication of anorectal swabs with sterile water or saline may reduce pain associated
with swabbing. Proctoscopy may help to identify ulcers or noninfective causes of anal symptoms, but it can be
painful and is usually unnecessary.
For general principles of STI management, including investigations and counselling, and considerations for
children in whom an STI is identified, see Principles of sexually transmitted infection management.
Empirical therapy for infective proctitis

The symptoms of anorectal infections are nonspecific; therefore, empirical therapy should treat Neisseria
gonorrhoeae, Chlamydia trachomatis and herpes simplex virus. If pain is minimal, therapy may be delayed
pending the results of investigations.
For empirical therapy of infective proctitis, use:

PLUS
doxycycline 100 mg orally, 12-hourly for 7 days. Men who have sex with men may
require a longer duration for lymphogranuloma venereum (see below)
PLUS
oral antiviral therapy as for a first clinical episode of genital herpes.
above.
Modify therapy based on the results of investigations.
For men who have sex with men, if C. trachomatis is identified, request lymphogranuloma venereum (LGV)
testing. If lymphogranuloma venereum is identified by nucleic acid amplification testing (NAAT) (eg polymerase
chain reaction [PCR]) or cannot be excluded, continue doxycycline for 21 days or switch to azithromycin—see
Lymphogranuloma venereum.
If C. trachomatis or N. gonorrhoeae is identified, perform a test of cure 1 month after the start of treatment.
Perform contact tracing and investigate sexual contacts for C. trachomatis and N. gonorrhoeae. If a pathogen is
identified in the index case, presumptively treat contacts for that pathogen (see Approach to Chlamydia
trachomatis infection or Approach to Neisseria gonorrhoeae infection). If a pathogen is identified in a sexual
contact, treat the infection and undertake contact tracing for that individual. See also Contact tracing for STIs.
Lymphogranuloma venereum
Lymphogranuloma venereum (LGV) is caused by Chlamydia trachomatis L serovars, and is endemic in Australia
among men who have sex with men (MSM). The majority of cases are in MSM who have concomitant HIV
infection; they usually present with symptoms of proctitis (eg anorectal discharge, pain, bleeding).
Lymphogranuloma venereum can cause anal ulceration followed by strictures and fistulas, and may also present
with a genital ulcer followed by lymphadenopathy.
Request nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]) for lymphogranuloma
venereum for MSM with anorectal symptoms and a positive culture result for C. trachomatis on an anorectal swab.
If lymphogranuloma venereum is identified or cannot be excluded (eg testing is not available), use:
OR if adherence is unlikely
2 azithromycin 1 g orally, once weekly for 3 weeks.
Repeat the C. trachomatis test 1 month after the start of treatment to test for cure.
Investigate sexual contacts from the 2 months before the onset of symptoms and treat with the above regimen. Full
treatment courses are usually given to contacts even if microbiological tests do not identify lymphogranuloma
venereum, because of the risk of serious complications. If lymphogranuloma venereum is identified in a sexual
contact, undertake contact tracing for that individual. See also Contact tracing for STIs.
Key references
Bissessor M, Fairley CK, Read T, Denham I, Bradshaw C, Chen M. The etiology of infectious proctitis in men who
have sex with men differs according to HIV status. Sex Transm Dis 2013;40(10):768–70.
Bissessor M, Tabrizi SN, Bradshaw CS, Fairley CK, Hocking JS, Garland SM, et al. The contribution of Mycoplasma
genitalium to the aetiology of sexually acquired infectious proctitis in men who have sex with men. Clin Microbiol Infect
2016;22(3):260–5.
de Vries HJ, Zingoni A, White JA, Ross JD, Kreuter A. 2013 European Guideline on the management of proctitis,
proctocolitis and enteritis caused by sexually transmissible pathogens. Int J STD AIDS 2014;25(7):465–74.
Leeyaphan C, Ong JJ, Chow EP, Kong FY, Hocking JS, Bissessor M, et al. Systematic review and meta-analysis of
doxycycline efficacy for rectal Lymphogranuloma venereum in men who have sex with men. Emerg Infect Dis
2016;22(10):1778–84.
Leeyaphan C, Ong JJ, Chow EP, Dimovski K, Kong FY, Hocking JS, et al. Treatment outcomes for rectal
Lymphogranuloma venereum in men who have sex with men using doxycycline, azithromycin, or both: A review of
clinical cases. Sex Transm Dis 2017;44(4):245–8.
World Health Organization (WHO). WHO Guidelines for the Treatment of Chlamydia trachomatis. Geneva,
Syphilis
Overview of management of syphilis
Syphilis diagnosis is based on a combination of history, clinical assessment and laboratory investigations.
The incidence of syphilis in Australia is increasing, particularly in Aboriginal and Torres Strait Islander people and
men who have sex with men (MSM). Typical presentations of syphilis in people from populations with a high
incidence of syphilis should be treated without waiting for laboratory confirmation.
Seek expert advice for the management of syphilis during pregnancy, congenital syphilis, patients with penicillin
hypersensitivity, or if serological results are difficult to interpret.
For general principles of sexually transmitted infection (STI) management, including advice on counselling, and
considerations for neonates, infants or children in whom an STI is identified, see Principles of sexually transmitted
Investigations for syphilis

Syphilis is usually diagnosed by serological testing or by identification of Treponema pallidum DNA on a swab
from a lesion, using nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]).
Diagnosis of active syphilis is confirmed with both:
a positive nontreponemal test result (such as rapid plasma reagin [RPR] test)
a positive treponemal test result (such as treponemal enzyme immunoassay [EIA], T. pallidum particle
agglutination test [TPPA] or T. pallidum haemagglutination assay [TPHA]).
Neither test alone is adequate for diagnosis.
False-positive nontreponemal test results are common and can also occur with treponemal enzyme immunoassay
tests, but are rare with the T. pallidum particle agglutination test and the T. pallidum haemagglutination assay.
Nontreponemal tests may be nonreactive in late latent or tertiary syphilis.
In the early stages of syphilis, even if a chancre is present, the results of serological testing may be negative.
Treponemal tests may not become reactive until up to 2 weeks after the chancre develops, and nontreponemal tests
may take up to 4 weeks to become reactive. A nonreactive nontreponemal test but reactive treponemal test may
indicate early syphilis.
A lumbar puncture may be required to investigate for neurosyphilis.
Check treatment response at 3, 6 and 12 months with a nontreponemal test. Syphilis is considered cured if the
nontreponemal titre falls by at least four-fold (two dilutions). Advise patients that despite curative treatment, their
treponemal test will probably remain reactive for life. Document curative treatment in the patient’s medical history.
A four-fold fall in the titre of a nontreponemal test occurs in about two-thirds of treated syphilis cases by 12
months. If this does not occur, or if the titre increases, consider treatment failure (particularly in patients treated
with a nonpenicillin regimen) or reinfection.
Screen patients with suspected syphilis for other sexually transmitted infections (STIs), including HIV; see
Investigations for STIs. Patients with undiagnosed HIV infection may present initially with syphilis. In patients
who need to be started on therapy for HIV, see Syphilis in adults with HIV infection for advice on starting
antiretroviral therapy.
Principles of antimicrobial therapy for syphilis

Penicillin remains the drug of choice for syphilis.
Assess patients reporting hypersensitivity to penicillins.
Assess patients reporting hypersensitivity to penicillins for immune-mediated hypersensitivity—see Types of

antimicrobial hypersensitivity. Desensitisation is strongly recommended for patients with immediate
hypersensitivity, especially pregnant women and patients with tertiary syphilis or neurosyphilis (at any stage).
Although treatment failure with penicillin can occur, there are no documented cases of penicillin resistance in
Treponema pallidum. Doxycycline is an alternative for nonpregnant patients with penicillin hypersensitivity with
early syphilis and late latent syphilis, but there is limited evidence to support its use. Azithromycin resistance is
widespread so azithromycin should not be used. If a drug other than a penicillin is used, close follow-up is
essential to monitor for treatment failure.
In patients with HIV infection taking antiretroviral therapy, check the potential for drug interactions when
prescribing other drugs (see Antiretroviral drug interactions).
Early syphilis
Assessment of early syphilis
Early syphilis (less than 2 years’ duration; based on the results of serological testing) includes primary, secondary
and early latent syphilis.
The clinical features of primary and secondary syphilis vary widely. Primary syphilis lesions are often indurated,
may be accompanied by lymphadenopathy and may not be painful. Consider secondary syphilis in patients with
psoriatic rashes or warty lesions. Consider investigating for syphilis in patients presenting with any unusual oral,
anorectal or genital lesion or a nonitchy rash.
Early latent syphilis is an asymptomatic infection of less than 2 years’ duration.
Treatment of early syphilis

For treatment of early syphilis, use:
1 benzathine benzylpenicillin 2.4 million units intramuscularly [Note 1], as a single dose
OR
2 procaine benzylpenicillin 1.5 g intramuscularly, daily for 10 days.
Benzathine benzylpenicillin is long acting and the drug of choice for early syphilis. Do not confuse benzathine
benzylpenicillin with benzylpenicillin, which is short acting.

antimicrobial hypersensitivity.
Desensitisation is strongly recommended for patients with immediate penicillin hypersensitivity.
For nonpregnant patients with penicillin hypersensitivity who cannot be desensitised, including those with delayed
penicillin hypersensitivity, use:
doxycycline 100 mg orally, 12-hourly for 14 days.
For pregnant patients with penicillin hypersensitivity, seek expert advice—see also Pregnancy and congenital
syphilis.
Intravenous antibiotic therapy is necessary for complicated presentations (eg neurological complications, including
otosyphilis and ocular syphilis)—see Tertiary syphilis for treatment recommendations.
For follow-up investigations to check treatment response, see Investigations for syphilis.
Patients with HIV infection and early syphilis are at an increased risk of neurological complications. They should
be evaluated clinically and serologically 3, 6, 12 and 24 months after therapy. If symptoms persist or recur, or if
nontreponemal titres rise or fail to decline four-fold within 6 to 12 months, cerebrospinal fluid (CSF) should be
examined to distinguish treatment failure (due to neurosyphilis) from reinfection—seek expert advice. If
cerebrospinal fluid analysis is consistent with neurosyphilis, treat as for tertiary syphilis.
Note 1: All benzathine benzylpenicillin preparations (benzathine benzylpenicillin 900 mg/2.3 mL [equivalent to 1.2 million units]; benzathine
benzylpenicillin tetrahydrate 1 200 000 units/2.3 mL [equivalent to 1016.6 mg benzathine benzylpenicillin tetrahydrate]; benzathine benzylpenicillin
tetrahydrate 600 000 units/1.17 mL [equivalent to 517 mg benzathine benzylpenicillin tetrahydrate]) contain the same concentration of benzathine
benzylpenicillin.
Management of sexual contacts
Undertake contact tracing for patients with early syphilis. Use the sexual history and records of serological tests as
guides, but generally, contact partners from the past 3 months if the patient has primary syphilis, and over a longer
period if they have secondary syphilis (eg 6 months) or latent syphilis (eg 12 months).
Perform serological testing of sexual contacts and then presumptively treat them with:
benzathine benzylpenicillin 2.4 million units intramuscularly [Note 2], as a single dose.
Benzathine benzylpenicillin is long acting and the drug of choice for treatment of syphilis. Do not confuse
benzathine benzylpenicillin with benzylpenicillin, which is short acting.
See also Contact tracing for STIs.
benzylpenicillin.
Late latent syphilis

Late latent syphilis is defined as latent (asymptomatic) syphilis of longer than 2 years’ duration, or of unknown
duration. Seek expert advice about the need for and interpretation of lumbar puncture. This is particularly
important for patients who have previously been treated for syphilis or for patients with HIV infection. If
neurosyphilis is confirmed, treat as for tertiary syphilis.
For treatment of late latent syphilis, use:
1 benzathine benzylpenicillin 2.4 million units intramuscularly [Note 3], once weekly for 3
weeks
OR
2 procaine benzylpenicillin 1.5 g intramuscularly, daily for 15 days.
Benzathine benzylpenicillin is long acting and the drug of choice for late latent syphilis. Do not confuse

Desensitisation is strongly recommended for patients with immediate penicillin hypersensitivity.
For nonpregnant patients who cannot be desensitised, including those with delayed penicillin hypersensitivity,
use:
For pregnant patients with penicillin hypersensitivity, seek expert advice (see also Pregnancy and congenital
syphilis).
Perform serological testing for current sexual partners and treat according to the results. Late latent syphilis may
have been acquired many years ago, so use the sexual history to determine if further contact tracing is
required. See also Contact tracing for STIs.
benzylpenicillin.
Tertiary syphilis
Tertiary syphilis refers to syphilis of longer than 2 years’ duration, or of unknown duration, with cardiovascular,
central nervous system or skin and bone (gummatous syphilis) involvement. Expert advice is essential.
For the treatment of tertiary syphilis, use:
benzylpenicillin 1.8 g intravenously, 4-hourly for 15 days.

Desensitisation is strongly recommended for patients with immediate penicillin hypersensitivity. For patients with
penicillin hypersensitivity who cannot be desensitised, including those with delayed penicillin hypersensitivity,
seek expert advice for alternative treatment.
Treatment of tertiary syphilis can be administered through an established community-based parenteral

antimicrobial therapy program.
Corticosteroids have been used in combination with antibiotic therapy for complicated presentations, but clinical
evidence to support this practice is limited. For cardiovascular syphilis or neurosyphilis, concomitant treatment
with prednis(ol)one may be administered initially with penicillin to reduce the likelihood of a Jarisch–Herxheimer
reaction.
Seek expert advice on contact tracing and the management of sexual contacts.
Pregnancy and congenital syphilis

Approach to managing syphilis during pregnancy
Screen pregnant women for syphilis at the first antenatal visit using serological testing. Repeat screening at 28
weeks’ gestation is recommended, and in some jurisdictions, more regular testing is recommended; particularly for
women with new sexual partners during pregnancy, women from high-prevalence communities and women
diagnosed with a new STI. Test women at delivery if they have not been tested previously.
Treat pregnant women with penicillin as recommended for nonpregnant patients (see Early syphilis, Late latent
syphilis or Tertiary syphilis). Assess patients reporting hypersensitivity to penicillins for immune-mediated
hypersensitivity—see Types of antimicrobial hypersensitivity. Perform desensitisation, if possible, for patients
with immediate penicillin hypersensitivity—seek expert advice. For patients who cannot be desensitised,
including those with delayed penicillin hypersensitivity, seek expert advice for alternative treatment. Do not use
tetracyclines in pregnant women or neonates. Macrolides do not reliably cross the placenta, and erythromycin and
azithromycin therapy has failed to prevent congenital syphilis.
Treatment for early syphilis during the second half of pregnancy carries a risk of premature labour and fetal
compromise, if treatment precipitates a Jarisch–Herxheimer reaction. Therefore, after treatment, advise women
that if they notice fever, contractions or a reduction in fetal movement, they need urgent obstetric review.
If syphilis is diagnosed during the second half of pregnancy, perform an ultrasound to evaluate the fetus for signs
of congenital syphilis. Do not delay antibiotic therapy to perform the ultrasound. The risk syphilis treatment failure
in the fetus is higher if the ultrasound shows fetal hepatomegaly, ascites, hydrops, polyhydramnios, fetal anaemia
or placental thickening—seek advice from an obstetrician with expertise in the management of congenital syphilis.
The risk of congenital syphilis is low if a mother with a positive serological test result or active syphilis received
adequate penicillin treatment 4 weeks or longer before delivery, her partner was adequately treated simultaneously,
and she was not re-infected.
Management of neonates born to mothers with syphilis
Thoroughly examine and investigate neonates of mothers with syphilis for congenital syphilis. If possible, perform
nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]) and silver stains on the placenta.
The diagnosis of congenital syphilis is suggested by any of the following:
abnormal clinical examination (features of congenital infection) with or without abnormal radiology (eg
long-bone X-ray or cranial ultrasound)
a positive Treponema pallidum-specific IgM test result
quantitative nontreponemal antibody titres (eg rapid plasma reagin [RPR] test) that are four-fold higher than
the mother’s titres
a positive nucleic acid amplification test result of mucosal lesion swabs or biopsy, tissue, cerebrospinal fluid
or placenta.
Treat neonates with suspected or confirmed congenital syphilis in consultation with an expert. For the treatment of
congenital syphilis in neonates, use:
benzylpenicillin 30 mg/kg intravenously, for 10 days

neonate 7 days or younger: 12-hourly
neonate older than 7 days: 8-hourly.
For more information about investigation and management of a neonate born to a mother with syphilis, see the
Australasian Society for Infectious Diseases (ASID) guideline Management of Perinatal Infections [URL].
Key references
Andrade R, Rodriguez-Barradas MC, Yasukawa K, Villarreal E, Ross M, Serpa JA. Single Dose Versus 3 Doses of
Intramuscular Benzathine Penicillin for Early Syphilis in HIV: A Randomized Clinical Trial. Clin Infect Dis
2017;64(6):759–764 .
ASHA. 2018. www.sti.guidelines.org.au/.
Ghanem KG. Management of Adult Syphilis: Key Questions to Inform the 2015 Centers for Disease Control and
Prevention Sexually Transmitted Diseases Treatment Guidelines. Clin Infect Dis 2015;61 Suppl 8:S818–S836
.
Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM. Doxycycline compared with benzathine penicillin for the
treatment of early syphilis. Clin Infect Dis 2006;42(6):e45–e49 .
Janier M, Hegyi V, Dupin N, Unemo M, Tiplica GS, Potočnik M, et al. 2014 European guideline on the management of
syphilis. J Eur Acad Dermatol Venereol 2014;28(12):1581–1593 .
Kingston M, French P, Higgins S, McQuillan O, Sukthankar A, Stott C, et al. UK national guidelines on the management
of syphilis 2015. Int J STD AIDS 2016;27(6):421–446 .
Li J, Zheng HY. Early syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin. J
Infect Dev Ctries 2014;8(2):228–232 .
Macy E, Romano A, Khan D. Practical Management of Antibiotic Hypersensitivity in 2017. J Allergy Clin Immunol Pract
2017;5(3):577–586 .
Rac MW, Revell PA, Eppes CS. Syphilis during pregnancy: a preventable threat to maternal-fetal health. Am J Obstet
Gynecol 2017;216(4):352–363 .
Tong ML, Lin LR, Liu GL, Zhang HL, Zeng YL, Zheng WH, et al. Factors associated with serological cure and the
serofast state of HIV-negative patients with primary, secondary, latent, and tertiary syphilis. PLoS One
2013;8(7):e70102. .
Tsai JC, Lin YH, Lu PL, Shen NJ, Yang CJ, Lee NY. Comparison of serological response to doxycycline versus
benzathine penicillin G in the treatment of early syphilis in HIV-infected patients: a multi-center observational study.
PLoS One 2014;9(10):e109813. .
Wong T, Singh AE, De P. Primary syphilis: serological treatment response to doxycycline/tetracycline versus
benzathine penicillin. Am J Med 2008;121(10):903–908 .
Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep
2015;64(RR-03):1–137 .
World Health Organization (WHO). WHO Guidelines for the Treatment of Treponema pallidum (Syphilis). Geneva,
Switzerland: WHO Press; 2016. .
Urethritis
Aetiology and assessment of urethritis
Urethritis is characterised by urethral irritation, dysuria or discharge. The most common bacterial causes of
urethritis are Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium. Other pathogens
include adenoviruses, herpes simplex virus and occasionally, Trichomonas vaginalis. In 50% or more of cases, no
pathogen is identified.
Collect a first-void urine sample for nucleic acid amplification testing (NAAT) (eg polymerase chain reaction
[PCR]) for C. trachomatis, N. gonorrhoeae and M. genitalium. Do not culture for Ureaplasma urealyticum or
Mycoplasma hominis when investigating urethritis [Note 1].
If urethral discharge is present, collect discharge on a swab for Gram stain and culture of N. gonorrhoeae for
susceptibility testing. Culture and susceptibility testing is important for N. gonorrhoeae because antimicrobial
resistance is emerging and most nucleic acid amplification tests do not detect antimicrobial resistance.
Gonococcal and chlamydial urethritis are commonly associated with extragenital (anorectal, pharyngeal) infection,
especially in men who have sex with men (MSM). As appropriate, test these sites and choose treatment
accordingly.
counselling, and considerations for children in whom an STI is identified, see Principles of sexually transmitted
Note 1: U. urealyticum, U. parvum and M. hominis are part of the normal genital flora. Treatment is not required if these organisms are identified from
a urethral swab.
Treatment of urethritis
Choice of empirical antibiotic therapy for urethritis
The choice of antibiotic therapy for urethritis depends on whether gonococcal infection is suspected.
If available, urgent microscopy of a stained urethral smear can distinguish gonococcal from nongonococcal
urethritis.
Gonococcal urethritis typically presents with a purulent discharge within a few days of acquisition, and is more
common in:
men who have sex with men (MSM)

people who have recently had sex with a new partner in a country with a high prevalence of gonorrhoea (eg
developing countries)
remote Aboriginal and Torres Strait Islander populations.
If gonococcal urethritis is suspected on clinical grounds (ie the patient has purulent urethral discharge), do not wait
for the results of investigations; treat immediately to prevent complications and further transmission—see
Treatment of suspected gonococcal urethritis.
If clinical assessment does not suggest gonorrhoea or it is not possible to distinguish nongonococcal urethritis from
gonococcal urethritis, see Treatment of suspected nongonococcal urethritis.
Treatment of suspected gonococcal urethritis

If gonococcal urethritis is suspected, do not wait for the results of investigations; treat immediately to prevent
complications and further transmission. Use:

PLUS
In areas where penicillin-resistant Neisseria gonorrhoeae is less common (mainly in some remote areas of
northern and central Australia), use:
amoxicillin 3 g orally, as a single dose
PLUS
probenecid 1 g orally, as a single dose
PLUS
Do not use the amoxicillin-based regimen for patients who have a pharyngeal or anorectal co-infection; use
ceftriaxone plus azithromycin (as above).
Quinolone resistance is widespread—do not use ciprofloxacin unless a susceptible infection is identified.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use ceftriaxone plus
azithromycin (as above).
See also Approach to Neisseria gonorrhoeae infection for information on additional testing and contact tracing.
Treatment of suspected nongonococcal urethritis
For the treatment of suspected or confirmed nongonococcal urethritis, use:
OR for patients likely to be nonadherent to doxycycline
2 azithromycin 1 g orally, as a single dose.
If it is not possible to distinguish nongonococcal urethritis from gonococcal urethritis, add ceftriaxone to the
above regimen. Use:

a single dose [Note 3].
Doxycycline is the preferred drug for nongonococcal urethritis because of increasing macrolide resistance in
Mycoplasma genitalium and because it is marginally more effective for the treatment of chlamydial urethritis. Both
doxycycline and azithromycin are generally effective against Chlamydia trachomatis. Although neither is
sufficient to eradicate most M. genitalium infections, they may reduce bacterial load and increase the likelihood of
cure by subsequent therapy for M. genitalium.
Modify therapy according to the results of investigations.
If N. gonorrhoeae is identified, see Approach to Neisseria gonorrhoeae infection for additional treatment (if
necessary), information on additional testing (including test of cure) and contact tracing.
If C. trachomatis is identified, finish the regimen for nongonococcal urethritis; further treatment is not required.
For information on additional testing (including test of cure) and contact tracing, see Approach to Chlamydia
trachomatis infection.
If M. genitalium is identified, the need for and choice of additional treatment depends on results of susceptibility
testing, the initial treatment regimen (doxycycline or azithromycin) and whether the man has sex with men. For
information on additional testing (including test of cure) and contact tracing, see Approach to Mycoplasma
genitalium infection.
If doxycycline was used for empirical therapy of infection caused by M. genitalium, additional treatment is
generally required once the doxycycline regimen has been completed. For men who have sex with men (if
macrolide susceptibility is confirmed), or for heterosexual men (if macrolide susceptibility is unknown or
confirmed with susceptibility testing), use:
azithromycin 1 g orally on the first day, then 500 mg daily for 3 days.
If doxycycline was used for empirical therapy of infection caused by M. genitalium and macrolide resistance is
confirmed with susceptibility testing, or for men who have sex with men (if results of susceptibility testing are not
available), use:
If azithromycin was used for empirical therapy of infection caused by M. genitalium, for men who have sex with
men (if macrolide susceptibility is confirmed), or for heterosexual men (if macrolide susceptibility is unknown or
confirmed with susceptibility testing), further treatment is not required, but a test of cure is recommended after at
least 3 weeks. However, if macrolide resistance is confirmed with susceptibility testing, or for men who have sex
with men (if results of susceptibility testing are not available), use:
doxycycline 100 mg orally, 12-hourly for 7 days
FOLLOWED BY
Persistent urethritis symptoms despite treatment
If urethritis symptoms persist or worsen despite treatment, consider:
an alternative pathogen (such as viral urethritis if dysuria is prominent)

infection with a resistant pathogen
nonadherence to therapy
reinfection; the index case and sexual partners may require retreatment
the timeframe; it may take a few weeks for symptoms to completely resolve after successful treatment.
Key references
Bjornelius E, Magnusson C, Jensen JS. Mycoplasma genitalium macrolide resistance in Stockholm, Sweden. Sex
Transm Infect 2017;93(3):167–8.
Guschin A, Ryzhikh P, Rumyantseva T, Gomberg M, Unemo M. Treatment efficacy, treatment failures and selection of
macrolide resistance in patients with high load of Mycoplasma genitalium during treatment of male urethritis with
josamycin. BMC Infect Dis 2015;15:40.
Horner PJ, Blee K, Falk L, van der Meijden W, Moi H. 2016 European guideline on the management of non-
gonococcal urethritis. Int J STD AIDS 2016;27(11):928–37.
Jensen JS, Bradshaw C. Management of Mycoplasma genitalium infections - can we hit a moving target? BMC Infect
Dis 2015;15:343.
Khosropour CM, Manhart LE, Colombara DV, Gillespie CW, Lowens MS, Totten PA, et al. Suboptimal adherence to
doxycycline and treatment outcomes among men with non-gonococcal urethritis: a prospective cohort study. Sex
Transm Infect 2014;90(1):3–7.
Kong FY, Tabrizi SN, Law M, Vodstrcil LA, Chen M, Fairley CK, et al. Azithromycin versus doxycycline for the
treatment of genital chlamydia infection: a meta-analysis of randomized controlled trials. Clin Infect Dis
2014;59(2):193–205.
Rep 2017;41(1):E.
Lau A, Bradshaw CS, Lewis D, Fairley CK, Chen MY, Kong FY, et al. The efficacy of azithromycin for the treatment of
genital Mycoplasma genitalium: A systematic review and meta-analysis. Clin Infect Dis 2015;61(9):1389–99.
Manhart LE, Gillespie CW, Lowens MS, Khosropour CM, Colombara DV, Golden MR, et al. Standard treatment
regimens for nongonococcal urethritis have similar but declining cure rates: a randomized controlled trial. Clin Infect
Dis 2013;56(7):934–42.
Manhart LE, Jensen JS, Bradshaw CS, Golden MR, Martin DH. Efficacy of antimicrobial therapy for Mycoplasma
genitalium Infections. Clin Infect Dis 2015;61 Suppl 8:S802–17.
Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global estimates of the prevalence
and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting.
PLoS One 2015;10(12):e0143304.
Schwebke JR, Rompalo A, Taylor S, Sena AC, Martin DH, Lopez LM, et al. Re-evaluating the treatment of
nongonococcal urethritis: emphasizing emerging pathogens--a randomized clinical trial. Clin Infect Dis 2011;52(2):163–
70.
Sena AC, Lensing S, Rompalo A, Taylor SN, Martin DH, Lopez LM, et al. Chlamydia trachomatis, Mycoplasma
genitalium, and Trichomonas vaginalis infections in men with nongonococcal urethritis: predictors and persistence after
therapy. J Infect Dis 2012;206(3):357–65.
Vulvovaginitis
Aetiology and assessment of vulvovaginitis
The two most common microbial causes of vulvovaginitis in women are bacterial vaginosis (BV) and candidiasis.
Bacterial vaginosis causes an offensive smelling discharge, whereas candidiasis causes itch, sometimes pain, and
often a red rash on the vulva.
When assessing vulvovaginitis, consider diagnoses other than bacterial vaginosis and candidiasis; such as:
the presence of a retained foreign body (eg toilet tissue, tampon, condom)
irritation (eg from over washing)
dermatoses
atrophic vaginitis
Trichomonas vaginalis.
In addition to the above, in prepubertal girls, other diagnoses to consider are:
infection with Streptococcus species, or rarely, Staphylococcus, Haemophilus and Shigella species
threadworm infection
sexually transmitted pathogens in cases of sexual abuse (see STIs in infants and children).
Increased cervical mucus production is a common cause of vaginal discharge, particularly in females taking oral
contraceptives. This does not require treatment.
Microscopy of a vaginal smear is key to the diagnosis of bacterial vaginosis and candidiasis. Culture adds little
value to microscopy because many organisms identified by culture are commonly present in low numbers in
healthy vaginal flora.
Candida species colonisation is common in women and treatment is not required unless there are symptoms
of vulvovaginitis. If yeasts or pseudohyphae are absent on vaginal microscopy, consider an alternative
diagnosis. For the management of candidal vulvovaginitis, see Candidal vulvovaginitis in women.
Gardnerella vaginalis has been associated with bacterial vaginosis. However, treatment is not required
unless there are symptoms and microscopic evidence of bacterial vaginosis.
Mycoplasma hominis and Ureaplasma species are common commensal organisms in sexually active women.
Treatment is not required.
Streptococcus agalactiae (group B streptococcus [GBS]) is a commensal organism of the gastrointestinal
and genital tracts in up to 30% of healthy women of childbearing age. Although group B streptococcus has
been associated with symptomatic vulvovaginitis, other causes of vulvovaginitis are more common. Other
than in pregnancy, it is generally an incidental finding. If group B streptococcus is identified in a pregnant
woman, see Prevention of neonatal Streptococcus agalactiae (group B streptococcus) disease.
Bacterial vaginosis
Aetiology and assessment of bacterial vaginosis
Bacterial vaginosis (BV) is a polymicrobial syndrome caused by a reduction of the hydrogen peroxide–producing
Lactobacillus species in the vagina, and overgrowth of anaerobic (eg Mobiluncus species) and other fastidious
bacteria (including Gardnerella vaginalis and Atopobium vaginae). Although it is a common cause of malodorous
vaginal discharge, around 50% of women with bacterial vaginosis are asymptomatic.
Microscopy of a vaginal smear is key to the diagnosis of bacterial vaginosis. Culture is not required because many
organisms identified by culture are commonly present in low numbers in healthy vaginal flora.
The Amsel criteria can be used to diagnose bacterial vaginosis; three of the following features must be present:
thin, white, homogeneous discharge

vaginal fluid pH more than 4.5
clue cells (epithelial cells covered with small curved coccobacilli and mixed flora) visualised on a wet
preparation of a vaginal swab or Gram-stained smear
fishy odour when adding alkali (potassium hydroxide 10%) to discharge.
Treatment of bacterial vaginosis

For treatment of symptomatic bacterial vaginosis in women, use:
1 metronidazole 400 mg orally, 12-hourly for 7 days
OR
1 metronidazole 0.75% vaginal gel, 1 applicatorful intravaginally, at bedtime for 5 nights
OR
2 clindamycin 2% vaginal cream, 1 applicatorful intravaginally, at bedtime for 7 nights
OR
2 clindamycin 300 mg orally, 12-hourly for 7 days
OR
3 metronidazole 2 g orally, as a single dose
OR
3 tinidazole 2 g orally, as a single dose.
Single-dose metronidazole and tinidazole regimens have better adherence than extended treatments; however, the
cure rate is lower for these regimens, and retreatment may be necessary. Use treatment regimens with a longer
duration for recurrent infection.
Clindamycin is preferred in women who are pregnant; oral clindamycin can be used at any stage of pregnancy.
Alternatively, for pregnant women before 20 weeks’ gestation, clindamycin 2% vaginal cream can be used. If
clindamycin is not suitable, use either of the multiple-day metronidazole regimens above.
Contact tracing is not required; however, for patients with an ongoing female sexual partner, assess the partner for
bacterial vaginosis. Treatment of ongoing male sexual partners is currently not recommended; however, clinical
trials are ongoing.
Key references
Arya OP, Tong CY, Hart CA, Pratt BC, Hughes S, Roberts P, et al. Is Mycoplasma hominis a vaginal pathogen? Sex
Transm Infect 2001;77(1):58–62.
Menard J-P. Antibacterial treatment of bacterial vaginosis: current and emerging therapies. Int J Womens Health
2011;3:295–305.
Oduyebo OO, Anorlu RI, Ogunsola FT. The effects of antimicrobial therapy on bacterial vaginosis in non-pregnant
women. Cochrane Database Syst Rev 2009;(3):CD006055.
Human immunodeficiency virus infection
What is covered in this topic?
This topic focuses on HIV pre-exposure prophylaxis (PrEP), and treatment of HIV infection in adults. It covers
benefits of antiretroviral therapy, an overview of commonly used antiretroviral drugs, recommendations for initial
antiretroviral therapy, and how patients are monitored during treatment. Management of HIV infection in
pregnant women and antiretroviral prophylaxis for neonates are also included in the topic.
This topic is not a comprehensive HIV management guide. See the Australian and international guidelines listed in
Further reading. The Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine website provides
resources and training for clinicians about HIV management and prevention.
For HIV postexposure prophylaxis (PEP), see Management of suspected or confirmed exposure to HIV.
Diagnosis and management of HIV in children requires consultation with a paediatric HIV or infectious diseases
physician. See also the paediatric HIV guidelines listed in Further reading.
For an overview of management of opportunistic and co-infections in adults with HIV infection, see Opportunistic
and co-infections in adults with HIV infection.
Benefits of antiretroviral therapy for HIV infection

Antiretroviral treatment of a person infected with HIV has the following benefits:
individual health benefit—reduction in HIV-associated morbidity and mortality, and improved quality of life
prevention of HIV transmission to sexual partners (also known as ‘treatment as prevention’)
prevention of HIV transmission from a mother to her baby.
Antiretroviral therapy taken by a person who is not infected with HIV reduces his or her risk of acquiring HIV
infection—this is termed pre-exposure antiretroviral prophylaxis (PrEP). Postexposure prophylaxis (PEP) can be
given after exposure to an HIV-infected source (see Management of suspected or confirmed exposure to HIV).
People who are provided with nonoccupational postexposure prophylaxis should be assessed for suitability for
PrEP.
Indications for HIV pre-exposure prophylaxis (PrEP)

Overview
Pre-exposure prophylaxis (PrEP), taken daily, reduces the risk of HIV infection. PrEP is recommended for people
at high risk of HIV infection. It should be considered for people at medium risk of HIV infection. If the person
does not meet the criteria for high risk or medium risk, HIV PrEP can also be considered on a case-by-case basis
if the clinician assesses the person as likely to be at high risk of HIV infection based on a complete sexual history,
a complete alcohol and other drug use history, and the personal circumstances of the individual.
Perform a risk assessment to determine the risk of HIV infection, according to the following patient groups:
men who have sex with men

transgender and gender diverse people
heterosexual people
people who inject drugs.
The level of risk is determined by the person’s recent and sustained risk of HIV infection.
For antiretroviral regimens for PrEP and considerations before starting therapy, see Antiretroviral therapy for pre-
exposure prophylaxis (PrEP).
Men who have sex with men
High risk
HIV PrEP is recommended for men who have sex with men who are at high risk of HIV infection, defined as
having both:
sustained risk of exposure to HIV—being likely to have multiple episodes of condomless anal intercourse
in the next 3 months; and
recent risk of HIV exposure—any of the following:
at least one episode of condomless anal intercourse with a regular HIV-positive partner (not on
treatment, or on treatment with a detectable viral load) in the last 3 months
at least one episode of receptive condomless anal intercourse with any casual HIV-positive male
partner or a male partner of unknown HIV status in the last 3 months
a diagnosis of rectal infection with Neisseria gonorrhoeae, Chlamydia trachomatis or syphilis during
the last 3 months or at screening for PrEP
metamfetamine use in the last 3 months.
When assessing sustained risk of HIV exposure, also ask whether the person shares intravenous drug equipment
(see People who inject drugs).
Medium risk
Consider HIV PrEP for men who have sex with men who are at medium risk of HIV infection, defined as having
both:
sustained risk of exposure to HIV—being likely to have multiple episodes of condomless anal intercourse
more than one episode of anal intercourse without proper condom use (eg condom slipped off or split)
with a partner of unknown HIV status, or HIV-positive partner (not on treatment or on treatment with
a detectable viral load) in the last 3 months
men who are uncircumcised and have had more than one episode of insertive condomless anal
intercourse with a partner of unknown HIV status, or HIV-positive partner (not on treatment or on
treatment with a detectable viral load) in the last 3 months.
Transgender and gender diverse people
High risk
HIV PrEP is recommended for transgender and gender diverse people at high risk of HIV infection, defined as
having both:
sustained risk of exposure to HIV—being likely to have multiple episodes of condomless anal or vaginal
intercourse in the next 3 months; and
being a regular sexual partner of an HIV-positive person (not on treatment, or on treatment with a
detectable viral load) with whom condoms have not been consistently used in the last 3 months
at least one episode of receptive condomless intercourse with any casual HIV-positive partner or a
male partner of unknown HIV status in the last 3 months
diagnosed with rectal or vaginal infection with Neisseria gonorrhoeae, Chlamydia trachomatis or
syphilis during the last 3 months or at screening for PrEP
metamfetamine use in the last 3 months.
Medium risk
Consider HIV PrEP for transgender and gender diverse people at medium risk of HIV infection, defined as having
both:
more than one episode of anal or vaginal intercourse without proper condom use (eg condom slipped
off or split) with a partner of unknown HIV status, or HIV-positive partner (not on treatment, or on
treatment with a detectable viral load) in the last 3 months
people with an uncircumcised penis who have had more than one episode of insertive condomless anal
intercourse with a partner of unknown HIV status, or HIV-positive partner (not on treatment, or on
treatment with a detectable viral load) in the last 3 months.
Heterosexual people
High risk
HIV PrEP is recommended for heterosexual people at high risk of HIV infection, defined as having both:
being a regular sexual partner of an HIV-positive person (not on treatment, or on treatment with a
detectable viral load) with whom condoms have not been consistently used in the last 3 months
at least one episode of receptive anal or vaginal condomless intercourse with any casual HIV-positive
partner or a male homosexual or bisexual partner of unknown HIV status in the last 3 months.
Women with an HIV-positive male partner who are planning natural conception in the next 3 months are also
considered to be at high risk of HIV infection—HIV PrEP is recommended.
Medium risk
HIV PrEP should be considered for heterosexual people at medium risk of HIV infection, defined as having both:
intercourse with a heterosexual partner (not known to be HIV positive but at high risk of being HIV positive)
recent risk of HIV exposure—at least one episode of condomless anal or vaginal intercourse with a
heterosexual partner of unknown HIV status from a country with high HIV prevalence in the last 3 months.
People who inject drugs
High risk
HIV PrEP is recommended for people who inject drugs who are at high risk of HIV infection, defined as having
both:
sustained risk of exposure to HIV—any of the following:

being likely to share injecting equipment multiple times with an HIV-positive individual or a
homosexual or bisexual man of unknown HIV status in the next 3 months
inadequate access to safe injecting equipment in the next 3 months, and
recent risk of HIV exposure—have shared injecting equipment with an HIV-positive individual or with a
homosexual or bisexual man of unknown HIV status in the last 3 months.
Antiretroviral therapy for HIV pre-exposure prophylaxis (PrEP)

Pre-exposure prophylaxis (PrEP), taken daily, reduces the risk of HIV infection. For indications for PrEP, see
Indications for HIV PrEP.
Before prescribing HIV PrEP:
Perform baseline testing for HIV, hepatitis B and C virus, sexually transmitted infections (see Investigations
for STIs), kidney function (including protein-to-creatinine ratio) and pregnancy (if applicable).
Provide advice about reducing the risk of HIV and sexually transmitted infections.
Assess the person’s need for HIV postexposure prophylaxis (PEP) if exposure to HIV may have occurred in
the previous 72 hours (see Management of suspected or confirmed exposure to HIV).
Ensure the patient can attend for regular follow-up (eg at least every 3 months).
For detailed information on prescribing HIV PrEP, see the Australasian Society for HIV, Viral Hepatitis and Sexual
Health Medicine HIV Pre-exposure Prophylaxis: Clinical Guidelines [URL].
For HIV PrEP in a patient at high or medium risk of HIV infection (see Indications for HIV PrEP), use [Note 1]:
1 tenofovir disoproxil fumarate+emtricitabine (Truvada) 300 mg+200 mg orally, daily
OR
1 tenofovir disoproxil maleate+emtricitabine (Tenofovir Disoproxil Emtricitabine Mylan

300/200) 300 mg+200 mg orally, daily
OR
1 tenofovir disoproxil phosphate+emtricitabine (Tenofovir EMT GH) 291 mg+200 mg

orally, daily.
‘On-demand’ (ie intermittent) PrEP regimens can be considered for certain patient groups—seek expert advice.
Note 1: Brand names are examples only; other brands may be available.
When to start antiretroviral therapy to treat HIV infection

Antiretroviral therapy reduces morbidity and mortality regardless of CD4 cell count, so it is recommended for all
people with HIV infection. For more detailed information, see the Australian and international HIV treatment
guidelines listed in Further reading.
In patients with newly diagnosed HIV, exclude other infections (see Before starting antiretroviral therapy for HIV
infection). For patients without opportunistic or co-infections, start antiretroviral therapy as soon as possible. See
Opportunistic and co-infections in adults with HIV for advice on when to start antiretroviral therapy in patients
with other infections.
Once started, treatment should be continued indefinitely without interruption, unless oral therapy cannot be taken
or severe toxicity develops.
Before starting antiretroviral therapy for HIV infection

Antiretroviral drug choice and monitoring depend on comorbidities, the potential for metabolic and other adverse
effects, co-administered drugs and social factors. Appropriate tests to perform before starting antiretroviral therapy
are listed in Box 2.7.
Immune reconstitution inflammatory syndrome (IRIS) is the development of an inflammatory reaction to latent or
subclinical infection with organisms such as Mycobacterium avium complex, Mycobacterium tuberculosis,
Cryptococcus neoformans, cytomegalovirus or varicella-zoster virus. IRIS can occur shortly after starting any
combination antiretroviral regimen, especially in patients with a low CD4 count (less than 100 cells/microlitre).
Ensure opportunistic infections are excluded and that appropriate screening for specific organisms occurs before
starting antiretroviral therapy (see Box 2.7).
Appropriate tests before starting antiretroviral therapy in Australia (Box 2.7)
The following tests, performed during initial patient visits, can be used to stage HIV disease and assist in the
selection or timing of commencement of antiretroviral therapy:
HIV antibody/antigen (if previous results are not available or if HIV RNA is below the assay’s limit of
detection)
CD4 cell count
plasma HIV RNA (viral load)
HIV genotypic resistance as soon as possible after diagnosis (viral amplification for resistance testing is
not always successful if HIV RNA is less than 1000 copies/mL)
HLA-B*5701 allele if treatment with abacavir is being considered (see Table 2.12 for further information)
hepatitis B and C virus serology
full blood count, serum electrolytes, serum phosphate, liver biochemistry, serum creatinine, estimated
glomerular filtration rate (eGFR), and urine protein
fasting blood glucose and serum lipids
serum cryptococcal antigen if CD4 cell count is less than 100 cells/microlitre
tests to exclude opportunistic and co-infections if the patient is symptomatic.
Newly diagnosed patients need additional tests that are not specifically related to starting antiretroviral therapy;
see the guidelines in Further reading for details.
Contact tracing (partner notification) is required when a patient is diagnosed with HIV infection and other sexually
transmitted infections. For details, see Contact tracing for STIs.
Overview of antiretroviral drugs for HIV infection in adults

At the time of writing, the classes of antiretroviral drugs available for treatment of HIV infection are:
nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)—abacavir, didanosine, emtricitabine,

lamivudine, stavudine, tenofovir alafenamide, tenofovir disoproxil fumarate, tenofovir disoproxil maleate,
tenofovir disoproxil phosphate and zidovudine
non-nucleoside reverse transcriptase inhibitors (NNRTIs)—efavirenz, etravirine, nevirapine and
rilpivirine
protease inhibitors (PIs)—atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, saquinavir
and tipranavir
integrase strand transfer inhibitors (INSTIs)—bictegravir, dolutegravir, elvitegravir and raltegravir
fusion inhibitors—enfuvirtide
entry inhibitors—maraviroc.
The boosting drugs cobicistat and ritonavir are cytochrome P450 inhibitors used to increase the plasma
concentrations of PIs, and the INSTI elvitegravir.
The antiretrovirals used for initial therapy are described in Initial antiretroviral therapy for HIV infection in adults.
Other antiretrovirals are reserved for use in resistant HIV infection or when patients are unable to tolerate standard
therapy.
At least three antiretroviral drugs are needed for initial therapy. Single-tablet once-daily combination products
containing three antiretroviral drugs (ie the complete antiretroviral regimen) improve adherence; products
currently available in Australia are listed in Table 2.9. Products containing one or two antiretroviral drugs (listed in
Table 2.10) need to be taken in combination for initial therapy, so are not as convenient for the patient.
Once viral suppression is achieved, some patients can change to a two-drug maintenance regimen—seek expert
advice. Some products listed in Table 2.10 can be used for this two-drug maintenance regimen.
The antiretroviral regimens listed in Table 2.11 are not routinely used for treatment of HIV infection due to pill
burden, adverse effects or drug resistance. Seek expert advice for management of patients on these regimens.
Practice points for initial antiretroviral therapy are listed in Table 2.12. For information about changing
antiretroviral therapy, see Changing antiretroviral therapy for HIV infection.
Single-tablet once-daily combination products containing three antiretroviral drugs (Table 2.9)
[NB1]
Brand name examples Antiretroviral drugs

NRTI plus INSTI products
Biktarvy tenofovir alafenamide+emtricitabine+bictegravir
Genvoya tenofovir alafenamide+emtricitabine+elvitegravir+cobicistat [NB2]
Stribild tenofovir disoproxil fumarate+emtricitabine+elvitegravir+cobicistat [NB2]
Triumeq dolutegravir+abacavir+lamivudine
NRTI plus NNRTI products
Atripla tenofovir disoproxil fumarate+emtricitabine+efavirenz
Eviplera tenofovir disoproxil fumarate+emtricitabine+rilpivirine
Odefsey emtricitabine+rilpivirine+tenofovir alafenamide
INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside/nucleotide reverse transcriptase
inhibitor
NB1: This table includes products available in Australia at the time of writing. Other brands may be available.
NB2: Cobicistat is not an antiretroviral drug; it is a cytochrome P450 3A4 inhibitor used to increase the plasma concentration of elvitegravir.
Commonly used combination products containing one or two antiretroviral drugs (Table 2.10)
[NB1]
Brand name examples Antiretroviral drugs

Dual-NRTI products
Descovy emtricitabine+tenofovir alafenamide
Kivexa abacavir+lamivudine
Truvada tenofovir disoproxil fumarate+emtricitabine [NB2]
Tenofovir Disoproxil
tenofovir disoproxil maleate+emtricitabine [NB2]
Emtricitabine Mylan 300/200
Tenofovir EMT GH tenofovir disoproxil phosphate+emtricitabine [NB2]
INSTI plus NNRTI products
Juluca [NB3] dolutegravir+rilpivirine
PI plus cobicistat products [NB4]
Evotaz atazanavir+cobicistat
Prezcobix darunavir+cobicistat
INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside/nucleotide reverse transcriptase
inhibitor; PI = protease inhibitor
NB1: This table includes products available in Australia at the time of writing that are usually taken in combination to ensure at least three drugs are used
for initial therapy. Other combination products and brands may be available.
NB2: Tenofovir disoproxil salts (tenofovir disoproxil fumarate, tenofovir disoproxil maleate and tenofovir disoproxil phosphate) are bioequivalent.
NB3: Juluca can be used as a two-drug maintenance regimen (ie the complete regimen) in select patients with a suppressed viral load.
NB4: Cobicistat is not an antiretroviral drug; it is a cytochrome P450 3A4 inhibitor used to increase the plasma concentration of atazanavir and
darunavir.
Antiretroviral drugs not routinely used for treatment of HIV infection in Australia (Table 2.11)
[NB1]
Antiretroviral drugs Combination products (brand name examples)

NRTIs
didanosine
abacavir+lamivudine+zidovudine (Trizivir)
stavudine
lamivudine+zidovudine (Combivir)
zidovudine
PIs
fosamprenavir
indinavir
lopinavir lopinavir+ritonavir (Kaletra)
saquinavir
tipranavir
Fusion inhibitors
enfuvirtide -
Entry inhibitors
maraviroc -
NRTIs = nucleoside/nucleotide reverse transcriptase inhibitors; PIs = protease inhibitors
NB1: This table includes products currently available in Australia at the time of writing. Other products and brands may be available.
Initial antiretroviral therapy for HIV infection in adults

At least three drugs are needed for initial antiretroviral therapy. Once viral suppression is achieved, some patients
can change to a two-drug maintenance regimen—seek expert advice.
First-line initial HIV therapy is currently a combination of two nucleoside/nucleotide reverse transcriptase
inhibitors (NRTIs) and an integrase strand transfer inhibitor (INSTI). Specific regimens are used to treat HIV and
hepatitis B virus co-infection—see below. Single-tablet once-daily combination products containing three
antiretroviral drugs improve adherence.
Ensure opportunistic infections are excluded and that appropriate screening for specific organisms occurs before
starting antiretroviral therapy (see Box 2.7). If antiretroviral drug resistance is detected, seek expert advice.
When prescribing antiretroviral combination products, carefully check the product (including ingredients and
strengths), practice points for safe prescribing (see Table 2.12), and whether drug interactions are possible (see
Antiretroviral drug interactions).
For INSTI-based initial antiretroviral therapy in adults, use [Note 2]:
1 dolutegravir+abacavir+lamivudine (Triumeq) 50 mg+600 mg+300 mg orally, daily. For

practice points for initiation of therapy, see Table 2.12 [Note 3]
OR
1 tenofovir alafenamide+emtricitabine+bictegravir (Biktarvy) 25 mg+200 mg+50 mg orally,

daily. For practice points for initiation of therapy, see Table 2.12
OR
1 tenofovir alafenamide+emtricitabine+elvitegravir+cobicistat (Genvoya) 10 mg+200

mg+150 mg+150 mg orally, daily. For practice points for initiation of therapy, see Table
2.12.
If the above regimens are not suitable, the following regimens are also effective as initial therapy. In adults, use
[Note 2]:
emtricitabine+tenofovir alafenamide (Descovy) 200 mg+25 mg orally, daily. For practice

points for initiation of therapy, see Table 2.12
PLUS EITHER
1 dolutegravir (Tivicay) 50 mg orally, daily. For practice points for initiation of therapy, see
Table 2.12
OR
1 raltegravir (Isentress HD) 1200 mg orally, daily. For practice points for initiation of
therapy, see Table 2.12.
If therapy with an INSTI-based regimen is not suitable, other effective combinations for initial therapy include two
NRTIs plus either a boosted protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI).
For PI-based initial antiretroviral therapy in adults, use [Note 2]:
darunavir+cobicistat (Prezcobix) 800 mg+150 mg orally, daily. For practice points for
initiation of therapy, see Table 2.12
PLUS EITHER
1 abacavir+lamivudine (Kivexa) 600 mg+300 mg orally, daily. For practice points for
initiation of therapy, see Table 2.12
OR
1 emtricitabine+tenofovir alafenamide (Descovy) 200 mg+10 mg orally, daily. For practice
points for initiation of therapy, see Table 2.12.
For NNRTI-based initial antiretroviral therapy in adults, use [Note 2]:
emtricitabine+rilpivirine+tenofovir alafenamide (Odefsey) 200 mg+25 mg+25 mg orally,

daily. For practice points for initiation of therapy, see Table 2.12.
For HIV and hepatitis B virus co-infection, use a regimen containing emtricitabine plus tenofovir alafenamide or
a tenofovir disoproxil salt. Seek expert advice for management of patients with HIV or hepatitis B strains that are
resistant to these drugs, and patients in whom resistance is suspected due to previous antiviral therapy. INSTI-
based single-tablet once-daily combination products suitable for HIV and hepatitis B co-infection include [Note 2]:
1 tenofovir alafenamide+emtricitabine+bictegravir (Biktarvy) 25 mg+200 mg+50 mg orally,

daily. For practice points for initiation of therapy, see Table 2.12
OR
1 tenofovir alafenamide+emtricitabine+elvitegravir+cobicistat (Genvoya) 10 mg+200

mg+150 mg+150 mg orally, daily. For practice points for initiation of therapy, see Table
2.12.
If these regimens are not suitable, any of the above regimens containing emtricitabine plus tenofovir alafenamide
also treat HIV and hepatitis B co-infection. If the patient cannot take tenofovir alafenamide or a tenofovir
disoproxil salt, do not use lamivudine or entecavir monotherapy to treat hepatitis B. For further information on
hepatitis B in patients with HIV infection, see Hepatitis B virus infection in adults with HIV infection.
For patients with HIV and hepatitis B co-infection who cannot take tenofovir alafenamide or a tenofovir disoproxil salt, do not
use lamivudine or entecavir monotherapy to treat hepatitis B.
For other antiretroviral regimens used for initial therapy, and for a detailed discussion about the relative merits of
various drug combinations, see the guidelines listed in Further reading.
Practice points for initial antiretroviral therapy (Table 2.12)
Antiretroviral drug Practice points [NB1]

Test for HLA-B*5701 allele before prescribing. Presence of HLA-B*5701 is highly
predictive of hypersensitivity, which can potentially be fatal. Do not prescribe unless
HLA-B*5701 allele test is negative. Reactions also occur rarely in absence of HLA-
B*5701. If hypersensitivity occurs, rechallenge is contraindicated.
abacavir Avoid in people with, or at high risk of, ischaemic heart disease.
Suitable for initial therapy in combination with dolutegravir in patients with any HIV
viral load. For patients with HIV viral load more than 100 000 copies/mL, seek
expert advice before prescribing abacavir with antiretroviral drugs other than
dolutegravir.
Associated with elevated serum creatinine concentration due to an effect on
bictegravir
creatinine secretion; however, does not reduce kidney function.
Significant drug interactions can occur (see Antiretroviral drug interactions).
cobicistat [NB2] Associated with elevated serum creatinine concentration due to an effect on
Always prescribed with the boosting drugs cobicistat or ritonavir.
An increased dosage is required for patients previously treated with a protease

darunavir inhibitor who have possible or proven darunavir resistance mutations (‘treatment
experienced’ patients).
Darunavir plus cobicistat is not recommended in pregnant women because this

regimen is less effective; seek expert advice for alternative regimens.
dolutegravir Associated with an increased risk of neural tube defects in an interim analysis of a
single study; further data are required to establish teratogenic risk in early pregnancy.
See the guidelines listed in Further reading for the latest advice.
elvitegravir Always coformulated with the boosting drug cobicistat.

Also treats hepatitis B virus. For patients with HIV and hepatitis B co-infection,
emtricitabine combine with tenofovir alafenamide or a tenofovir disoproxil salt. If therapy is
stopped, an acute exacerbation of hepatitis B can occur.
Also treats hepatitis B virus, but is not routinely recommended for HIV and hepatitis
lamivudine
B co-infection. If therapy is stopped, an acute exacerbation of hepatitis B can occur.
Can increase serum creatine kinase concentration. Monitor the patient for symptoms
raltegravir
of myopathy or rhabdomyolysis.

rilpivirine
Should be taken with a main meal for optimal absorption.
Only use rilpivirine for initial therapy if the HIV viral load is less than 100 000
copies/mL and CD4 count is more than 200 cells/microlitre.
Can be used as an alternative to cobicistat to increase the plasma concentration of
ritonavir some other antiretroviral drugs.

Tenofovir alafenamide is not interchangeable with tenofovir disoproxil formulations
—check the intended formulation carefully before prescribing.
Check kidney function before prescribing. Monitor kidney function for patients
taking a tenofovir-based regimen (see Monitoring antiretroviral therapy for HIV
infection).
tenofovir alafenamide Dosing depends on the antiretroviral regimen used—check carefully before
prescribing.
Also treats hepatitis B virus. For patients with HIV and hepatitis B co-infection,
combine with emtricitabine. If therapy is stopped, an acute exacerbation of hepatitis
B can occur.
If tenofovir alafenamide is not suitable (eg because of drug interactions), tenofovir

disoproxil fumarate, tenofovir disoproxil maleate or tenofovir disoproxil phosphate
can be used instead.
Tenofovir disoproxil fumarate, tenofovir disoproxil maleate and tenofovir disoproxil
phosphate are bioequivalent. However, they are not interchangeable with tenofovir
alafenamide—check the intended formulation carefully before prescribing.
tenofovir disoproxil
fumarate Check kidney function before prescribing tenofovir disoproxil salts. Monitor kidney
function for patients taking a tenofovir-based regimen (see Monitoring antiretroviral
tenofovir disoproxil therapy for HIV infection).
maleate
Tenofovir disoproxil salts have a higher risk of kidney and bone toxicity than
tenofovir disoproxil tenofovir alafenamide.
phosphate
Tenofovir disoproxil salts also treat hepatitis B virus. For patients with HIV and
hepatitis B co-infection, combine with emtricitabine. If therapy is stopped, an acute
exacerbation of hepatitis B can occur.
NB1: Monitor patients taking antiretroviral drugs—see Monitoring antiretroviral therapy for HIV infection.
NB2: Cobicistat is not an antiretroviral drug; it is a cytochrome P450 3A4 inhibitor used to increase the plasma concentration of atazanavir, darunavir or
elvitegravir.
Note 2: Brand names are examples only; other brands may be available.
Note 3: Test for HLA-B*5701 allele before prescribing abacavir—see Table 2.12.
Antiretroviral drug interactions
Antiretroviral drugs, especially protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors
(NNRTIs), and boosting drugs (cobicistat and ritonavir) interact with many drugs (including other antiretroviral
drugs). The cytochrome P450 enzyme system is responsible for the metabolism of many antiretroviral drugs and is
the main mechanism of drug interactions. Interactions can also occur due to other mechanisms (eg reduced
absorption with acid-reducing drugs). Check for drug interactions before prescribing antiretroviral drugs for the
treatment or prevention of HIV infection, or when changing drug therapy for a person taking antiretrovirals.
Check for drug interactions before prescribing antiretroviral drugs, or when changing drug therapy for a person taking
antiretrovirals.
In addition to standard drug interaction references, consult specialised resources such as:
the University of Liverpool (UK) HIV Drug Interactions website

the University of California San Francisco (USA) Database of Antiretroviral Drug Interactions.
Monitoring antiretroviral therapy for HIV infection

Patients taking antiretroviral therapy require careful monitoring. Review patients 2 to 4 weeks after starting
treatment, then every 3 to 4 months if stable. The interval between reviews can be extended to 6 months for
adherent patients with suppressed viral load who are clinically and immunologically stable for more than 2 years.
Monitor:
clinical status and treatment adherence—some patients may need the support of a multidisciplinary team
HIV viral load—the viral load should fall at least 10-fold 4 to 6 weeks after starting antiretroviral therapy,
and to below 50 copies/mL after 3 to 6 months. Once the viral load has fallen below the level of detection,
measure the viral load every 3 to 6 months
CD4 cell count—check the CD4 cell count 3 months after starting antiretroviral therapy, then every 3 to 6
months; the count usually increases by 100 to 200 cells/microlitre after 12 months. For patients with a
suppressed HIV viral load and a CD4 count more than 200 cells/microlitre for 2 years or longer, measure
less frequently (eg every 12 months). For patients with a suppressed HIV viral load and a CD4 count more
than 500 cells/microlitre, further CD4 cell count monitoring is optional
toxicity of antiretroviral therapy—check full blood count, serum electrolytes, creatinine and liver
biochemistry at each scheduled visit [Note 4]. Recheck the creatinine level 4 weeks after starting drugs that
affect creatinine secretion (eg bictegravir, cobicistat, dolutegravir, rilpivirine) to establish a new baseline
creatinine. In patients taking tenofovir, check serum creatinine, urine protein-to-creatinine ratio, glycosuria
and serum phosphate every 3 months for the first year and then 6 to 12 monthly thereafter in people without
kidney disease or risk factors for kidney disease. Consider whether abnormalities could be due to
antiretroviral therapy, other drugs or disease
risk factors for cardiovascular disease [Note 5]—address behavioural risk factors (smoking, diet, exercise
—see Cardiovascular disease risk modification) and check blood pressure and weight regularly. Check
fasting blood glucose and lipid levels before and 3 to 6 months after starting therapy, and then every 12
months, or more frequently if abnormal
risk factors for osteoporosis—assess risk factors and manage accordingly (see Osteoporosis)
risk of cervical cancer—regularly screen all women with HIV infection for human papillomavirus.
Therapeutic drug monitoring for antiretroviral therapy is rarely indicated. For further information, see the
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine website.
Note 4: For patients taking nevirapine, monitor liver biochemistry after 2, 4 and 12 weeks of therapy, then every
3 months.
Note 5: Cardiovascular risk calculators for patients with HIV infection are available at [URL].
Changing antiretroviral therapy for HIV infection

Antiretroviral therapy should only be changed by a doctor with experience in HIV management.
Once viral suppression is achieved, some patients can change to a two-drug maintenance regimen.
For patients with a fully suppressed viral load who cannot tolerate the initial treatment regimen, it may be possible
to change a single drug in the regimen, provided resistance to the new drug was not detected on baseline testing.
For patients without a sustained viral load of less than 200 copies/mL (‘virological failure’), perform resistance
testing while the patient is still taking the failing regimen. Seek expert advice on selection of a new antiretroviral
regimen.
HIV infection in pregnancy

Introduction
The rate of mother-to-child transmission of HIV is less than 2% when effective prevention strategies are used.
These include antepartum antiretroviral treatment of pregnant women with HIV infection to achieve viral
suppression, postpartum antiretroviral prophylaxis for infants, and avoidance of breastfeeding.
The management of HIV infection in pregnancy is a highly specialised area; early referral and close collaboration
between adult and paediatric HIV specialists, and an obstetrician (ideally with experience in HIV management) is
essential. For more detailed information, see the guidelines listed in Further reading.
General principles
HIV-negative women with an HIV-positive male partner who are planning natural conception in the next 3
months are considered to be at high risk of HIV infection—HIV pre-exposure prophylaxis (PrEP) is
recommended (for regimens, see Antiretroviral therapy for HIV pre-exposure prophylaxis).
HIV testing is recommended for pregnant women at the first antenatal visit and should be repeated during
the pregnancy for women at high risk of HIV infection (eg women with an HIV-positive partner, women
with new sexual partners during pregnancy, women with sexual partners from high-prevalence countries).
Antiretroviral therapy should be recommended to all pregnant women with HIV infection.
In general, if a woman with HIV infection conceives while on an effective antiretroviral regimen, the
regimen should not be changed.
Intrapartum zidovudine is indicated for the prevention of mother-to-child transmission if predelivery
maternal viral suppression has been inadequate or is unknown, as in cases of late presentation. Other
additional therapies may be used—seek expert advice.
Consider a caesarean section if the maternal plasma viral load is more than 50 HIV RNA copies/mL at 36
weeks’ gestation. Caesarean section is recommended when viral load is more than 400 copies/mL at 36
weeks’ gestation. If the viral load can be promptly reduced before 38 weeks’ gestation, a caesarean section
may not be required—seek expert advice.
Neonatal antiretroviral prophylaxis should be started as soon as possible after birth (within 6 to 12 hours)
and continued for 4 weeks.
Mothers with HIV infection are advised not to breastfeed. There is an increased risk of transmission of HIV
from mother to child if the infant is breastfed, even when mothers have an undetectable plasma HIV viral
load.
Antiretroviral therapy during pregnancy
Management of antiretroviral therapy during pregnancy is complex and requires consultation with an HIV
specialist. Offer all women antiretroviral therapy for their own health benefit as well as for prevention of mother-
to-child transmission of HIV infection. Start treatment as soon as possible.
For detailed information about antiretroviral drugs and regimens recommended in pregnancy, see the guidelines
listed in Further reading.
Pregnancy affects the pharmacokinetics of some antiretrovirals, particularly in the third trimester, so dosages may
need to be adjusted.
Intrapartum antiretroviral therapy

Intrapartum antiretroviral therapy to prevent mother-to-child transmission of HIV is not required if the mother is
taking antiretroviral therapy and has an undetectable viral load near delivery.
If the mother’s HIV viral load near delivery is more than 1000 HIV RNA copies/mL or is unknown, intrapartum
zidovudine is indicated. In addition to the mother’s usual antiretroviral regimen, use:
zidovudine 2 mg/kg intravenously over 1 hour, 3 hours before anticipated caesarean

section or at the onset of labour, followed by 1 mg/kg/hour intravenously until the
umbilical cord is clamped [Note 6] [Note 7].
If the mother’s HIV viral load near delivery is detectable but less than 1000 copies/mL, intrapartum zidovudine
may be considered on a case-by-case basis. The decision depends on the plan for neonatal antiretroviral
prophylaxis—seek expert advice.
Note 6: Intravenous zidovudine is not registered for use in Australia but is available via the Special Access
Scheme.
Note 7: If oral zidovudine is a component of the mother’s usual antiretroviral regimen, withhold oral dose
during intravenous therapy.
Neonatal antiretroviral prophylaxis

For neonates at low risk of mother-to-child transmission (estimated transmission risk less than 2%),
antiretroviral prophylaxis with zidovudine monotherapy is recommended, even if the mother has a history of
zidovudine resistance. Risk of mother-to-child transmission is low if the mother had an undetectable predelivery
viral load. Prophylaxis should start as soon as possible after birth (within 6 to 12 hours). Neonatal antiretroviral
prophylaxis is complex and requires consultation with an HIV specialist.
For neonates born at 35 weeks’ or more gestation, use:
zidovudine 4 mg/kg orally, 12-hourly for 4 weeks.
For neonates born at 30 to 34 weeks’ gestation, use:
zidovudine 2 mg/kg orally, 12-hourly for 2 weeks, then 2 mg/kg 8-hourly for 2 weeks.
For neonates born at less than 30 weeks’ gestation, use:
zidovudine 2 mg/kg orally, 12-hourly for 4 weeks.
For neonates at high risk of mother-to-child transmission (estimated transmission risk more than 2%), additional
antiretroviral drugs are required—seek expert advice. Risk of mother-to-child transmission is high if the mother
had a detectable viral load near delivery or did not receive antepartum antiretroviral therapy (including those who
only received intrapartum therapy), or if the predelivery viral load was unknown. In these cases, add lamivudine
plus nevirapine to zidovudine. The dose of nevirapine depends on whether the mother has been taking nevirapine.
For neonates at high risk of mother-to-child transmission, if the mother has never taken nevirapine or has been
taking nevirapine for less than 3 days, add to zidovudine:
lamivudine 2 mg/kg orally, 12-hourly for 4 weeks
PLUS
nevirapine 2 mg/kg orally, daily for 1 week, then 4 mg/kg daily for 1 week.
For neonates at high risk of mother-to-child transmission, if the mother has been taking nevirapine for the last 3
days or more, add to zidovudine:
lamivudine 2 mg/kg orally, 12-hourly for 4 weeks
PLUS
nevirapine 4 mg/kg orally, daily for 2 weeks.
For more detailed information, see the Australasian Society for Infectious Diseases (ASID) guideline Management
of Perinatal Infections.
Further reading
For opportunistic and co-infection guidelines in adults with HIV, see here.
Australian HIV guidelines and resources:
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) Sub-Committee for Guidance
on HIV Management in Australia. Antiretroviral guidelines - US DHHS guidelines with Australian commentary.
[regularly updated]. [URL]
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM). HIV management in
Australasia - a guide for clinical care. [regularly updated]. [URL]
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM). Update on PrEP for HIV
Clinicians. [regularly updated]. [URL] (choose ‘PrEP Clinical Guidelines’)
Communicable Diseases Network Australia (CDNA). Human Immunodeficiency virus (HIV): CDNA national
guidelines for public health units [version 1.0]. Canberra: Department of Health; 2014. [URL]
International HIV guidelines:
British HIV Association (BHIVA). Guidelines for the treatment of HIV-1 positive adults with antiretroviral
therapy. [regularly updated]. [URL]
European AIDS Clinical Society (EACS). European Guidelines for treatment of HIV-positive adults in Europe.
International Antiviral Society–USA. Antiretroviral drugs for treatment and prevention of HIV infection in adults:
2018 Recommendations of the International Antiviral Society–USA Panel. 2018. [URL]
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in
adults and adolescents living with HIV. US Department of Health and Human Services (DHHS); [regularly
updated]. [URL]
World Health Organization (WHO). Consolidated guidelines on the use of antiretroviral drugs for treating and
preventing HIV infection - Recommendations for a public health approach. 2013. [URL]
World Health Organization (WHO). HIV/AIDS. [regularly updated]. [URL] (choose ‘HIV guidelines’, or ‘HIV
news’ for current drug information)
Guidelines on HIV infection in pregnancy:
British HIV Association (BHIVA). British HIV Association guidelines for the management of HIV infection in
pregnant women [regularly updated]. [URL]
Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission.
Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to
reduce perinatal HIV transmission in the United States. [regularly updated]. [URL]
Palasanthiran P, Starr M, Jones C, Giles M, editors. Management of perinatal infections. Sydney: Australasian
Society for Infectious Diseases; 2014. [URL]
Paediatric HIV guidelines:
Children’s HIV Association (CHIVA). CHIVA guidelines. [URL]
Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the use of
antiretroviral agents in pediatric HIV infection. [regularly updated]. [URL]
Key references
HIV in pregnancy
Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry Interim Report for 1 January
1989 through 31 January 2018. Wilmington, NC; 2017. http://www.apregistry.com/InterimReport.aspx
British HIV Association (BHIVA). British HIV Association guidelines for the management of HIV in pregnancy and
postpartum 2018. London: BHIVA; 2018. https://www.bhiva.org/pregnancy-guidelines
Ferguson W, Goode M, Walsh A, Gavin P, Butler K. Evaluation of 4 weeks' neonatal antiretroviral prophylaxis as a
component of a prevention of mother-to-child transmission program in a resource-rich setting. Pediatr Infect Dis J
2011;30(5):408–12.
Furner V. HIV and pregnancy. In: HIV management in Australasia: a guide for clinical care [online]. Sydney:
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM); Accessed Aug 2018.
http://hivmanagement.ashm.org.au/index.php/populations-and-situations/hiv-in-pregnancy-children-and-transitioning-
adolescents/hiv-and-pregnancy#
National HIV Testing Policy Expert Reference Committee. National HIV testing policy. Barton: Australian Department
of Health and Ageing; 2017. http://testingportal.ashm.org.au/hiv
Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations
for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce
perinatal HIV transmission in the United States. Rockville, MD: US Department of Health and Human Services (DHHS);
2017 [updated 2018]. https://aidsinfo.nih.gov/guidelines/html/3/perinatal/513/counseling-and-management-of-women-
living-with-hiv-who-breastfeed
The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Routine antenatal assessment in
the absence of pregnancy complications. Royal Australian and New Zealand College of Obstetricians and
Gynaecologists; July 2016. http://www.ranzcog.edu.au/
Benefits of antiretroviral therapy for HIV infection
Bavinton BR, Pinto AN, Phanuphak N, Grinsztejn B, Prestage GP, Zablotska-Manos IB, et al. Viral suppression and
HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study. Lancet HIV
2018;5(8):e438–e47.
Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Antiretroviral therapy for the
prevention of HIV-1 transmission. N Engl J Med 2016;375(9):830–9.
Grinsztejn B, Hosseinipour MC, Ribaudo HJ, Swindells S, Eron J, Chen YQ, et al. Effects of early versus delayed
initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052
randomised controlled trial.[Erratum appears in Lancet Infect Dis. 2014 Apr;14(4):269]. Lancet Infect Dis
2014;14(4):281–90.
Insight Start Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, et al. Initiation of antiretroviral
therapy in early asymptomatic HIV infection. N Engl J Med 2015;373(9):795–807.
Rodger AJ, Cambiano V, Bruun T, Vernazza P, Collins S, van Lunzen J, et al. Sexual activity without condoms and risk
of HIV transmission in serodifferent couples when the HIV-positive partner is using suppressive antiretroviral therapy.
[Erratum appears in JAMA. 2016 Aug 9;316(6):667; PMID: 27532931], [Erratum appears in JAMA. 2016 Nov
15;316(19):2048; PMID: 27838699]. JAMA 2016;316(2):171–81.
Tang Z, Lan G, Chen YQ, Zhu Q, Yang X, Shen Z, et al. HIV-1 treatment-as-prevention: A cohort study analysis of
serodiscordant couples in rural southwest China. Medicine 2015;94(24):e902.
Indications for HIV pre-exposure prophylaxis (PrEP)
Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leethochawalit M, et al. Antiretroviral prophylaxis
for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-
blind, placebo-controlled phase 3 trial. Lancet 2013;381(9883):2083–90.
McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure prophylaxis to prevent the
acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label
randomised trial. Lancet 2016;387(10013):53–60.
Molina JM, Clotet B, van Lunzen J, Lazzarin A, Cavassini M, Henry K, et al. Once-daily dolutegravir versus darunavir
plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-
label, phase 3b study.[Erratum appears in Lancet HIV. 2015 Apr;2(4):e126]. Lancet HIV 2015;2(4):e127–36.
Murnane PM, Celum C, Mugo N, Campbell JD, Donnell D, Bukusi E, et al. Efficacy of preexposure prophylaxis for HIV-
1 prevention among high-risk heterosexuals: subgroup analyses from a randomized trial. AIDS 2013;27(13):2155–60.
Riddell Jt, Amico KR, Mayer KH. HIV preexposure prophylaxis: A review. JAMA 2018;319(12):1261–8.
Wright E, Grulich A, Roy K, Boyd M, Cornelisse V, Russell D, et al. Australasian Society for HIV, Viral Hepatitis and
Sexual Health Medicine HIV pre-exposure prophylaxis: clinical guidelines. J Virus Erad 2017;3(3):168–84.
Antiretroviral therapy for HIV pre-exposure prophylaxis (PrEP)

Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leethochawalit M, et al. Antiretroviral prophylaxis
for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-
blind, placebo-controlled phase 3 trial. Lancet 2013;381(9883):2083–90.
McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure prophylaxis to prevent the
acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label
randomised trial. Lancet 2016;387(10013):53–60.
Molina JM, Clotet B, van Lunzen J, Lazzarin A, Cavassini M, Henry K, et al. Once-daily dolutegravir versus darunavir
plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-
label, phase 3b study.[Erratum appears in Lancet HIV. 2015 Apr;2(4):e126]. Lancet HIV 2015;2(4):e127–36.
Murnane PM, Celum C, Mugo N, Campbell JD, Donnell D, Bukusi E, et al. Efficacy of preexposure prophylaxis for HIV-
1 prevention among high-risk heterosexuals: subgroup analyses from a randomized trial. AIDS 2013;27(13):2155–60.
Riddell Jt, Amico KR, Mayer KH. HIV preexposure prophylaxis: A review. JAMA 2018;319(12):1261–8.
Wright E, Grulich A, Roy K, Boyd M, Cornelisse V, Russell D, et al. Australasian Society for HIV, Viral Hepatitis and
Sexual Health Medicine HIV pre-exposure prophylaxis: clinical guidelines. J Virus Erad 2017;3(3):168–84.
When to start antiretroviral therapy to treat HIV infection
British HIV Association (BHIVA). British HIV Association guidelines for the treatment of HIV-1-positive adults with
antiretroviral therapy 2015 (2016 interim update). London: BHIVA; 2016. http://www.bhiva.org/guidelines.aspx
Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Antiretroviral therapy for the
prevention of HIV-1 transmission. N Engl J Med 2016;375(9):830–9.
European Aids Clinical Society (EACS). European Guidelines for treatment of HIV-positive adults in Europe. Version
9.0. Brussels: EACS; 2017. http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html
Grinsztejn B, Hosseinipour MC, Ribaudo HJ, Swindells S, Eron J, Chen YQ, et al. Effects of early versus delayed
initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052
randomised controlled trial.[Erratum appears in Lancet Infect Dis. 2014 Apr;14(4):269]. Lancet Infect Dis
2014;14(4):281–90.
Gunthard HF, Aberg JA, Eron JJ, Hoy JF, Telenti A, Benson CA, et al. Antiretroviral treatment of adult HIV infection:
2014 recommendations of the International Antiviral Society-USA Panel. JAMA 2014;312(4):410–25.
Insight Start Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, et al. Initiation of antiretroviral
therapy in early asymptomatic HIV infection. N Engl J Med 2015;373(9):795–807.
Panel on Antiretroviral Guidelines for Adults and Adolescents Guidelines for the use of antiretroviral agents in adults
and adolescents living with HIV Washington, D.C.: Department of Health and Human Services (USA); 2017.
https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/0.
Before starting antiretroviral therapy for HIV infection
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM). HIV management in Australasia: a
guide for clinical care. Sydney: ASHM; Accessed Aug 2018. http://hivmanagement.ashm.org.au/
Bisson GP, Molefi M, Bellamy S, Thakur R, Steenhoff A, Tamuhla N, et al. Early versus delayed antiretroviral therapy
and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitis.[Erratum appears in Clin Infect
Dis. 2013 Oct;57(7):1067]. Clin Infect Dis 2013;56(8):1165–73.
Ford N, Shubber Z, Jarvis JN, Chiller T, Greene G, Migone C, et al. CD4 cell count threshold for cryptococcal antigen
screening of HIV-infected individuals: A systematic review and meta-analysis. Clin Infect Dis 2018;66(suppl_2):S152–
S9.
McKenney J, Bauman S, Neary B, Detels R, French A, Margolick J, et al. Prevalence, correlates, and outcomes of
cryptococcal antigen positivity among patients with AIDS, United States, 1986-2012. Clin Infect Dis 2015;60(6):959–65.
Mfinanga S, Chanda D, Kivuyo SL, Guinness L, Bottomley C, Simms V, et al. Cryptococcal meningitis screening and
community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in
Tanzania and Zambia: an open-label, randomised controlled trial. Lancet 2015;385(9983):2173–82.
Society of America. Rockville, MD: US Department of Health and Human Services (DHHS); 2013 [updated 2017].
World Health Organization (WHO). Guidelines for the diagnosis, prevention and management of cryptococcal disease
in HIV-infected adults, adolescents and children (Supplement to the 2016 consolidated guidelines on the use of
antiretroviral drugs for treating and preventing HIV infection). Geneva: WHO; 2018.
https://www.who.int/hiv/pub/guidelines/cryptococcal-disease/en/.
Overview of antiretroviral drugs for HIV infection in adults
Llibre JM, Hung CC, Brinson C, Castelli F, Girard PM, Kahl LP, et al. Efficacy, safety, and tolerability of dolutegravir-
rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority
SWORD-1 and SWORD-2 studies. Lancet 2018;391(10123):839–49.
Initial antiretroviral therapy for HIV infection in adults
Ciaffi L, Koulla-Shiro S, Sawadogo AB, Ndour CT, Eymard-Duvernay S, Mbouyap PR, et al. Boosted protease inhibitor
monotherapy versus boosted protease inhibitor plus lamivudine dual therapy as second-line maintenance treatment for
HIV-1-infected patients in sub-Saharan Africa (ANRS12 286/MOBIDIP): a multicentre, randomised, parallel, open-label,
superiority trial. Lancet HIV 2017;4(9):e384–e92.
Department of Health and Human Services Antiretroviral Guidelines Panels. Recommendations regarding the use of
dolutegravir in adults and adolescents with HIV who are pregnant or of child-Bearing potential. Washington, D.C.: U.S.
Department of Health and Human Services; May 30, 2018. https://aidsinfo.nih.gov/news/2109/recommendations-
regarding-the-use-of-dolutegravir-in-adults-and-adolescents-with-hiv-who-are-pregnant-or-of-child-bearing-potential
Kryst J, Kawalec P, Pilc A. Efavirenz-based regimens in antiretroviral-naive HIV-infected patients: A systematic review
and meta-analysis of randomized controlled trials. PLoS ONE 2015;10(5):e0124279.
Llibre JM, Hung CC, Brinson C, Castelli F, Girard PM, Kahl LP, et al. Efficacy, safety, and tolerability of dolutegravir-
rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority
SWORD-1 and SWORD-2 studies. Lancet 2018;391(10123):839–49.
Messiaen P, Wensing AM, Fun A, Nijhuis M, Brusselaers N, Vandekerckhove L. Clinical use of HIV integrase
inhibitors: a systematic review and meta-analysis. PLoS ONE 2013;8(1):e52562.
Patel DA, Snedecor SJ, Tang WY, Sudharshan L, Lim JW, Cuffe R, et al. 48-week efficacy and safety of dolutegravir
relative to commonly used third agents in treatment-naive HIV-1-infected patients: a systematic review and network
meta-analysis. PLoS ONE 2014;9(9):e105653.
Perez-Molina JA, Rubio R, Rivero A, Pasquau J, Suarez-Lozano I, Riera M, et al. Simplification to dual therapy
(atazanavir/ritonavir + lamivudine) versus standard triple therapy [atazanavir/ritonavir + two nucleos(t)ides] in
virologically stable patients on antiretroviral therapy: 96 week results from an open-label, non-inferiority, randomized
clinical trial (SALT study). J Antimicrob Chemother 2017;72(1):246–53.
Pulido F, Ribera E, Lagarde M, Perez-Valero I, Palacios R, Iribarren JA, et al. Dual therapy with darunavir and ritonavir
plus lamivudine vs triple therapy with darunavir and ritonavir plus tenofovir disoproxil fumarate and emtricitabine or
abacavir and lamivudine for maintenance of human immunodeficiency virus type 1 viral suppression: Randomized,
open-label, noninferiority DUAL-GESIDA 8014-RIS-EST45 trial. Clin Infect Dis 2017;65(12):2112–8.
Schomaker M, Davies MA, Cornell M, Ford N. Assessing the risk of dolutegravir for women of childbearing potential.
Lancet Glob Health 2018;6(9):e958–e9.
Wang H, Lu X, Yang X, Xu N. The efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate in
antiretroviral regimens for HIV-1 therapy: Meta-analysis. Medicine 2016;95(41):e5146.
Monitoring antiretroviral therapy for HIV infection

Chow EP, Read TR, Chen MY, Fehler G, Bradshaw CS, Fairley CK. Routine CD4 cell count monitoring seldom
contributes to clinical decision-making on antiretroviral therapy in virologically suppressed HIV-infected patients. HIV
Med 2015;16(3):196–200.
Gale HB, Gitterman SR, Hoffman HJ, Gordin FM, Benator DA, Labriola AM, et al. Is frequent CD4+ T-lymphocyte
count monitoring necessary for persons with counts >=300 cells/muL and HIV-1 suppression? Clin Infect Dis
2013;56(9):1340–3.
Girard PM, Nelson M, Mohammed P, Hill A, van Delft Y, Moecklinghoff C. Can we stop CD4+ testing in patients with
HIV-1 RNA suppression on antiretroviral treatment? AIDS 2013;27(17):2759–63.
Opportunistic and co-infections in adults with HIV
infection
Introduction to opportunistic and co-infections in adults with HIV
infection
The management of opportunistic and co-infections in adults with HIV infection is a specialised area—seek expert
advice on patient management. Check for potential drug interactions when prescribing any drug for a person with
HIV infection (see Antiretroviral drug interactions).
Check for drug interactions before prescribing a drug for a person with HIV infection.
For management of opportunistic and co-infections in children with HIV infection, see the guidelines listed in
Further reading.
This topic provides an overview of management of opportunistic and co-infections. Prevention of infection is
included when applicable. For primary prophylaxis recommendations, see Primary prophylaxis in adults in with
HIV infection.
The following opportunistic or co-infections in adults with HIV infection are discussed in this topic:
candidiasis—oropharyngeal candidiasis and oesophageal candidiasis

cryptococcal infections—cryptococcal meningitis and pulmonary cryptococcosis
gastrointestinal protozoal infections—Cryptosporidium species, Cyclospora cayetanensis, Cystoisospora
(Isospora) belli and microsporidia species
cytomegalovirus (CMV)
hepatitis B virus (HBV)
hepatitis C virus (HCV)
herpes simplex virus—genital herpes simplex virus (HSV) and oral mucocutaneous herpes simplex virus
(HSV)
Mycobacterium avium complex (MAC)
tuberculosis
Pneumocystis jirovecii pneumonia (PJP)
syphilis
varicella-zoster virus—see chickenpox and shingles.
Primary prophylaxis in adults with HIV infection

Primary prophylaxis is indicated for selected patients at risk of Mycobacterium avium complex (MAC) infection,
Pneumocystis jirovecii pneumonia (PJP) and Toxoplasma gondii encephalitis—see Table 2.13. Antimicrobial
therapy to prevent other opportunistic infections is not recommended, except for patients at risk of tuberculosis
reactivation (see Tuberculosis in adults with HIV infection).
Primary prophylaxis for opportunistic infections in adults with HIV infection (Table 2.13)
Pathogen When to start primary prophylaxis Primary prophylaxis regimen

CD4 count less than 50 cells/microlitre
Mycobacterium avium complex
Ensure the patient does not have active See here for details.
(MAC)
MAC infection before starting
prophylaxis.
See here for details.
CD4 count less than 200
cells/microlitre, or If prophylaxis against both PJP and T.
Pneumocystis jirovecii gondii is required, use the primary
CD4 cell percentage less than 14% prophylaxis regimens for T. gondii
encephalitis.
CD4 count less than 100 See here for details. These regimens
Toxoplasma gondii cells/microlitre and T. gondii IgG provide prophylaxis against both PJP
antibody detected and T. gondii.
Oropharyngeal candidiasis in adults with HIV infection

Treatment
Fluconazole is the preferred treatment for oropharyngeal candidiasis adults with HIV infection. Use:
fluconazole 50 to 100 mg orally, daily for 7 to 14 days until symptoms resolve.
Use the higher dose of fluconazole for more severe disease.
If fluconazole is not suitable, use:
1 itraconazole (Lozanoc capsule) 50 mg orally, daily for 7 to 14 days until symptoms

resolve [Note 1]
OR (if an oral liquid formulation is required)
1 itraconazole (Sporanox oral liquid) 100 mg orally, daily for 7 to 14 days until symptoms
resolve [Note 1]
OR
2 nystatin liquid 100 000 units/mL 1 mL topically (then swallowed), 6-hourly for 7 to 14
days until symptoms resolve.
In patients with newly diagnosed HIV, exclude other infections before starting antiretroviral therapy for HIV
infection. For patients with HIV and oropharyngeal candidiasis but no other infection, start antiretroviral therapy
as soon as possible (see Initial antiretroviral therapy for HIV infection in adults).
Note 1: Oral preparations of itraconazole are not bioequivalent; appropriate dosing and administration depends
on the preparation.
Maintenance therapy
Maintenance therapy (secondary prophylaxis) for oropharyngeal candidiasis is not required for patients taking
adequate antiretroviral therapy.
Oesophageal candidiasis in adults with HIV infection

Treatment
For treatment of oesophageal candidiasis in adults with HIV infection, use:
1 fluconazole 200 mg orally, for the first dose, then 100 mg daily for 14 days
OR
2 itraconazole (Lozanoc capsule) 100 mg orally, daily for 14 days [Note 2]
2 itraconazole (Sporanox oral liquid) 200 mg orally, daily for 14 days [Note 2].
If response to therapy is inadequate, see the Australasian Society for HIV, Viral Hepatitis and Sexual Health
Medicine Oesophageal candidiasis guidelines [URL].
infection. For patients with HIV and oesophageal candidiasis but no other infection, start antiretroviral therapy as
soon as possible (see Initial antiretroviral therapy for HIV infection in adults).
on the preparation.
Maintenance therapy
Maintenance therapy (secondary prophylaxis) for oesophageal candidiasis is not required for patients taking
adequate antiretroviral therapy.
Cryptococcal meningitis in adults with HIV infection

For treatment and maintenance therapy (secondary prophylaxis) of Cryptococcus neoformans meningitis in adults
with HIV infection, see Cryptococcal meningitis.
In patients with newly diagnosed HIV and cryptococcal meningitis, the timing of antiretroviral therapy initiation is
complex—seek expert advice.
Pulmonary cryptococcosis in adults with HIV infection

For treatment and maintenance therapy (secondary prophylaxis) of Cryptococcus neoformans pulmonary disease
in adults with HIV infection, see Pulmonary cryptococcosis.
infection. For patients with HIV and pulmonary cryptococcosis but no other infection, start antiretroviral therapy
within 2 weeks if the patient is clinically stable and cryptococcal meningitis has been excluded (see Initial
antiretroviral therapy for HIV infection in adults).
Cryptosporidium species gastroenteritis in adults with HIV infection

For treatment of Cryptosporidium species gastroenteritis, see Cryptosporidium species infection.
infection. For patients with HIV and Cryptosporidium species gastroenteritis but no other infection, start
antiretroviral therapy as soon as possible (see Initial antiretroviral therapy for HIV infection in adults).
Cyclospora cayetanensis gastroenteritis in adults with HIV infection

For treatment and maintenance therapy (secondary prophylaxis) of Cyclospora cayetanensis gastroenteritis, see
Cyclospora cayetanensis infection.
infection. For patients with HIV and C. cayetanensis gastroenteritis but no other infection, start antiretroviral
therapy as soon as possible (see Initial antiretroviral therapy for HIV infection in adults).
Cystoisospora (Isospora) belli gastroenteritis in adults with HIV

infection
For treatment and maintenance therapy (secondary prophylaxis) of Cystoisospora (Isospora) belli gastroenteritis,
see Cystoisospora (Isospora) belli infection.
infection. For patients with HIV and C. belli gastroenteritis but no other infection, start antiretroviral therapy as
Cytomegalovirus (CMV) disease in adults with HIV infection

For treatment and maintenance therapy (secondary prophylaxis) of cytomegalovirus disease, see Cytomegalovirus
(CMV) infection.
In patients with newly diagnosed HIV and CMV disease, the timing of antiretroviral therapy initiation is complex
Hepatitis B virus infection in adults with HIV infection

Combination antiretroviral therapy can be used to treat HIV and hepatitis B virus co-infection. Use an
antiretroviral regimen containing emtricitabine plus tenofovir alafenamide or a tenofovir disoproxil salt; see Initial
antiretroviral therapy for HIV infection in adults. Seek expert advice for management of patients with HIV or
hepatitis B strains that are resistant to these drugs, and patients in whom resistance is suspected due to previous
antiviral therapy.
For patients with HIV and hepatitis B co-infection who are not taking tenofovir alafenamide or a tenofovir disoproxil salt, do not
use lamivudine or entecavir monotherapy to treat hepatitis B.
For patients with HIV and hepatitis B co-infection who are not taking tenofovir alafenamide or a tenofovir
disoproxil salt, do not use lamivudine or entecavir monotherapy to treat hepatitis B.
An acute exacerbation of hepatitis B can occur if antiretroviral drugs active against hepatitis B virus are stopped—
seek expert advice before stopping or changing therapy.
All people with HIV infection should be tested for hepatitis B infection. If they are not immune, provide hepatitis
B virus vaccination. See the Australian Immunisation Handbook [URL].
Hepatitis C virus infection in adults with HIV infection

Direct-acting antivirals for hepatitis C virus are as efficacious in people with HIV as those without. Check for drug
interactions before prescribing (see Antiretroviral drug interactions) and assess the patient for cirrhosis.
Check for drug interactions before prescribing hepatitis C treatment for a person with HIV infection.
For treatment of hepatitis C, see the Australian recommendations for the management of hepatitis C virus
infection: a consensus statement website.
Genital herpes in adults with HIV infection

For treatment and maintenance therapy (secondary prophylaxis) of genital herpes simplex virus (HSV) infection,
see Genital herpes.
infection. For patients with HIV and genital herpes but no other infection, start antiretroviral therapy as soon as
possible (see Initial antiretroviral therapy for HIV infection in adults).
Oral mucocutaneous herpes in adults with HIV infection

Treatment
For treatment of initial oral mucocutaneous herpes simplex virus (HSV) infection, use:
1 famciclovir 500 mg orally, 12-hourly for 7 to 10 days
OR
1 valaciclovir 1 g orally, 12-hourly for 7 to 10 days.
For infrequent severe recurrences of oral mucocutaneous HSV, use one of the regimens above for 5 days. For
frequent severe recurrences, see Maintenance therapy.
infection. For patients with HIV and oral mucocutaneous HSV but no other infection, start antiretroviral therapy as
Maintenance therapy
For maintenance therapy (secondary prophylaxis) for frequent severe recurrences of oral mucocutaneous HSV, as
continuous prophylaxis, use:
1 famciclovir 500 mg orally, 12-hourly
OR
1 valaciclovir 500 mg orally, 12-hourly.
Microsporidia species gastroenteritis in adults with HIV infection

For treatment and maintenance therapy (secondary prophylaxis) of microsporidia species gastroenteritis, see
Microsporidia infection.
infection. For patients with HIV and microsporidia species gastroenteritis but no other infection, start antiretroviral
therapy as soon as possible (see Initial antiretroviral therapy for HIV infection in adults).
Mycobacterium avium complex (MAC) infection in adults with HIV

infection
Primary prophylaxis
Drug interactions between HIV and MAC drugs are complex—check for drug interactions before prescribing (see
Antiretroviral drug interactions).
Check for drug interactions before prescribing MAC prophylaxis for a person with HIV infection.
Start primary prophylaxis for MAC when the patient’s CD4 count is less than 50 cells/microlitre. Ensure the
patient does not have active MAC infection before starting prophylaxis. Use:
1 azithromycin 1.2 g orally, once weekly
OR
2 clarithromycin 500 mg orally, 12-hourly.
Duration of therapy: for patients taking combination antiretroviral therapy with a suppressed HIV viral load, stop
primary prophylaxis when the CD4 count is more than 100 cells/microlitre for 3 months.
Treatment and maintenance therapy
For treatment and maintenance therapy (secondary prophylaxis) of disseminated Mycobacterium avium complex
(MAC), see Disseminated Mycobacterium avium complex infection.
infection. For patients with HIV and MAC but no other infection, start antiretroviral therapy within 2 weeks if the
patient is clinically stable (see Initial antiretroviral therapy for HIV infection in adults).
Tuberculosis in adults with HIV infection

Management of patients with active tuberculosis and HIV co-infection is complex. Patients must be managed by
specialists with HIV and tuberculosis expertise.
Drug interactions between drugs for HIV and tuberculosis are complex—check for drug interactions before
prescribing (see Antiretroviral drug interactions).
Check for drug interactions before prescribing drugs for tuberculosis for a person with HIV infection.
For general information on management of tuberculosis, see Tuberculosis.

In patients with newly diagnosed HIV and tuberculosis, the timing of antiretroviral therapy initiation depends on
the level of immunodeficiency and is complex—seek expert advice.
For management of latent tuberculosis, see Latent tuberculosis.
Pneumocystis jirovecii pneumonia (PJP) in adults with HIV infection

Primary prophylaxis
Start primary prophylaxis for Pneumocystis jirovecii pneumonia (PJP) when the patient’s CD4 count is less than
200 cells/microlitre, or if CD4 cell percentage less than 14%.
Trimethoprim+sulfamethoxazole is the most effective prophylaxis against PJP and is recommended unless
contraindicated (eg in patients hypersensitive to trimethoprim+sulfamethoxazole). If the patient also requires
prophylaxis against Toxoplasma gondii infection, use the primary prophylaxis regimens for T. gondii encephalitis.
Trimethoprim+sulfamethoxazole is the most effective prophylaxis against PJP.
The choice of trimethoprim+sulfamethoxazole regimen for primary PJP prophylaxis depends on patient
preference, adherence and tolerability. Use:
1 trimethoprim+sulfamethoxazole 80+400 mg orally, daily; see below for advice on

duration of therapy
OR

duration of therapy
OR
2 trimethoprim+sulfamethoxazole 160+800 mg orally, 3 times weekly; see below for advice

on duration of therapy [Note 3].
Assess patients reporting hypersensitivity to trimethoprim+sulfamethoxazole—see Diagnosis of antimicrobial

hypersensitivity for guidance. Desensitisation is an option for clinically stable patients; however, do not
desensitise patients with severe hypersensitivity (eg drug rash with eosinophilia and systemic symptoms [DRESS],
Stevens–Johnson syndrome / toxic epidermal necrolysis [SJS/TEN]) or if adherence to therapy is unlikely. If 1 day
of therapy is missed, the patient’s hypersensitivity will return and desensitisation must be performed again. Seek
expert advice if desensitisation is being considered. If desensitisation is not an option, alternative regimens are
provided below.
Assess patients reporting hypersensitivity to trimethoprim+sulfamethoxazole.
For patients with nonsevere hypersensitivity to trimethoprim+sulfamethoxazole, use:
1 dapsone 100 mg orally, daily; see below for advice on duration of therapy [Note 4] [Note
5] [Note 6]
OR
2 pentamidine 300 mg via nebuliser, every 4 weeks; see below for advice on duration of
therapy [Note 7] [Note 8]
OR
3 atovaquone 1500 mg orally with fatty food or full-fat milk, daily; see below for advice on
For patients with severe hypersensitivity to trimethoprim+sulfamethoxazole (eg anaphylaxis, DRESS, SJS/TEN),
use pentamidine or atovaquone (see dosages above). Do not give dapsone because there is a possibility of cross-
reactivity between dapsone and sulfamethoxazole (see Cross-reactivity between sulfonamides).
Note 3: Do not use the 3-times weekly regimen if the patient has undergone desensitisation for
trimethoprim+sulfamethoxazole hypersensitivity.
Note 4: Test for glucose-6-phosphate dehydrogenase (G6PD) deficiency before starting treatment with dapsone
—seek expert advice if the patient is G6PD deficient.
Note 5: The cross-reactivity rate between dapsone and sulfamethoxazole is approximately 9 to 12%; do not use
dapsone in patients with severe hypersensitivity (eg drug rash with eosinophilia and systemic symptoms
[DRESS], Stevens–Johnson syndrome / toxic epidermal necrolysis [SJS/TEN]; see Types of antimicrobial
hypersensitivity).
Note 6: Reduce dapsone dosage to 50 mg daily in patients who develop toxicity (methaemoglobinaemia,
chemical haemolysis).
Note 7: Administer pentamidine via a jet nebuliser producing a droplet size of 1 to 2 microns.
Note 8: Use with caution in patients with lung disease (eg asthma, COPD) because nebulised pentamidine may
cause cough and bronchospasm.

For treatment and maintenance therapy (secondary prophylaxis) of PJP, see Pneumocystis jirovecii pneumonia .
infection. For patients with HIV and PJP but no other infection, start antiretroviral therapy within 2 weeks if the
patient is clinically stable (see Initial antiretroviral therapy for HIV infection in adults).
Toxoplasma gondii encephalitis in adults with HIV infection

Primary prophylaxis
Start primary prophylaxis for toxoplasmosis when the patient’s CD4 count is less than 100 cells/microlitre and the
patient has Toxoplasma gondii IgG antibodies.
The regimens below also provide protection against Pneumocystis jirovecii pneumonia (PJP).
Before prescribing toxoplasmosis prophylaxis, check if the patient is taking prophylaxis against Pneumocystis jirovecii
pneumonia.
Trimethoprim+sulfamethoxazole is the most effective prophylaxis against T. gondii. The high-strength (160+800
mg) daily regimen is preferred for T. gondii prophylaxis in patients with HIV infection. Use:

duration of therapy
OR

duration of therapy
OR
2 trimethoprim+sulfamethoxazole 160+800 mg orally, 3 times weekly; see below for advice

on duration of therapy [Note 9].

expert advice if desensitisation is being considered. If desensitisation is not an option, alternative regimens are
provided below.
For patients with nonsevere hypersensitivity to trimethoprim+sulfamethoxazole, use dapsone daily or weekly (in
combination with weekly pyrimethamine and calcium folinate). Consider patient preference, adherence and
tolerability when choosing between the daily and weekly regimens.
If a daily dapsone-based regimen is preferred, use:
dapsone 50 mg orally, daily; see below for advice on duration of therapy [Note 10] [Note
11]
PLUS
pyrimethamine 50 mg orally, once weekly; see below for advice on duration of therapy
PLUS
calcium folinate 30 mg orally, once weekly (preferably not on the same day
pyrimethamine is taken); see below for advice on duration of therapy.
If a weekly dapsone-based regimen is preferred, use:
dapsone 200 mg orally, once weekly; see below for advice on duration of therapy [Note
10] [Note 11]
PLUS
pyrimethamine 75 mg orally, once weekly (on the same day dapsone is taken); see below
for advice on duration of therapy
PLUS
calcium folinate 30 mg orally, once weekly (preferably not on the day dapsone and
pyrimethamine are taken); see below for advice on duration of therapy.
choosing a safe and effective regimen is complex—seek expert advice. Do not give dapsone because there is a
possibility of cross-reactivity between dapsone and sulfamethoxazole (see Cross-reactivity between sulfonamides).
hypersensitivity).

For treatment and maintenance therapy (secondary prophylaxis) of T. gondii encephalitis, see Toxoplasma gondii
encephalitis.
In patients with newly diagnosed HIV and T. gondii encephalitis, the timing of antiretroviral therapy initiation is
Syphilis in adults with HIV infection
For treatment of syphilis, see Syphilis.
infection. For patients with HIV and syphilis but no other infection, start antiretroviral therapy as soon as possible
(see Initial antiretroviral therapy for HIV infection in adults).
Chickenpox in adults with HIV infection

For treatment of chickenpox, see Immunocompetent patients with complications of chickenpox and
immunocompromised patients with chickenpox.
infection. For patients with HIV and chickenpox but no other infection, start antiretroviral therapy as soon as
possible (see Initial antiretroviral therapy for HIV infection in adults).
Shingles in adults with HIV infection

For treatment and maintenance therapy (secondary prophylaxis) of shingles (herpes zoster), see Shingles.
infection. For patients with HIV and shingles but no other infection, start antiretroviral therapy as soon as possible
(see Initial antiretroviral therapy for HIV infection in adults).
Further reading
For general HIV guidelines, see here.
Opportunistic and co-infection guidelines for adults with HIV infection:
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM). HIV management in
Australasia - a guide for clinical care. [regularly updated]. [URL]
British HIV Association (BHIVA). British HIV Association and British Infection Association guidelines for the
treatment of opportunistic infection in HIV-seropositive individuals. [regularly updated]. [URL]
European AIDS Clinical Society (EACS). European Guidelines for treatment of HIV-positive adults in Europe.
Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and
treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers
for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the
Infectious Diseases Society of America. [regularly updated]. [URL]
Opportunistic and co-infection guidelines for children with HIV infection:
Children’s HIV Association (CHIVA). CHIVA guidelines. [URL]
treatment of opportunistic infections in HIV-exposed and HIV-infected children. [regularly updated]. [URL]
Key references
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM). HIV management in Australasia: a
guide for clinical care. Sydney: ASHM; Accessed Aug 2018. http://hivmanagement.ashm.org.au/
European AIDS Clinical Society (EACS). European Guidelines for treatment of HIV-positive adults in Europe. Version
Nelson M, Dockrell D, Edwards S, BHIVA Guidelines Subcommittee, Angus B, Barton S, et al. British HIV Association
and British Infection Association guidelines for the treatment of opportunistic infection in HIV-seropositive individuals
2011. HIV Med 2011;12 Suppl 2:1–140.
Approach to managing intra-abdominal infections
Assessment of intra-abdominal infections
Before starting antibiotic therapy for an intra-abdominal infection, consider noninfectious differential
diagnoses. For example, ischaemic colitis usually presents as sudden-onset abdominal pain, associated with
rectal bleeding and progressively worsening diarrhoea. Uncomplicated ischaemic colitis does not require
antibiotic treatment unless there is a strong suspicion of perforated viscus and peritonitis (or peritoneal
soiling).
Obtain samples from infected sites for culture and susceptibility testing; samples of pus are preferred to
swabs. Direct aspiration of potentially infected fluid collections, or operative debridement of infected tissue
are the most reliable methods of obtaining samples for culture. Samples collected from indwelling surgical
drains are often contaminated; avoid using these samples for culture, as the results can be inaccurate and
misleading.
Rationale for empirical therapy for intra-abdominal infections

Intra-abdominal infections are generally polymicrobial and caused by intestinal flora.
Empirical therapy of intra-abdominal infections should include antibiotics with activity against
Enterobacteriaceae (enteric aerobic Gram-negative bacilli) and streptococci. Activity against enteric
anaerobic bacteria is also required if the distal small bowel, appendix or colon is involved, and for more
proximal gastrointestinal perforations in the presence of obstruction or paralytic ileus. Additional anaerobic
therapy (eg metronidazole) is not required if amoxicillin+clavulanate, piperacillin+tazobactam, clindamycin
or lincomycin are used.
Empirical therapy does not need to have activity against enterococci; therapy should be modified if
enterococci are isolated from diagnostic samples. Empirical antifungal therapy is not usually required;
however, consider antifungal therapy if yeasts are identified in samples from deep surgical sites—seek expert
advice.
Gentamicin (in combination with amoxicillin or ampicillin) is preferred to broad-spectrum penicillins or

cephalosporins for empirical therapy because it is active against a greater percentage of Enterobacteriaceae,
and is more rapidly bactericidal. Gentamicin is also less likely to contribute to the development of
Clostridium difficile infection and the selection of antibiotic-resistant organisms.
Intravenous amoxicillin+clavulanate is not recommended for first-line empirical therapy for intra-abdominal
infections in these guidelines. In Australia, amoxicillin+clavulanate resistance among some Gram-negative
bacteria is higher than rates of resistance to other (first-line) antibiotics. Local guidelines should be guided by
local susceptibility data. Oral amoxicillin+clavulanate is recommended for empirical therapy for nonsevere
intra-abdominal infections and as oral continuation therapy because in these situations, illness is not severe
and the bacterial load is likely to be low.
In community-acquired infections, the antimicrobial susceptibility of intestinal flora is usually predictable.

However, highly resistant pathogens (such as vancomycin-resistant enterococci and multidrug-resistant
Enterobacteriaceae) are sometimes seen in patients with risk factors for infection with a multidrug-resistant
Gram-negative bacterium (see Box 2.30). These patients may also develop infection with pathogens (such as
Candida species) that are otherwise uncommon in intra-abdominal infections. Seek expert advice to guide
antimicrobial choice.
Adjustments to empirical therapy for intra-abdominal infections in

patients undergoing surgery
Patients with an intra-abdominal infection who are undergoing surgery require surgical prophylaxis. If the
regimen used to treat the intra-abdominal infection has an appropriate spectrum of activity for prophylaxis,
additional surgical prophylaxis is not required. However, adjust the timing of the dose to achieve adequate
plasma and tissue concentrations at the time of surgical incision and for the duration of the procedure—see
also Surgical antibiotic prophylaxis for patients receiving treatment for established infection.
Key references
Australian Commission on Safety and Quality in Health Care (ACSQHC). AURA 2017: second Australian report
on antimicrobial use and resistance in human health. Sydney: ACSQHC; 2017.
https://www.safetyandquality.gov.au/antimicrobial-use-and-resistance-in-australia/resources-page/.
Everts RJ, Heneghan JP, Adholla PO, Reller LB. Validity of cultures of fluid collected through drainage catheters
versus those obtained by direct aspiration. J Clin Microbiol 2001;39(1):66–68 .
Knitsch W, Vincent JL, Utzolino S, François B, Dinya T, Dimopoulos G, et al. A randomized, placebo-controlled
trial of preemptive antifungal therapy for the prevention of invasive candidiasis following gastrointestinal surgery
for intra-abdominal infections. Clin Infect Dis 2015;61(11):1671–1678 .
Acute appendicitis
Assessment of acute appendicitis
Appendicitis begins as inflammation of the appendiceal wall, and may be followed by localised ischaemia,
perforation, and the development of an appendiceal abscess or generalised peritonitis. The incidence of acute
appendicitis is declining; children remain most commonly affected. Ultrasound or computed tomography (CT)
enables a more precise diagnosis before surgery and decreases the chance of a normal appendix being removed.
Ultrasound is preferred for children, young adults and pregnant women, to avoid radiation from CT. Magnetic
resonance imaging (MRI) is highly sensitive and specific and may be used for patients with inconclusive findings
on ultrasound or CT.
See also Assessment of intra-abdominal infections.
Treatment of acute appendicitis

Approach to treatment of acute appendicitis
Surgical drainage and appendicectomy are the mainstays of treatment for appendicitis; evidence does not support
the routine treatment of appendicitis with antibiotic therapy alone. Multiple randomised controlled trials have
shown that antibiotic therapy alone is less effective than appendicectomy (with or without antibiotic therapy) for
acute uncomplicated appendicitis (acute nonperforated appendicitis). Treatment failure rates for antibiotics alone
(ie readmission, complications and need for repeat surgery) in the first year were 15 to 30% and up to 40% at 5
years. Treatment failure rates for appendicectomy were less than 2%. Initial treatment with antibiotic therapy alone
may avoid the need for surgery in 60 to 85% of patients; however, this is at the cost of a significant failure rate.
Empirical antibiotic therapy for acute appendicitis

For the treatment of patients with acute appendicitis who have sepsis or septic shock, see Sepsis and septic shock
from a biliary or gastrointestinal tract source. For definitions of sepsis and septic shock, see Early recognition of
sepsis or septic shock in adults or Early recognition of sepsis or septic shock in neonates, infants and children.
For empirical therapy of acute appendicitis, pending surgery, as a three-drug regimen, use:
gentamicin intravenously; see Principles of aminoglycoside use for dosage and principles
of use and see Modification and duration of therapy for acute appendicitis
PLUS
Modification and duration of therapy for acute appendicitis
PLUS EITHER
1 amoxicillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly; see Modification and

duration of therapy for acute appendicitis
OR
1 ampicillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly; see Modification and

duration of therapy for acute appendicitis.
See also Rationale for empirical therapy for intra-abdominal infections and Adjustments to empirical therapy for
intra-abdominal infections in patients undergoing surgery.
If gentamicin is contraindicated (see Box 2.42), use:
1 ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously, daily; see

OR
1 cefotaxime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly; see Modification and
duration of therapy for acute appendicitis
OR (as a single drug)
2 amoxicillin+clavulanate intravenously; see Modification and duration of therapy for acute

appendicitis
adult: 1+0.2 g 8-hourly. If the patient has an appendiceal abscess, use a dose of 1+0.2 g 6-
hourly [Note 1]
child 3 months or older: 25+5 mg/kg up to 1+0.2 g 8-hourly. If the child has an
appendiceal abscess, use a dose of 25+5 mg/kg up to 1+0.2 g 6-hourly [Note 2].
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use the ceftriaxone-
or cefotaxime-containing regimen above.
of use and see Modification and duration of therapy for acute appendicitis
PLUS EITHER
1 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly; see

OR
2 lincomycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly; see

Modification and duration of therapy for acute appendicitis.
adults with an appendiceal abscess, a reasonable alternative regimen is 2+0.2 g intravenously, 8-hourly.
children with an appendiceal abscess who weigh 40 kg or more, a reasonable alternative regimen is 2+0.2 g intravenously, 8-hourly.
For patients with acute uncomplicated appendicitis, stop antibiotic therapy immediately after appendicectomy.
For patients with acute uncomplicated appendicitis, stop antibiotic therapy immediately after appendicectomy.
For patients with complicated appendicitis (perforated appendicitis or appendiceal abscess), modify therapy based
on the results of culture and susceptibility testing (if available). If the results of susceptibility testing are not
and use the ceftriaxone- or cefotaxime-containing regimen, or amoxicillin+clavulanate as for Empirical antibiotic
therapy for acute appendicitis.
Switch to oral therapy once the patient is improving, haemodynamically stable and able to tolerate oral medication
—see Guidance for antimicrobial intravenous to oral switch. If results of susceptibility testing are not available, for
oral continuation therapy for patients with perforated appendicitis or appendiceal abscess, use:

875+125 mg) orally, 12-hourly [Note 3].

trimethoprim+sulfamethoxazole 160+800 mg (child 1 month or older: 4+20 mg/kg up to
160+800 mg) orally, 12-hourly
PLUS
metronidazole 400 mg (child: 10 mg/kg up to 400 mg) orally, 12-hourly.
For patients with a perforated appendix or an appendiceal abscess, the total duration of therapy is 5 days
(intravenous + oral) after adequate surgical control of the source of infection has been achieved.
Key references
Ansaloni L, Catena F, Coccolini F, Ercolani G, Gazzotti F, Pasqualini E, et al. Surgery versus conservative antibiotic
treatment in acute appendicitis: a systematic review and meta-analysis of randomized controlled trials. Dig Surg
2011;28(3):210–221 .
antimicrobial use and resistance in human health. Sydney: ACSQHC; 2017.
https://www.safetyandquality.gov.au/antimicrobial-use-and-resistance-in-australia/resources-page/ .
Barger RL Jr, Nandalur KR. Diagnostic performance of magnetic resonance imaging in the detection of appendicitis in
adults: a meta-analysis. Acad Radiol 2010;17(10):1211–1216 .
Coakley BA, Sussman ES, Wolfson TS, Bhagavath AS, Choi JJ, Ranasinghe NE, et al. Postoperative antibiotics
correlate with worse outcomes after appendectomy for nonperforated appendicitis. J Am Coll Surg 2011;213(6):778–
783 .
Huang L, Yin Y, Yang L, Wang C, Li Y, Zhou Z. Comparison of Antibiotic Therapy and Appendectomy for Acute
Uncomplicated Appendicitis in Children: A Meta-analysis. JAMA Pediatr 2017;171(5):426–434 .
Kronman MP, Oron AP, Ross RK, Hersh AL, Newland JG, Goldin A, et al. Extended- Versus Narrower-Spectrum
Antibiotics for Appendicitis. Pediatrics 2016;138(1): .
Mason RJ, Moazzez A, Sohn H, Katkhouda N. Meta-analysis of randomized trials comparing antibiotic therapy with
appendectomy for acute uncomplicated (no abscess or phlegmon) appendicitis. Surg Infect (Larchmt) 2012;13(2):74–
84 .
Sakran JV, Mylonas KS, Gryparis A, Stawicki SP, Burns CJ, Matar MM, et al. Operation versus antibiotics--The
"appendicitis conundrum" continues: A meta-analysis. J Trauma Acute Care Surg 2017;82(6):1129–1137 .
Salminen P, Paajanen H, Rautio T, Nordström P, Aarnio M, Rantanen T, et al. Antibiotic Therapy vs Appendectomy for
Treatment of Uncomplicated Acute Appendicitis: The APPAC Randomized Clinical Trial. JAMA 2015;313(23):2340–
2348 .
Salminen P, Tuominen R, Paajanen H, Rautio T, Nordström P, Aarnio M, et al. Five-Year Follow-up of Antibiotic
Therapy for Uncomplicated Acute Appendicitis in the APPAC Randomized Clinical Trial. JAMA 2018;320(12):1259–
1265 .
Sawyer RG, Claridge JA, Nathens AB, Rotstein OD, Duane TM, Evans HL, et al. Trial of short-course antimicrobial
therapy for intraabdominal infection. N Engl J Med 2015;372(21):1996–2005 .
van Rossem CC, Schreinemacher MH, Treskes K, van Hogezand RM, van Geloven AA. Duration of antibiotic
treatment after appendicectomy for acute complicated appendicitis. Br J Surg 2014;101(6):715–719 .
Varadhan KK, Neal KR, Lobo DN. Safety and efficacy of antibiotics compared with appendicectomy for treatment of
uncomplicated acute appendicitis: meta-analysis of randomised controlled trials. BMJ 2012;344:e2156. .
Acute cholangitis
Treatment of acute cholangitis
Approach to treatment of acute cholangitis
Acute (ascending) cholangitis is a medical emergency; it is usually associated with Gram-negative bacteraemia.
Patients with chronic biliary obstruction are more likely to have an infection involving anaerobic bacteria. Urgent
relief of biliary obstruction and prompt antibiotic therapy is required. Take blood samples for culture and
susceptibility testing before starting antibiotic therapy. See also Assessment of intra-abdominal infections.
Empirical antibiotic therapy for acute cholangitis
For the treatment of patients with acute cholangitis who have sepsis or septic shock, see Sepsis and septic shock
from a biliary or gastrointestinal tract source. For definitions of sepsis and septic shock, see Early recognition of
sepsis or septic shock in adults or Early recognition of sepsis or septic shock in neonates, infants and children.
For empirical therapy of acute cholangitis, as a two-drug regimen, use:
of use and see Modification and duration of therapy for acute cholangitis
PLUS EITHER

duration of therapy for acute cholangitis
OR

duration of therapy for acute cholangitis.
For patients with chronic biliary obstruction, add metronidazole to the above regimen:
Modification and duration of therapy for acute cholangitis.

Modification and duration of therapy for acute cholangitis
OR

duration of therapy for acute cholangitis
OR

hourly; see Modification and duration of therapy for acute cholangitis.
For patients with chronic biliary obstruction, add metronidazole (see dosage above) to the ceftriaxone or
cefotaxime regimens. Metronidazole is not required if piperacillin+tazobactam is used.
cefotaxime as above.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, gentamicin as a single drug
is usually adequate.
Modification and duration of therapy for acute cholangitis
Modify therapy based on the results of culture and susceptibility testing, if available. If the results of susceptibility
testing are not available by 72 hours and empirical intravenous therapy is still required, stop the gentamicin-
containing regimen and use ceftriaxone, cefotaxime or piperacillin+tazobactam, as for Empirical antibiotic therapy
for acute cholangitis.
oral continuation therapy for acute cholangitis, use:


PLUS for patients with chronic biliary obstruction
For patients who have not undergone biliary drainage, the total duration of therapy is 7 to 10 days (intravenous
+ oral).
For patients who have undergone biliary drainage, the total duration of therapy is 5 days (intravenous + oral)
after drainage.
Prevention of recurrent cholangitis

For patients with recurrent cholangitis associated with ongoing bile duct disease, long-term antibiotic prophylaxis
may reduce the frequency of recurrences. Seek expert advice on antibiotic choice; the susceptibility of bacteria
isolated from the patient in previous episodes should guide therapy. Antimicrobial resistance often emerges over
time and, if possible, a definitive surgical approach is preferred.
Key references
Mayumi T, Okamoto K, Takada T, Strasberg SM, Solomkin JS, Schlossberg D, et al. Tokyo Guidelines 2018:
management bundles for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci 2018;25(1):96–100
.
Park TY, Choi JS, Song TJ, Do JH, Choi SH, Oh HC. Early oral antibiotic switch compared with conventional
intravenous antibiotic therapy for acute cholangitis with bacteremia. Dig Dis Sci 2014;59(11):2790–2796 .
Acute cholecystitis
Acute calculous cholecystitis
Approach to managing acute calculous cholecystitis
Acute calculous cholecystitis is usually caused by Enterobacteriaceae (eg Escherichia coli and Klebsiella species)
and, less commonly, Enterococcus faecalis. Infrequently, infection is caused by anaerobic bacteria.
In addition to antibiotic therapy, laparoscopic cholecystectomy should be considered at an early stage of initial
presentation. Several randomised controlled trials have demonstrated superior outcomes when cholecystectomy is
performed during the initial admission rather than delaying the procedure.
Empirical antibiotic therapy for acute calculous cholecystitis
For the treatment of patients with acute calculous cholecystitis who have sepsis or septic shock, see Sepsis and
septic shock from a biliary or gastrointestinal tract source. For definitions of sepsis and septic shock, see Early
and children.
For empirical therapy of acute calculous cholecystitis, as a two-drug regimen, use:
of use and see Modification and duration of therapy for acute calculous cholecystitis
PLUS EITHER

duration of therapy for acute calculous cholecystitis
OR

duration of therapy for acute calculous cholecystitis.
1 amoxicillin+clavulanate intravenously; see Modification and duration of therapy for acute

calculous cholecystitis
adult: 1+0.2 g 8-hourly. If the patient has an abscess, use a dose of 1+0.2 g 6-hourly [Note
1]
child 3 months or older: 25+5 mg/kg up to 1+0.2 g 8-hourly. If the child has an abscess,
use a dose of 25+5 mg/kg up to 1+0.2 g 6-hourly [Note 2]
OR

Modification and duration of therapy for acute calculous cholecystitis
OR

duration of therapy for acute calculous cholecystitis.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, gentamicin as a single drug
is usually adequate.
adults with an abscess, a reasonable alternative regimen is 2+0.2 g intravenously, 8-hourly.
children with an abscess who weigh 40 kg or more, a reasonable alternative regimen is 2+0.2 g intravenously, 8-hourly.
Modification and duration of therapy for acute calculous cholecystitis
For patients who undergo a cholecystectomy, stop antibiotic therapy immediately after the procedure as the source
of infection has been removed and several randomised controlled trials show no benefit from postoperative
antibiotics.
Stop antibiotic therapy immediately after cholecystectomy.
If empirical intravenous therapy is required beyond 72 hours, stop the gentamicin-containing regimen and use
amoxicillin+clavulanate, ceftriaxone or cefotaxime as for Empirical antibiotic therapy for acute calculous
cholecystitis. Switch to oral therapy once the patient is improving, haemodynamically stable and able to tolerate
oral medication—see Guidance for antimicrobial intravenous to oral switch. If oral continuation therapy is
required for acute calculous cholecystitis, use:

For patients with hypersensitivity to penicillins, for oral continuation therapy, use:

The total duration of therapy should not exceed 7 days (intravenous + oral).
Acute acalculous cholecystitis

Approach to managing acute acalculous cholecystitis
Acute acalculous cholecystitis is an uncommon variant of cholecystitis and accounts for about 10% of cases.
Acalculous cholecystitis presents without gall stones and is usually associated with a thickened or emphysematous
gallbladder wall. It is more likely to occur in patients who are critically ill, immunocompromised or those with
diabetes. Pathogens include those that commonly cause calculous cholecystitis (eg Enterobacteriaceae and
streptococci), Pseudomonas aeruginosa and anaerobes.
If acalculous cholecystitis is not promptly treated, there is a high risk of gall bladder perforation and mortality.
Early cholecystotomy or cholecystectomy is essential. Take blood samples for culture and susceptibility testing
before starting antibiotic therapy.
Empirical antibiotic therapy for acute acalculous cholecystitis
For the treatment of patients with acute acalculous cholecystitis who have sepsis or septic shock, see Sepsis and
septic shock from a biliary or gastrointestinal tract source. For definitions of sepsis and septic shock, see Early
and children.
For empirical therapy of acute acalculous cholecystitis, as a three-drug regimen, use:
of use and see Modification and duration of therapy for acute acalculous cholecystitis
PLUS
Modification and duration of therapy for acute acalculous cholecystitis
PLUS EITHER

duration of therapy for acute acalculous cholecystitis
OR

duration of therapy for acute acalculous cholecystitis.

hourly; see Modification and duration of therapy for acute acalculous cholecystitis.
For patients with hypersensitivity to penicillins, as a two-drug regimen, use:
of use and see Modification and duration of therapy for acute acalculous cholecystitis
PLUS EITHER

OR

Modification and duration of therapy for acute acalculous cholecystitis.
If intravenous therapy is required beyond 72 hours, stop the gentamicin-containing regimen and use the results of
culture and susceptibility testing to guide ongoing therapy.
The total duration of therapy is 5 days (intravenous + oral) after adequate surgical control of the source of
infection has been achieved. For the appropriateness of intravenous to oral switch and oral antibiotic choice, seek
expert advice.
Key references
Cao AM, Eslick GD, Cox MR. Early Cholecystectomy Is Superior to Delayed Cholecystectomy for Acute Cholecystitis:
a Meta-analysis. J Gastrointest Surg 2015;19(5):848–857 .
Kim EY, Yoon YC, Choi HJ, Kim KH, Park JH, Hong TH. Is there a real role of postoperative antibiotic administration for
mildmoderate acute cholecystitis? A prospective randomized controlled trial. J Hepatobiliary Pancreat Sci
2017;24(10):550–558 .
Loozen CS, van Santvoort HC, van Duijvendijk P, Besselink MG, Gouma DJ, Nieuwenhuijzen GA, et al. Laparoscopic
cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high risk patients (CHOCOLATE):
multicentre randomised clinical trial. BMJ 2018;363:k3965. .
Menahem B, Mulliri A, Fohlen A, Guittet L, Alves A, Lubrano J. Delayed laparoscopic cholecystectomy increases the
total hospital stay compared to an early laparoscopic cholecystectomy after acute cholecystitis: an updated meta-
analysis of randomized controlled trials. HPB (Oxford) 2015;17(10):857–862 .
Ozkardeş AB, Tokaç M, Dumlu EG, Bozkurt B, Ciftçi AB, Yetişir F, et al. Early versus delayed laparoscopic
cholecystectomy for acute cholecystitis: a prospective, randomized study. Int Surg 2014;99(1):56–61 .
Regimbeau JM, Fuks D, Pautrat K, Mauvais F, Haccart V, Msika S. Effect of postoperative antibiotic administration on
postoperative infection following cholecystectomy for acute calculous cholecystitis: a randomized clinical trial. JAMA
2014;312(2):145–154 .
Roulin D, Saadi A, Di Mare L, Demartines N, Halkic N. Early Versus Delayed Cholecystectomy for Acute Cholecystitis,
Are the 72 hours Still the Rule?: A Randomized Trial. Ann Surg 2016;264(5):717–722 .
Soria Aledo V, Galindo Iñíguez L, Flores Funes D, Carrasco Prats M, Aguayo Albasini JL. Is cholecystectomy the
treatment of choice for acute acalculous cholecystitis? A systematic review of the literature. Rev Esp Enferm Dig
2017;109(10):708–718 .
van Dijk AH, de Reuver PR, Tasma TN, van Dieren S, Hugh TJ, Boermeester MA. Systematic review of antibiotic
treatment for acute calculous cholecystitis. Br J Surg 2016;103(7):797–811 .
Diverticulitis
Assessment of diverticulitis
Diverticulitis occurs when a colonic diverticulum becomes inflamed. Diverticulitis usually presents with
abdominal pain in the left lower quadrant and fever, often with an altered bowel habit. Consider alternative
diagnoses (eg irritable bowel syndrome, colonic malignancy), because a diagnosis of diverticulitis made by clinical
criteria alone is often incorrect. See also Assessment of intra-abdominal infections.
Diverticulitis ranges in severity from subclinical local inflammation to generalised peritonitis following
perforation. The majority of diverticulitis episodes are uncomplicated (nonsevere).
Complicated (severe) diverticulitis refers to diverticulitis with a positive blood culture result, perforation,
peritonitis, sepsis or septic shock, or an abscess larger than 5 cm in diameter. Diverticulitis without any of these
features is considered uncomplicated—see Uncomplicated (nonsevere) diverticulitis.
See also Diverticulosis for prevention of diverticulitis, and Diverticular bleeding.
Uncomplicated (nonsevere) diverticulitis

Patients with uncomplicated diverticulitis (ie diverticulitis without perforation, peritonitis, sepsis or septic shock,
or an abscess larger than 5 cm in diameter) may not require antibiotic therapy. Immunocompetent patients with
uncomplicated left-sided diverticulitis do not routinely require antibiotics. Several randomised controlled trials
have demonstrated that antibiotic therapy is not beneficial to these patients. Antibiotic therapy is appropriate for
patients with any of the following features:
immune compromise
right-sided diverticulitis
failure to improve after 72 hours of conservative treatment (ie no antibiotic therapy).
If antibiotic therapy is indicated for uncomplicated diverticulitis, use:
PLUS
Complicated (severe) diverticulitis

Approach to managing complicated diverticulitis
Complicated diverticulitis (ie diverticulitis with a positive blood culture result, perforation, peritonitis, sepsis or
septic shock, or an abscess larger than 5 cm in diameter) is managed with bowel rest, intravenous fluids and
intravenous antibiotic therapy. Surgery should be considered if there is peritonitis associated with perforation, an
abscess that is not amenable to percutaneous drainage, or bowel obstruction.
Empirical antibiotic therapy for complicated diverticulitis

For the treatment of patients with diverticulitis who have sepsis or septic shock, see Sepsis and septic shock from a
biliary or gastrointestinal tract source. For definitions of sepsis and septic shock, see Early recognition of sepsis or
septic shock in adults or Early recognition of sepsis or septic shock in neonates, infants and children.
For empirical therapy of complicated diverticulitis, as a three-drug regimen, use:
of use and see Modification and duration of therapy for complicated diverticulitis
PLUS

for complicated diverticulitis
PLUS EITHER

complicated diverticulitis
OR
1 ampicillin 2 g intravenously, 6-hourly; see Modification and duration of therapy for

complicated diverticulitis.
1 ceftriaxone 2 g intravenously, daily; see Modification and duration of therapy for

OR
1 cefotaxime 2 g intravenously, 8-hourly; see Modification and duration of therapy for


for complicated diverticulitis
2 amoxicillin+clavulanate 1+0.2 g intravenously, 8-hourly; if the patient has an abscess, use

a dose of 1+0.2 g 6-hourly [Note 1]. See Modification and duration of therapy for
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use the ceftriaxone
or cefotaxime-containing regimen above.
of use and see Modification and duration of therapy for complicated diverticulitis
PLUS EITHER
OR
adults with an abscess, a reasonable alternative regimen is 2+0.2 g intravenously, 8-hourly.
Modification and duration of therapy for complicated diverticulitis
Modify therapy based on the results of culture and susceptibility testing, if available. If results of susceptibility
containing regimen and use the ceftriaxone or cefotaxime-containing regimen, or amoxicillin+clavulanate as for
Empirical antibiotic therapy for complicated diverticulitis above.
oral continuation therapy, see the regimens in Uncomplicated (nonsevere) diverticulitis.
For patients who have not undergone surgery, the total duration of therapy is 7 to 10 days (intravenous + oral).
For patients who have undergone surgery, the total duration of therapy is 5 days (intravenous + oral) after
adequate surgical control of the source of infection has been achieved.
Key references
Daniels L, Ünlü Ç, de Korte N, van Dieren S, Stockmann HB, Vrouenraets BC, et al. Randomized clinical trial of
observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis. Br J Surg
2017;104(1):52–61 .
Mazuski JE, Tessier JM, May AK, Sawyer RG, Nadler EP, Rosengart MR, et al. The Surgical Infection Society Revised
Guidelines on the Management of Intra-Abdominal Infection. Surg Infect (Larchmt) 2017;18(1):1–76 .
van Dijk ST, Daniels L, Ünlü Ç, de Korte N, van Dieren S, Stockmann HB, et al. Long-Term Effects of Omitting
Antibiotics in Uncomplicated Acute Diverticulitis. Am J Gastroenterol 2018;113(7):1045–1052 .
Peritonitis due to perforated viscus
Approach to managing peritonitis due to perforated viscus
Peritonitis due to perforated viscus is usually a polymicrobial infection caused by aerobic and anaerobic bowel
flora. Surgery is usually required.
Intra-abdominal abscesses (eg subphrenic and paracolic abscesses) may complicate peritonitis and initially be
difficult to diagnose, presenting as a spiking fever with no clear clinical focus. If possible, a diagnostic sample of
intra-abdominal pus should be obtained to help guide therapy—see also Assessment of intra-abdominal infections.
Adequate drainage is required for the successful treatment of intra-abdominal abscesses.
Empirical antibiotic therapy for peritonitis due to perforated viscus

For the treatment of patients with peritonitis due to perforated viscus who have sepsis or septic shock, see Sepsis
and septic shock from a biliary or gastrointestinal tract source. For definitions of sepsis and septic shock, see Early
and children.
For empirical therapy of peritonitis due to perforated viscus, as a three-drug regimen, use:
of use and see Modification and duration of therapy for peritonitis due to perforated viscus
PLUS
Modification and duration of therapy for peritonitis due to perforated viscus
PLUS EITHER

duration of therapy for peritonitis due to perforated viscus
OR

duration of therapy for peritonitis due to perforated viscus.
intra-abdominal infection in patients undergoing surgery.
Empirical antifungal therapy is not usually required; however, consider antifungal therapy if yeasts are identified in
samples from deep surgical sites—seek expert advice.

hourly; see Modification and duration of therapy for peritonitis due to perforated viscus.
regimen, use:

OR

duration of therapy for peritonitis due to perforated viscus

Modification and duration of therapy for peritonitis due to perforated viscus.
of use and see Modification and duration of therapy for peritonitis due to perforated viscus
PLUS EITHER

OR

Modification and duration of therapy for peritonitis due to perforated viscus.
Modification and duration of therapy for peritonitis due to perforated

viscus
Modify therapy based on the results of culture and susceptibility testing, if available, ensuring the regimen has
activity against streptococci, Enterobacteriaceae and anaerobes. However, if the patient is improving and surgical
control of the source of infection was adequate, do not broaden antibiotic therapy. If the results of susceptibility
containing regimen and use piperacillin+tazobactam as for Empirical antibiotic therapy for peritonitis due to
perforated viscus.
oral continuation therapy for peritonitis due to perforated viscus, use:

For patients with hypersensitivity to penicillins, for oral continuation therapy, use:

PLUS
The total duration of therapy is 5 days (intravenous + oral) after adequate control of the source of infection has
been achieved.
Patients with residual undrained intra-abdominal collections or abscesses often require a longer duration of therapy
(up to 4 to 6 weeks depending on clinical and radiological progress). For the appropriateness of intravenous to oral
switch and duration of therapy, seek expert advice. Community-based parenteral antimicrobial therapy may be
appropriate for patients requiring a longer duration of intravenous therapy.
Key references
Knitsch W, Vincent JL, Utzolino S, François B, Dinya T, Dimopoulos G, et al. A randomized, placebo-controlled trial of
preemptive antifungal therapy for the prevention of invasive candidiasis following gastrointestinal surgery for intra-
abdominal infections. Clin Infect Dis 2015;61(11):1671–1678 .
Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, et al. Diagnosis and management of
complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the
Infectious Diseases Society of America. Clin Infect Dis 2010;50(2):133–164 .
Sepsis and septic shock from a biliary or
gastrointestinal tract source
Empirical therapy for sepsis and septic shock from a biliary or
gastrointestinal tract source
For patients with sepsis or septic shock from a biliary or gastrointestinal tract source (see Early recognition of
sepsis or septic shock in adults or Early recognition of sepsis or septic shock in neonates, infants and children for
definitions), start antibiotic therapy within 1 hour of the patient presenting to medical care or, for a ward-based
patient, developing sepsis or septic shock; antibiotics should be given immediately after blood samples are taken
shock. For additional assessment considerations, see Assessment of intra-abdominal infections.
Treatment of sepsis or septic shock from a biliary or gastrointestinal tract source in neonates is complex and should
be based on local protocols, or clinical microbiology or infectious diseases advice. If these are not immediately
available, for treatment of term neonates with early-onset infection (occurring within 72 hours of birth), see here;
for treatment of neonates with late-onset infection (occurring more than 72 hours after birth), see here. Prompt
antibiotic initiation in sepsis and septic shock improves outcomes.
The following empirical regimens are intended for initial therapy only (up to 48 hours). Modify therapy as soon as
additional information is available (eg results of Gram stain, culture and susceptibility testing). Evaluate
appropriateness of antimicrobial therapy daily, with consideration given to the patient’s clinical status and the
For empirical therapy of sepsis or septic shock from a biliary or gastrointestinal tract source, as a three-drug
regimen, use:

adults without septic shock and not requiring intensive care support: 4 to 5 mg/kg
intravenously, for the first dose. See Principles of aminoglycoside use for subsequent
dosing [Note 2] [Note 3]
child younger than 10 years: 7.5 mg/kg up to 320 mg, for the first dose; see Principles of
child 10 years and older with septic shock or requiring intensive care support: 7 mg/kg
for the first dose; see Principles of aminoglycoside use for subsequent dosing [Note 5]
child 10 years and older without septic shock and not requiring intensive care support: 6
PLUS
metronidazole 500 mg (child: 12.5 mg/kg up to 500 mg) intravenously, 12-hourly
PLUS EITHER
1 amoxicillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly
OR
1 ampicillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly.


hourly.
regimen, use:

older: 50 mg/kg up to 1 g) intravenously, 12-hourly
OR

septic shock or requiring intensive care support, use 2 g (child 1 month or older: 50 mg/kg
up to 2 g) intravenously, 6-hourly

for the first dose; see Principles of aminoglycoside use for subsequent dosing [Note 5]
child 10 years and older without septic shock and not requiring intensive care support: 6
PLUS EITHER
OR
calculate the dose.
function.
Key references
Spontaneous bacterial peritonitis
Aetiology and assessment of spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis (SBP) is usually a complication of large-volume ascites in patients with cirrhosis.
In adults, the most common pathogens are Enterobacteriaceae (such as Escherichia coli and Klebsiella species).
Streptococcus pneumoniae, other streptococci, and enterococci occasionally cause infection; anaerobic bacteria are
uncommon pathogens. In children, spontaneous bacterial peritonitis may occur as a primary phenomenon (without
prior pathology) or as a complication of nephrotic syndrome; in both cases S. pneumoniae is the most common
cause.
Suspect spontaneous bacterial peritonitis in patients with ascites whose clinical state deteriorates. Abdominal
tenderness may be absent. Perform an ascitic tap for patients with chronic liver disease and ascites who develop
fever (temperature higher than 38°C), encephalopathy, septic shock or deteriorating kidney function, unless there is
an alternative explanation. Request ascitic fluid microscopy for Gram stain and cell count, and inoculate ascitic
fluid directly into blood culture bottles for culture and susceptibility testing. Microscopy of ascitic fluid that
identifies total white cell count more than 0.5 x 109/L or neutrophil count more than 0.25 x 109/L is diagnostic of
spontaneous bacterial peritonitis.
Treatment of spontaneous bacterial peritonitis

For empirical therapy of spontaneous bacterial peritonitis (SBP), use:
OR
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use the above
regimen.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, ciprofloxacin or aztreonam
are treatment options—seek expert advice.
Streptococcal or enterococcal infection is more common in patients who develop spontaneous bacterial peritonitis
while receiving prophylaxis with trimethoprim+sulfamethoxazole or norfloxacin. Nosocomial spontaneous
bacterial peritonitis is more likely to be caused by ceftriaxone-resistant Gram-negative bacteria. For these patient
groups, use piperacillin+tazobactam for empirical therapy.
Modify antibiotic therapy according to the results of culture and susceptibility testing. If signs and symptoms of
infection improve rapidly, treat for 5 days.
Patients with spontaneous bacterial peritonitis and chronic liver disease who have kidney impairment or jaundice
are at high risk of developing hepatorenal syndrome. Albumin reduces the rate of acute kidney injury and
improves survival. For these adults, use:
albumin 20% 7.5 mL/kg intravenously, within 6 hours of diagnosis and 5 mL/kg
intravenously, as a single dose on day 3.
Seek expert advice about the use of albumin in children.
Prevention of spontaneous bacterial peritonitis in patients with

cirrhosis
After a first episode of spontaneous bacterial peritonitis (SBP), secondary antibiotic prophylaxis reduces the risk of
subsequent episodes and all-cause mortality in patients with ascites due to cirrhosis.
For secondary prophylaxis of spontaneous bacterial peritonitis, use:

160+800 mg) orally, daily.
For patients with hypersensitivity to trimethoprim+sulfamethoxazole or if a trimethoprim+sulfamethoxazole-

resistant organism is cultured, use:
norfloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally, daily [Note 1] [Note 2].
Primary antibiotic prophylaxis is only recommended for patients at high risk of spontaneous bacterial
peritonitis; prophylaxis reduces the risk of spontaneous bacterial peritonitis and all-cause mortality in these
patients. To be considered at high risk, patients must have cirrhosis, ascites, an ascitic fluid protein concentration
less than 15 g/L, and at least one of:
impaired kidney function (serum creatinine 110 micromol/L or more, serum urea nitrogen 8.9 mmol/L or
more, or serum sodium 130 mmol/L or less), or
liver failure (Child–Turcotte–Pugh [Child–Pugh] score 9 or more and serum bilirubin 50 micromol/L or
more).
For primary antibiotic prophylaxis, use the same regimen as for secondary prophylaxis.
Note 1: Norfloxacin is not licensed for use in children on the basis of animal studies that showed an adverse effect on cartilage development with
quinolone use; however, there are few data from human trials to support this finding. Norfloxacin can be used in children when it is the drug of choice.
Note 2: An oral liquid formulation of norfloxacin is not commercially available; for formulation options for children or people with swallowing
Key references
European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with
decompensated cirrhosis. J Hepatol 2018;69(2):406–460 .
Fernández J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, et al. Primary prophylaxis of spontaneous
bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology
2007;133(3):818–824 .
Grangé JD, Roulot D, Pelletier G, Pariente EA, Denis J, Ink O, et al. Norfloxacin primary prophylaxis of bacterial
infections in cirrhotic patients with ascites: a double-blind randomized trial. J Hepatol 1998;29(3):430–436 .
Lontos S, Shelton E, Angus PW, Vaughan R, Roberts SK, Gordon A, et al. A randomized controlled study of
trimethoprim-sulfamethoxazole versus norfloxacin for the prevention of infection in cirrhotic patients. J Dig Dis
2014;15(5):260–267 .
Runyon BA. Practice Guideline. Management of adult patients with ascites due to cirrhosis: Update 2012. Alexandria,
Virginia: American Association for the Study of Liver Diseases; 2012. https://www.aasld.org/publications/practice-
guidelines-0.
Salerno F, Navickis RJ, Wilkes MM. Albumin infusion improves outcomes of patients with spontaneous bacterial
peritonitis: a meta-analysis of randomized trials. Clin Gastroenterol Hepatol 2013;11(2):123–30.e1 .
Peritonitis complicating peritoneal dialysis
Assessment and aetiology of peritonitis complicating peritoneal dialysis
Suspect peritonitis in patients undergoing peritoneal dialysis who have cloudy dialysate. The diagnosis is
confirmed by microscopy and culture of dialysate. The most common pathogens are coagulase-negative
staphylococci (eg Staphylococcus epidermidis), Staphylococcus aureus, Enterobacteriaceae, and Streptococcus and
Enterococcus species. Fungal infection is uncommon.
General principles of antibiotic administration for peritonitis

complicating peritoneal dialysis
The intraperitoneal route of administration is preferred for most antibiotics when treating peritonitis complicating
peritoneal dialysis, because it delivers high local concentrations. However, most antibiotics are also significantly
absorbed after intraperitoneal administration and may cause systemic effects.
The two most common modalities for peritoneal dialysis are automated peritoneal dialysis (APD), also called
continuous cycler peritoneal dialysis (CCPD), and continuous ambulatory peritoneal dialysis (CAPD). The
recommendations in this topic apply to both continuous ambulatory peritoneal dialysis and automated peritoneal
dialysis.
To be effective, antibiotics must stay within the peritoneal cavity for at least 6 hours, and this cannot be achieved
with automated peritoneal dialysis, which has 1 to 3 hour cycles. To ensure patients undergoing automated
peritoneal dialysis are adequately treated, either:
put the antibiotics in a separate 6-hour dwell, which can either be performed by the cycler (called a ‘last fill’)
or as a manual continuous ambulatory peritoneal dialysis exchange by the patient, or
temporarily switch to continuous ambulatory peritoneal dialysis for the duration of antibiotic treatment.
Treatment of peritonitis complicating peritoneal dialysis

Empirical antibiotic therapy for peritonitis complicating peritoneal dialysis
Checklist for prescribing empirical therapy for peritonitis complicating peritoneal dialysis (Box
2.8)
Is intermittent or continuous administration preferred?
The choice of intermittent or continuous administration of the drugs recommended below has not been shown to
influence patient outcomes, and is largely a matter of local preference. If intermittent dosing is used, the
antibiotic dwell time should be at least 6 hours (see also General principles of antibiotic administration for
peritonitis complicating peritoneal dialysis).
Is vancomycin required?
Vancomycin is not routinely recommended for empirical therapy because of concerns about the development of
vancomycin-resistant enterococci. However, if the patient is colonised with methicillin-resistant Staphylococcus
aureus (MRSA), has sepsis or septic shock, immediate severe or delayed severe hypersensitivity to penicillins,
or local susceptibility data suggest high cefazolin resistance rates, replace cefazolin in the intermittent regimen
with vancomycin. Compared to continuous administration, intermittent administration of vancomycin is more
convenient (less frequent dosing) and it simplifies therapeutic drug monitoring and, subsequently, dosage
adjustment.
Is diverticular disease or intestinal perforation suspected?
If diverticular disease or intestinal perforation is suspected, add metronidazole to the empirical regimen for
intermittent or continuous intraperitoneal administration.
Is gentamicin contraindicated?
See Box 2.42.
Short-term gentamicin therapy has minimal risk of affecting residual kidney function.
If gentamicin is contraindicated, replace the empirical regimen for intermittent or continuous intraperitoneal
administration (the combination of cefazolin plus gentamicin) with cefepime (as a single drug).
For empirical therapy of peritonitis complicating peritoneal dialysis, with intermittent intraperitoneal
administration, use:
gentamicin (adult and child) 0.6 mg/kg up to 50 mg, added to 1 bag of dialysis fluid per
day; see Modification and duration of therapy for peritonitis complicating peritoneal
dialysis
PLUS
cefazolin (adult and child) 15 mg/kg added to 1 bag of dialysis fluid per day; see
Modification and duration of therapy for peritonitis complicating peritoneal dialysis.
For empirical therapy of peritonitis complicating peritoneal dialysis, with continuous intraperitoneal
administration, use:
gentamicin (adult and child) added to the initial bag of dialysis fluid to achieve a
concentration of 8 mg/L, then to each subsequent bag of dialysis fluid to achieve a
concentration of 4 mg/L, up to a maximum dose of 40 mg daily; see Modification and
duration of therapy for peritonitis complicating peritoneal dialysis
PLUS
cefazolin (adult and child) added to the initial bag of dialysis fluid to achieve a
concentration of 125 mg/L; see Modification and duration of therapy for peritonitis
complicating peritoneal dialysis.
Clinical monitoring for vestibular and auditory toxicity associated with gentamicin is required—see here. Monitor
gentamicin plasma concentration if therapy is planned for longer than 48 hours—seek expert advice.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use either of the
above regimens.
If vancomycin is required (see Box 2.8), replace cefazolin in the above intermittent regimen with:
vancomycin (adult and child) 15 to 30 mg/kg up to 2 g added to 1 bag of dialysis fluid

every 3 to 7 days; see Modification and duration of therapy for peritonitis complicating
peritoneal dialysis.
Monitor trough vancomycin plasma concentration every 3 to 5 days. If the concentration falls below 15 mg/L,
repeat the dose of vancomycin, and measure the trough vancomycin plasma concentration in 3 days—see also
Principles of vancomycin use.
The dosage of vancomycin for continuous intraperitoneal administration is poorly defined; if intermittent
administration is not possible, seek expert advice for dosage.
If diverticular disease or intestinal perforation is suspected, add to all regimens:
metronidazole 400 mg (child: 10 mg/kg up to 400 mg) orally, 12-hourly; see Modification
and duration of therapy for peritonitis complicating peritoneal dialysis
OR (if oral therapy is not possible)
If gentamicin is contraindicated (see Box 2.8) use cefepime monotherapy for empirical therapy.
For intermittent intraperitoneal administration, use:
cefepime 1 g (child: 15 mg/kg up to 1 g) added to 1 bag of dialysis fluid per day; see
For continuous intraperitoneal administration, use:
cefepime (adult and child) added to the initial bag of dialysis fluid to achieve a
concentration of 125 mg/L; see Modification and duration of therapy for peritonitis
complicating peritoneal dialysis.
If the patient in whom gentamicin is contraindicated is colonised with methicillin-resistant Staphylococcus aureus
(MRSA), has sepsis or septic shock, or local susceptibility data suggest high cefazolin resistance rates, add
vancomycin (see dosage above) to the intermittent cefepime regimen. If diverticular disease or intestinal
perforation is suspected, add metronidazole (see dosage above) to either cefepime regimen.
Modification and duration of therapy for peritonitis complicating peritoneal dialysis

Modify therapy based on the results of culture and susceptibility testing, if available. After 72 hours of antibiotic
therapy, repeat microscopy and culture of dialysate. If results of susceptibility testing are not available by 72 hours
and empirical intraperitoneal therapy is still required, stop the gentamicin-containing regimen and seek expert
advice. Directed therapy for Gram-positive infections should not include gentamicin.
If the patient has not improved after 5 days of antibiotic therapy, consider removing the peritoneal dialysis catheter.
The total duration of therapy is 14 days. For peritonitis caused by S. aureus, Enterococcus species or Gram-
negative bacteria, the total duration of therapy is 21 days (irrespective of whether the peritoneal dialysis catheter
has been removed).
Indications for removal of the peritoneal dialysis catheter include:
refractory peritonitis (failure to respond to appropriate antibiotics within 5 days)

relapsing peritonitis
refractory exit-site and tunnel infection
fungal or mycobacterial peritonitis.
Prevention of peritoneal dialysis catheter exit-site and tunnel infections

Peritoneal dialysis catheter exit-site and tunnel infections increase the risk of peritonitis. Therefore, measures to
prevent these infections are important.
The risk of exit-site and tunnel infections is reduced by ensuring patients and healthcare workers practice
meticulous hand hygiene before accessing peritoneal dialysis catheters. Cleansing exit-sites with antiseptic
solution (eg chlorhexidine or povidone-iodine) may reduce the risk of infection compared to using soap and water
alone.
A Cochrane review [Note 1] concluded that nasal or topical mupirocin to prevent exit-site or tunnel infection or
peritonitis was of uncertain benefit because of the low quality of available studies. Mupirocin resistance in
Staphylococcus aureus isolates from patients undergoing continuous ambulatory peritoneal dialysis is increasing.
Note 1: Campbell D, Mudge DW, Craig JC, Johnson DW, Tong A, Strippoli GF. Antimicrobial agents for preventing peritonitis in peritoneal dialysis
patients. Cochrane Database Syst Rev 2017;(4):CD004679. [URL]
Key references
Campbell D, Mudge DW, Craig JC, Johnson DW, Tong A, Strippoli GF. Antimicrobial agents for preventing peritonitis in
peritoneal dialysis patients. Cochrane Database Syst Rev 2017;4:CD004679. .
Gucek A, Bren AF, Hergouth V, Lindic J. Cefazolin and netilmycin versus vancomycin and ceftazidime in the treatment
of CAPD peritonitis. Adv Perit Dial 1997;13:218–220 .
Khairullah Q, Provenzano R, Tayeb J, Ahmad A, Balakrishnan R, Morrison L. Comparison of vancomycin versus

cefazolin as initial therapy for peritonitis in peritoneal dialysis patients. Perit Dial Int 2002;22(3):339–344 .
Li PK, Szeto CC, Piraino B, de Arteaga J, Fan S, Figueiredo AE. ISPD Peritonitis Recommendations: 2016 Update on
Prevention and Treatment. Perit Dial Int 2016;36(5):481–508 .
Olga B, Fotis Z, Margarita I, Sofia X, Konstantinos S. Chlorhexidine for routine PD catheter exit-site care. Int Urol
Nephrol 2016;48(9):1543–1546 .
Warady BA, Bakkaloglu S, Newland J, Cantwell M, Verrina E, Neu A. Consensus guidelines for the prevention and
treatment of catheter-related infections and peritonitis in pediatric patients receiving peritoneal dialysis: 2012 update.
Perit Dial Int 2012;32 Suppl 2:S32–S86 .
Wiggins KJ, Johnson DW, Craig JC, Strippoli GF. Treatment of peritoneal dialysis-associated peritonitis: a systematic
review of randomized controlled trials. Am J Kidney Dis 2007;50(6):967–988 .
Liver abscess
Aetiology and assessment of liver abscess
Liver abscesses are usually bacterial (pyogenic) or amoebic.
In children, liver abscesses are rare and most commonly caused by Staphylococcus aureus. Seek expert paediatric
advice for management—it may be necessary to involve a multidisciplinary team, including a paediatric infectious
diseases physician.
Bacterial liver abscess can be a primary infection (eg caused by Klebsiella pneumoniae) or a secondary infection
(eg following spread from an intra-abdominal source, such as diverticulitis or biliary tract infection, or seeding
from a bacteraemia).
Spontaneous primary bacterial liver abscess is increasingly caused by K. pneumoniae, particularly among patients
from Asia or those with diabetes. K. pneumoniae is usually the sole pathogen, and can be associated with
metastatic infections such as endophthalmitis, meningitis and discitis.
Secondary infection is often polymicrobial, caused by aerobic and anaerobic bowel flora. Occasionally, an
organism of the Streptococcus anginosus (milleri) group (S. anginosus, S. constellatus, S. intermedius) may be the
sole pathogen.
In areas of northern Australia where Burkholderia pseudomallei is endemic [Note 1], liver abscess may be a
clinical manifestation of melioidosis. If suspected, see Melioidosis for antibiotic therapy.
Amoebic liver abscess (caused by Entamoeba histolytica) most commonly occurs in travellers returned from an
endemic country; however, it can also occur in individuals who have not travelled outside Australia.
The presentation of bacterial and amoebic liver abscess can be identical, so in all cases, take blood samples for
culture and susceptibility testing (for bacterial causes) and serological testing (for E. histolytica). Ultrasound- or
computed tomography (CT)–guided needle aspiration of the abscess, together with microbiological examination of
the aspirate, is usually necessary for diagnosis. If radiological imaging suggests hydatid disease, needle aspiration
should be delayed to avoid intraperitoneal spillage of hydatid contents—seek expert advice. See also Hydatid
disease.
Note 1: Areas of northern Australia where Burkholderia pseudomallei is endemic are regions north of 20°S latitude. This includes areas of Queensland
north of Mackay, the Northern Territory north of Tennant Creek, and Western Australia north of Port Hedland.
Treatment of liver abscess

Drainage of liver abscess
Drainage is the mainstay of therapy for the treatment of bacterial liver abscess. For abscesses less than 5 cm in
diameter, closed-needle drainage is usually sufficient. For abscesses more than 5 cm in diameter, radiologically
guided catheter drainage is recommended. Surgical drainage is needed in more complicated situations, including
multiple or loculated abscesses, and for cases with inadequate response to catheter drainage and antibiotics after 7
days.
Drainage is rarely necessary for the treatment of amoebic liver abscess.
Empirical therapy for liver abscess
The empirical antibiotic regimen for liver abscess should contain metronidazole to treat potential Entamoeba
histolytica infection until the aetiology of the abscess is confirmed.
For empirical therapy of liver abscess, as a three-drug regimen, use:
of use
PLUS
metronidazole 750 mg intravenously, 8-hourly
PLUS EITHER
1 amoxicillin 2 g intravenously, 6-hourly
OR
1 ampicillin 2 g intravenously, 6-hourly.
If gentamicin is contraindicated (see Box 2.42) or for patients with immediate nonsevere or delayed nonsevere
hypersensitivity to penicillins, as a two-drug regimen, use:
1 ceftriaxone 2 g intravenously, daily
OR
metronidazole 750 mg intravenously, 8-hourly.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, seek expert advice—
treatment options include metronidazole in combination with either gentamicin, ciprofloxacin or aztreonam.
Modify therapy based on the results of culture and susceptibility testing, if available. If the results of susceptibility
containing regimen and use metronidazole plus ceftriaxone or cefotaxime as above.
The total duration of therapy is usually 4 to 6 weeks (intravenous + oral). If response to initial drainage is good,
switch to directed oral therapy after 2 weeks. If results of culture and susceptibility testing are not available, a
reasonable oral option is amoxicillin+clavulanate. If drainage was incomplete, 4 to 6 weeks of intravenous
antibiotic therapy may be required. Community-based parenteral antimicrobial therapy may be appropriate for
patients requiring longer durations of intravenous therapy.
Klebsiella pneumoniae liver abscess
Promptly and thoroughly assess the vision of patients diagnosed with K. pneumoniae liver abscess, because there
is a risk of endophthalmitis.
For confirmed K. pneumoniae liver abscess, use:
OR
above regimens.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, ciprofloxacin or aztreonam
are treatment options—seek expert advice.
Use the results of susceptibility testing to guide ongoing therapy.
The total duration of therapy is usually 4 to 6 weeks (intravenous + oral). If response to initial drainage is good,
switch to directed oral therapy after 2 weeks. If drainage was incomplete, 4 to 6 weeks of intravenous antibiotic
therapy may be required. Community-based parenteral antimicrobial therapy may be appropriate for patients
requiring longer durations of intravenous therapy.
Amoebic liver abscess
For confirmed amoebic (E. histolytica) liver abscess, use:
1 metronidazole 800 mg orally, 8-hourly for 7 days
OR
1 tinidazole 2 g orally, daily for 5 days.
If the patient is unable to tolerate oral therapy, use:
metronidazole 750 mg intravenously, 8-hourly for 7 days.
In order to prevent relapse, eradicate cysts in the gut with a luminal amoebicide. Use (either concurrently or
following the above therapy):
paromomycin 500 mg orally, 8-hourly for 7 days [Note 2].
Note 2: Paromomycin is not registered for use in Australia but is available via the Special Access Scheme.
Key references
Aetiology and assessment of liver abscess
Mishra K, Basu S, Roychoudhury S, Kumar P. Liver abscess in children: an overview. World J Pediatr 2010;6(3):210–
216 .
Treatment of liver abscess
Ahmed S, Chia CL, Junnarkar SP, Woon W, Shelat VG. Percutaneous drainage for giant pyogenic liver abscess--is it
safe and sufficient?. Am J Surg 2016;211(1):95–101 .
Cai YL, Xiong XZ, Lu J, Cheng Y, Yang C, Lin YX, et al. Percutaneous needle aspiration versus catheter drainage in
the management of liver abscess: a systematic review and meta-analysis. HPB (Oxford) 2015;17(3):195–201
.
Ch Yu S, Hg Lo R, Kan PS, Metreweli C. Pyogenic liver abscess: treatment with needle aspiration. Clin Radiol
1997;52(12):912–916 .
Liao WI, Tsai SH, Yu CY, Huang GS, Lin YY, Hsu CW. Pyogenic liver abscess treated by percutaneous catheter
drainage: MDCT measurement for treatment outcome. Eur J Radiol 2012;81(4):609–615 .
Liu CH, Gervais DA, Hahn PF, Arellano RS, Uppot RN, Mueller PR. Percutaneous hepatic abscess drainage: do
multiple abscesses or multiloculated abscesses preclude drainage or affect outcome?. J Vasc Interv Radiol
2009;20(8):1059–1065 .
Singh O, Gupta S, Moses S, Jain DK. Comparative study of catheter drainage and needle aspiration in management of
large liver abscesses. Indian J Gastroenterol 2009;28(3):88–92 .
Tan YM, Chung AY, Chow PK, Cheow PC, Wong WK, Ooi LL, et al. An appraisal of surgical and percutaneous
drainage for pyogenic liver abscesses larger than 5 cm. Ann Surg 2005;241(3):485–490 .
Yu SC, Ho SS, Lau WY, Yeung DT, Yuen EH, Lee PS, et al. Treatment of pyogenic liver abscess: prospective
randomized comparison of catheter drainage and needle aspiration. Hepatology 2004;39(4):932–938 .
Acute infected pancreatitis
Role of antibiotics in the management of acute pancreatitis
General management of acute pancreatitis is discussed in detail in here.
Antibiotic therapy is not recommended for the management of acute pancreatitis except to treat infected pancreatic
necrosis or pancreatic abscess. Multiple studies have found that the use of antibiotics to prevent pancreatic
infection does not reduce mortality, and prophylaxis is not recommended.
Patients with severe pancreatitis can intermittently appear septic during a prolonged hospitalisation; however, this
may not necessarily indicate infection.
Infected pancreatic necrosis and pancreatic abscess

Treatment of infected pancreatic necrosis is a step-up approach using percutaneous drainage, minimally invasive
surgery and, if necessary, open surgical debridement. For pancreatic abscess, prompt percutaneous or surgical
drainage is important.
Before starting antibiotic therapy, perform image-guided percutaneous aspiration of any pancreatic collection to
collect aspirate for Gram stain, culture and susceptibility testing.
For empirical therapy of infected pancreatic necrosis or pancreatic abscess, use:

hourly.
regimen, use:
OR
Although initial clinical trials suggested carbapenems were beneficial for empirical therapy of acute infected
pancreatitis, more recent trials and a meta-analysis have refuted this finding.
Modify therapy according to the results of culture and susceptibility testing. Reserve carbapenems for infections
caused by pathogens resistant to other antibiotics.
The optimal duration of therapy is uncertain. An initial course of 7 days is commonly used. The decision to
prolong therapy should be based on careful review of the patient’s clinical status, and radiology and pathology
results.
For cases that do not resolve within 7 to 10 days, consider secondary infection with Candida species or multidrug-
resistant organisms such as vancomycin-resistant enterococci and carbapenem-resistant Enterobacteriaceae.
Antimicrobial therapy should be directed by the results of culture and susceptibility testing of samples taken from
a deep site—seek expert surgical, infectious diseases and clinical microbiology advice.
Key references
Crockett SD, Wani S, Gardner TB, Falck-Ytter Y, Barkun AN. American Gastroenterological Association Institute
Guideline on Initial Management of Acute Pancreatitis. Gastroenterology 2018;154(4):1096–101. .
Villatoro E, Mulla M, Larvin M. Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute
pancreatitis. Cochrane Database Syst Rev 2010;(5):CD002941. .
Leptospirosis
Leptospirosis
Leptospirosis is a zoonotic systemic infection caused by Leptospira interrogans serovars. Diagnosis is usually
based on serology, but seroconversion is sometimes delayed for several weeks. Leptospirosis-specific blood culture
and nucleic acid amplification testing (eg polymerase chain reaction [PCR]) can identify the serovar if positive.
Leptospirosis is often self-limited so may not require antimicrobial therapy. If the diagnosis is made after clinical
recovery and antibiotics have not been given, then they are not required.
If leptospirosis is suspected clinically, start antimicrobial therapy before the diagnosis is confirmed. Use:
1 doxycycline orally, 12-hourly for 7 days
adult: 100 mg
OR
2 benzylpenicillin 1.2 g (child: 50 mg/kg up to 1.2 g) intravenously, 6-hourly for 7 days
OR
3 ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously, daily for 7

days.
Doxycycline is preferred for empirical therapy because it also treats rickettsial infections, which have a similar
presentation to leptospirosis.
Key references
Charan J, Saxena D, Mulla S, Yadav P. Antibiotics for the treatment of leptospirosis: systematic review and meta-
analysis of controlled trials. Int J Prev Med 2013;4(5):501–10.
Chusri S, McNeil EB, Hortiwakul T, Charernmak B, Sritrairatchai S, Santimaleeworagun W, et al. Single dosage of
doxycycline for prophylaxis against leptospiral infection and leptospirosis during urban flooding in southern Thailand: a
non-randomized controlled trial. J Infect Chemother 2014;20(11):709–15.
Naing C, Reid SA, Aung K. Comparing antibiotic treatment for leptospirosis using network meta-analysis: a tutorial.
BMC Infect Dis 2017;17(1):29.
Rodrigo C, Lakshitha de Silva N, Goonaratne R, Samarasekara K, Wijesinghe I, Parththipan B, et al. High dose
corticosteroids in severe leptospirosis: a systematic review. Trans R Soc Trop Med Hyg 2014;108(12):743–50.
Lyme disease
Lyme disease
Lyme disease is caused by Borrelia species, transmitted to humans via tick bite. It is not endemic in Australia
but can occur in travellers returning from Europe or North America. If Lyme disease is suspected, seek
advice on diagnosis and management from an infectious diseases physician or a clinical microbiologist. The
Royal College of Pathologists of Australasia has a position statement about laboratory testing for Lyme
disease Diagnostic Laboratory testing for Borreliosis (‘Lyme Disease’ or similar syndromes) in Australia and
New Zealand [URL]. Guidelines for the prevention, assessment and treatment of Lyme disease are available
from the Infectious Diseases Society of America (IDSA) [URL].
Prolonged intravenous or oral antimicrobial therapy for Lyme disease did not significantly improve outcomes
in studies performed in North America and Europe, and can be associated with significant adverse effects.
Key references
Collignon PJ, Lum GD, Robson JM. Does Lyme disease exist in Australia? Med J Aust 2016;205(9):413–7.
The Royal College of Pathologists of AustralasiaThe Royal College of Pathologists of Australasia. Diagnostic
Laboratory testing for Borreliosis (‘Lyme Disease’ or similar syndromes) in Australia and New Zealand [Position
statement]. 2014. www.rcpa.edu.au/Library/College-Policies/Position-Statements
Mediastinitis
Approach to managing mediastinitis
There are three distinct presentations of mediastinitis:
extension of a perioral or parapharyngeal infection (often caused by mixed anaerobic bacteria, streptococci
or Haemophilus species)
infection following perforation of the oesophagus, either spontaneously (following severe vomiting
[Boerhaave syndrome]) or after instrumentation of the oesophagus or hypopharynx; these infections are
often polymicrobial, involving oral bacteria or Candida species
infection following cardiac surgery in patients who had a median sternotomy (common pathogens include
Staphylococcus aureus, enteric Gram-negative bacteria [eg Enterobacter species] and Pseudomonas
aeruginosa; polymicrobial infection is possible).
Successful treatment requires early recognition of infection, adequate surgical debridement and drainage, and
antimicrobial therapy.
Mediastinitis can be associated with sepsis or septic shock (for definitions, see here for adults or here for children).
for ward-based patients, development of sepsis or septic shock; antibiotics should be given immediately after
Expert advice is essential for managing mediastinitis.
The choice of empirical antimicrobial therapy for mediastinitis depends on the presentation (see above) and, when
available, the results of culture and susceptibility testing. There is a lack of evidence to guide empirical
antimicrobial choice and duration of therapy. If the results of culture are not available to guide initial therapy, the
following approach is recommended by the Antibiotic Expert Groups. Expert advice is essential for ongoing
management.
Mediastinitis related to perioral or parapharyngeal infection

For mediastinitis related to perioral or parapharyngeal infection, use the results of culture and susceptibility testing
to guide initial therapy. If microbiology results are not available, use:
1 amoxicillin+clavulanate intravenously
adult: 1+0.2 g 8-hourly. If the patient has an abscess, or has septic shock or requires
intensive care support, use a dose of 1+0.2 g 6-hourly [Note 1]
child 3 months or older: 25+5 mg/kg up to 1+0.2 g 8-hourly. If the child has an abscess, or
has septic shock or requires intensive care support, use a dose of 25+5 mg/kg up to 1+0.2
g 6-hourly [Note 2] [Note 3]

PLUS
metronidazole (see dosage above).
clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly

1
OR
If the patient is not improving with initial antibiotic therapy and adequate surgical drainage (if indicated), and is at
increased risk of methicillin-resistant Staphylococcus aureus (MRSA) (see Box 2.31), consider adding empirical
therapy for MRSA:
Consider replacing vancomycin with clindamycin or lincomycin (see dosages above) if local epidemiology
indicates that MRSA is likely to be susceptible to lincosamides and the patient is not severely unwell.
If MRSA is not subsequently identified by culture, consider stopping additional therapy for MRSA. If MRSA is
identified, modify therapy based on susceptibility results.
Seek expert advice for ongoing management, timing of switch to oral therapy and duration of therapy. For severe
mediastinitis (eg life-threatening or complicated infection), treatment for 4 to 6 weeks (intravenous + oral) may be
required.
adults with an abscess, or with septic shock or requiring intensive care support, a reasonable alternative regimen is 2+0.2 g intravenously, 8-hourly.
children who weigh 40 kg or more who have an abscess, or have septic shock or require intensive care support, a reasonable alternative regimen is
2+0.2 g intravenously, 8-hourly.
Note 3: Intravenous amoxicillin+clavulanate may be suitable for children aged 1 month to younger than 3 months but a different dosage is required.
Mediastinitis following oesophageal rupture

Oesophageal rupture occurring in the community
Empirical therapy with activity against oropharyngeal bacteria is required for patients with mediastinitis following
an oesophageal rupture that occurred in the community. Broader-spectrum treatment with activity against Gram-
negative bacteria or Candida species is required in certain circumstances.
If the patient is at increased risk of oesophageal colonisation with Gram-negative bacteria, consider treating as for
oesophageal rupture occurring in hospitalised patients. Patients at increased risk of oesophageal colonisation with
Gram-negative bacteria include:
patients with haematological or solid organ malignancies

residents of aged-care facilities
patients who have had a prolonged stay in hospital or have been frequently hospitalised, particularly if the
patient received antibiotics during their hospital stay.
Most patients do not require empirical therapy for Candida species. Consider empirical antifungal therapy for
patients at risk of invasive candidal infection (eg patients with oesophageal candidiasis, immunocompromised
patients [eg organ transplant recipients], patients with neutropenia, patients with advanced HIV infection).
For patients with mediastinitis following oesophageal rupture in the community setting who are not at increased
risk of Gram-negative infection, use the results of culture and susceptibility testing to guide initial therapy. If
microbiological results are not available, use:
adult: 1+0.2 g 8-hourly. If the patient has septic shock or requires intensive care support,
use a dose of 1+0.2 g 6-hourly [Note 4]
child 3 months or older: 25+5 mg/kg up to 1+0.2 g 8-hourly. If the child has septic shock
or requires intensive care support, use a dose of 25+5 mg/kg up to 1+0.2 g 6-hourly [Note
5] [Note 6]

PLUS
metronidazole (see dosage above).
OR
If the patient is at risk of invasive candidal infection (see above), consider empirical antifungal therapy. Use an
echinocandin (anidulafungin, caspofungin or micafungin) as initial therapy if the patient is critically ill.
Fluconazole is an alternative in patients who are not critically ill and are considered unlikely to have infection with
fluconazole-resistant Candida species (eg patients who have not had previous exposure to azole antifungals). If an
echinocandin is used initially, change therapy to fluconazole if the Candida isolate is identified as fluconazole-
susceptible (eg most Candida albicans isolates) and the patient is not critically ill.
If empirical fluconazole therapy is indicated, add:
fluconazole 800 mg (child: 12 mg/kg up to 800 mg) intravenously for the first dose, then
400 mg (child: 6 mg/kg up to 400 mg) intravenously, daily.
If empirical echinocandin therapy is indicated, add:
1 anidulafungin (adult) 200 mg intravenously, for the first dose, then 100 mg intravenously,
daily [Note 7]
OR
1 caspofungin intravenously
adult 80 kg or less: 70 mg for the first dose, then 50 mg daily

adult more than 80 kg: 70 mg daily
child 3 months or older: 70 mg/m2 up to 70 mg for the first dose, then 50 mg/m2 up to 70
mg daily [Note 8] [Note 9]
OR
1 micafungin 100 mg (child less than 40 kg: 2 mg/kg up to 80 mg; child 40 kg or more: 100
mg) intravenously, daily [Note 10].
Seek expert advice for ongoing management and duration of therapy. For severe mediastinitis (eg life-threatening
or complicated infection), treatment for 4 to 6 weeks may be required.
adults with septic shock or requiring intensive care support, a reasonable alternative regimen is 2+0.2 g intravenously, 8-hourly.
children who weigh 40 kg or more who have septic shock or require intensive care support, a reasonable alternative regimen is 2+0.2 g intravenously,
8-hourly.
Note 6: Intravenous amoxicillin+clavulanate may be suitable for children aged 1 month to younger than 3 months but a different dosage is required.
Note 7: There are few data to support the use of anidulafungin in children. If anidulafungin is the treatment of choice, seek expert advice on dosing.
Note 9: If treatment is well tolerated but response is inadequate, increase the maintenance dose to 70 mg/m2 (up to 70 mg).
Note 10: For adults, or children weighing 40 kg or more, who have an inadequate response to treatment, increase the dose to 200 mg. For children
weighing less than 40 kg who have an inadequate response to treatment, increase the dose to 4 mg/kg (up to 160 mg).
Oesophageal rupture occurring in hospitalised patients
Empirical therapy with activity against Gram-negative and oropharyngeal bacteria is required for patients with
mediastinitis following an oesophageal rupture that occurred in hospital.
Most patients do not require empirical therapy for Candida species. Consider empirical antifungal therapy for
patients at risk of invasive candidal infection (eg patients with oesophageal candidiasis, immunocompromised
patients [eg organ transplant recipients], patients with neutropenia, patients with advanced HIV infection).
For patients with mediastinitis following oesophageal rupture in hospital, use the results of culture and
susceptibility testing to guide initial therapy. If microbiological results are not available, use:

hourly; use 6-hourly dosing for patients with septic shock or requiring intensive care
support.
cefepime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly
PLUS
For patients with immediate severe or delayed severe hypersensitivity to penicillins, meropenem may be suitable
[Note 11]. Use:
meropenem 1 g (child: 20 mg/kg up to 1 g) intravenously, 8-hourly [Note 12].
If the patient is at risk of invasive candidal infection (see above), consider empirical antifungal therapy. Use an
echinocandin (anidulafungin, caspofungin or micafungin) as initial therapy if the patient is critically ill.
Fluconazole is an alternative in patients who are not critically ill and are considered unlikely to have infection with
fluconazole-resistant Candida species (eg patients who have not had previous exposure to azole antifungals). If an
echinocandin is used initially, change therapy to fluconazole if the Candida isolate is identified as fluconazole-
susceptible (eg most Candida albicans isolates) and the patient is not critically ill.
If empirical fluconazole therapy is indicated, add:
fluconazole 800 mg (child: 12 mg/kg up to 800 mg) intravenously, for the first dose, then
If empirical echinocandin therapy is indicated, add:
daily [Note 13]
OR
1 caspofungin intravenously
adult 80 kg or less: 70 mg for the first dose, then 50 mg daily

adult more than 80 kg: 70 mg daily
child 3 months or older: 70 mg/m2 up to 70 mg for the first dose, then 50 mg/m2 up to 70
mg daily [Note 14] [Note 15]
OR
Oesophageal perforation following planned endoscopy is usually detected immediately or shortly after the injury.
Unlike in patients with spontaneous oesophageal rupture caused by severe vomiting (eg Boerhaave syndrome),
these patients usually have minimal pleural and mediastinal contamination because they were fasting at the time of
injury.
If mediastinitis, and mediastinal or pleural contamination, are subsequently excluded, prolonged broad-spectrum
intravenous antimicrobial therapy may not be required. Review the need for ongoing antibiotic therapy at 48 to 72
hours, then daily if therapy continues.
Seek expert advice for ongoing management and duration of therapy. For severe mediastinitis (eg life-threatening
or complicated infection), treatment for 4 to 6 weeks may be required.
Note 13: There are few data to support the use of anidulafungin in children. If anidulafungin is the treatment of choice, seek expert advice on dosing.
Note 15: If treatment is well tolerated but response is inadequate, increase the maintenance dose to 70 mg/m2 (up to 70 mg).
Note 16: For adults, or children weighing 40 kg or more, who have an inadequate response to treatment, increase the dose to 200 mg. For children
weighing less than 40 kg who have an inadequate response to treatment, increase the dose to 4 mg/kg (up to 160 mg).
Mediastinitis following cardiac surgery

Adults
For hospital-acquired mediastinitis following cardiac surgery in adults who had a median sternotomy, use the
results of culture and susceptibility testing to guide initial therapy. If microbiological results are not available, use:
piperacillin+tazobactam 4+0.5 g intravenously, 6-hourly.
cefepime 2 g intravenously, 8-hourly.
For adults with immediate severe or delayed severe hypersensitivity to penicillins, meropenem may be suitable
[Note 17]. Use:
meropenem 1 g intravenously, 8-hourly.
For adults at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) (see Box 2.31), add:
use. Consider a 25 to 30 mg/kg loading dose for patients with septic shock or requiring
intensive care support.
Seek expert advice for ongoing management, timing of switch to oral therapy and duration of therapy. If
Pseudomonas aeruginosa is not subsequently identified by culture, continued antipseudomonal therapy is not
required. Switch to a narrower-spectrum empirical regimen or modify therapy based on the results of culture and
susceptibility testing. For severe mediastinitis (eg life-threatening or complicated infection), treatment for 4 to 6
weeks (intravenous + oral) may be required.
Children
Staphylococcus aureus is the main cause of mediastinitis following cardiac surgery in children who had a median
sternotomy. Additional Gram-negative therapy is reserved for children who do not improve with initial therapy.
If microbiological results are not available to guide initial therapy, use:
For children with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use cefazolin (as
above).
OR
For children at increased risk of methicillin-resistant S. aureus (MRSA) (see Box 2.31), add:
If the child is not improving on cefazolin (with or without vancomycin), change antibiotic therapy to:
piperacillin+tazobactam 100+12.5 mg/kg up to 4+0.5 g intravenously, 6-hourly
PLUS if increased risk of MRSA (see Box 2.31)
For children with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, who are not
improving on cefazolin (with or without vancomycin), change antibiotic therapy to:
cefepime 50 mg/kg up to 2 g intravenously, 8-hourly
For children with immediate severe or delayed severe hypersensitivity to penicillins who are not improving on
clindamycin or lincomycin (with or without vancomycin), a meropenem-based regimen may be a suitable
replacement for the lincosamide-based regimen [Note 18]:
meropenem 20 mg/kg up to 1 g intravenously, 8-hourly [Note 19]

Seek expert advice for ongoing management, timing of switch to oral therapy and duration of therapy. For severe
mediastinitis (eg life-threatening or complicated infection), treatment for 4 to 6 weeks (intravenous + oral) may be
required.
Key references
Cornely OA, Bassetti M, Calandra T, Garbino J, Kullberg BJ, Lortholary O, et al. ESCMID* guideline for the diagnosis
and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect 2012;18 Suppl 7:19–
37.
Long CB, Shah SS, Lautenbach E, Coffin SE, Tabbutt S, Gaynor JW, et al. Postoperative mediastinitis in children:
epidemiology, microbiology and risk factors for Gram-negative pathogens. Pediatr Infect Dis J 2005;24(4):315–9.
Dis 2016;16(8):e139–52.
Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical Practice Guideline for
the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis
2016;62(4):e1–50.
Prado-Calleros HM, Jimenez-Fuentes E, Jimenez-Escobar I. Descending necrotizing mediastinitis: Systematic review

on its treatment in the last 6 years, 75 years after its description. Head Neck 2016;38 Suppl 1:E2275–83.
Ryom P, Ravn JB, Penninga L, Schmidt S, Iversen MG, Skov-Olsen P, et al. Aetiology, treatment and mortality after
oesophageal perforation in Denmark. Dan Med Bull 2011;58(5):A4267.
Melioidosis
Overview of melioidosis
Melioidosis is caused by the soil and water saprophyte Burkholderia pseudomallei. It is endemic in northern
Australia and parts of the Asia–Pacific region, and more recently has been found in Africa and the Americas. It
may present in returned travellers, sometimes months or years after exposure.
The clinical presentation varies. People with diabetes, chronic kidney disease, chronic respiratory disease
(especially cystic fibrosis), a history of hazardous alcohol consumption and those on immunosuppressive therapy
are at risk of developing more severe illness. Pneumonia is the most common presentation, but bacteraemic spread
can cause abscesses in any organ (especially the spleen and prostate). Localised cutaneous ulcers or abscesses are
also common. Asymptomatic infection, latent infection and relapse can occur.
The use of selective culture media, serology, nucleic acid amplification testing (eg polymerase chain reaction
[PCR]) and antigen detection (eg lateral flow immunoassay) can assist diagnosis, but culture of B. pseudomallei
remains the only way to make a definitive diagnosis. Perform imaging in all cases to look for deep-seated
infection. Computed tomography (CT) of the abdomen and pelvis is recommended for adult males; abdominal
ultrasound (to reduce exposure to radiation) is recommended for adult females and children. Seek advice from an
infectious diseases physician or a clinical microbiologist.
Treatment of melioidosis
Treatment consists of an initial phase of intravenous (with or without oral) therapy, followed by oral eradication
therapy.
For initial therapy of non-neurological melioidosis, use:
1 ceftazidime 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly for at least 14 days

(duration depends on site of infection—see Table 2.14)
OR
1 meropenem 1 g (child: 25 mg/kg up to 1 g) intravenously, 8-hourly for at least 14 days

(duration depends on site of infection—see Table 2.14).
For initial therapy of neurological melioidosis, use:
meropenem 2 g (child: 40 mg/kg up to 2 g) intravenously, 8-hourly (duration depends on

site of infection—see Table 2.14).
For patients with neurological infection, osteomyelitis, septic arthritis, genitourinary infection (including prostatic
abscess), or skin and soft tissue infection, add to the initial therapy regimens above:

240+1200 mg; child 1 month or older: 6+30 mg/kg up to 240+1200 mg) orally, 12-hourly
(duration depends on site of infection—see Table 2.14)
PLUS
folic acid 5 mg (child: 0.1 mg/kg up to 5 mg) orally, daily (duration depends on site of
infection—see Table 2.14).
Consider granulocyte colony-stimulating factor (G-CSF) for critically ill patients with melioidosis.
When the patient is stable and if treatment will be continued at home with community-based parenteral
antimicrobial therapy, ceftazidime or meropenem given by intermittent dosing can be switched to ceftazidime
given by continuous infusion, if a suitable preparation is available.
Once the course of initial therapy is completed, follow with oral eradication therapy:

for a further 3 to 6 months (duration depends on site of infection—see Table 2.14)
PLUS
folic acid 5 mg (child: 0.1 mg/kg up to 5 mg) orally, daily for a further 3 to 6 months
(duration depends on site of infection—see Table 2.14).
If trimethoprim+sulfamethoxazole is contraindicated or not tolerated and drug desensitisation is not possible,

alternative options for oral therapy include doxycycline or high-dose amoxicillin+clavulanate—seek expert advice.
Duration of therapy for melioidosis (Table 2.14)
Clinical focus Initial phase of therapy— Eradication therapy—duration

minimum duration [NB1]
Skin infection 2 weeks 3 months
Bacteraemia with no focus 2 weeks 3 months
Pneumonia 2 to 4 weeks 3 months
Prostatic abscess, septic arthritis
and organ or deep-seated tissue 4 weeks [NB2] 3 months
collection
Osteomyelitis 6 weeks 6 months
Neurological and vascular
8 weeks 6 months
infections
NB1: The duration of the initial phase of therapy may need to be extended if improvement is slow or if blood culture results remain positive at 7 days.
NB2: The duration of the initial phase of therapy depends on the date and results of culture of the most recent sample following drainage of collection
(eg prostatic abscess or joint washout). If the culture grows B. pseudomallei, or if the sample is not sent for culture, the clock is reset to day 1. If the
culture is negative, the clock is usually not reset.
Adapted from Pitman MC, Luck T, Marshall CS, Anstey NM, Ward L, Currie BJ. Intravenous therapy duration
and outcomes in melioidosis: a new treatment paradigm. PLoS Negl Trop Dis 2015;9(3):e0003586.
doi:10.1371/journal.pntd.0003586. © 2015 Pitman et al. https://creativecommons.org/licenses/by/4.0/
Key references
Chewapreecha C, Holden MT, Vehkala M, Valimaki N, Yang Z, Harris SR, et al. Global and regional dissemination and
evolution of Burkholderia pseudomallei. Nat Microbiol 2017;2:16263.
Crowe A, McMahon N, Currie BJ, Baird RW. Current antimicrobial susceptibility of first-episode melioidosis
Burkholderia pseudomallei isolates from the Northern Territory, Australia. Int J Antimicrob Agents 2014;44(2):160–2.
Currie BJ. Melioidosis: evolving concepts in epidemiology, pathogenesis, and treatment. Semin Respir Crit Care Med
2015;36(1):111–25.
Dance DA, Davong V, Soeng S, Phetsouvanh R, Newton PN, Turner P. Trimethoprim/sulfamethoxazole resistance in
Burkholderia pseudomallei. Int J Antimicrob Agents 2014;44(4):368–9.
Geake JB, Reid DW, Currie BJ, Bell SC, Melioid CFI, Bright-Thomas R, et al. An international, multicentre evaluation
and description of Burkholderia pseudomallei infection in cystic fibrosis. BMC Pulm Med 2015;15:116.
Limmathurotsakul D, Golding N, Dance DA, Messina JP, Pigott DM, Moyes CL, et al. Predicted global distribution of
Burkholderia pseudomallei and burden of melioidosis. Nat Microbiol 2016;1:15008.
Pitman MC, Luck T, Marshall CS, Anstey NM, Ward L, Currie BJ. Intravenous therapy duration and outcomes in
melioidosis: a new treatment paradigm. PLoS Negl Trop Dis 2015;9(3):e0003586.
Saiprom N, Amornchai P, Wuthiekanun V, Day NP, Limmathurotsakul D, Peacock SJ, et al.

Trimethoprim/sulfamethoxazole resistance in clinical isolates of Burkholderia pseudomallei from Thailand. Int J
Antimicrob Agents 2015;45(5):557–559.
Sarovich DS, Garin B, De Smet B, Kaestli M, Mayo M, Vandamme P, et al. Phylogenomic analysis reveals an Asian
origin for African Burkholderia pseudomallei and further supports melioidosis endemicity in Africa. mSphere 2016;1(2).
Nocardiosis
Clinical manifestations of nocardiosis
Nocardiosis is caused by environmental Gram-positive Actinobacteria of the Nocardia genus. It is found
throughout Australia but more commonly in tropical and subtropical regions.
Single or multiple skin lesions can occur in immunocompetent individuals. Disseminated disease usually occurs in
immunocompromised patients, and is commonly associated with central nervous system infection with brain
abscesses. Pulmonary Nocardia ranges from mild acute or mild chronic disease with minimal or no changes on
chest X-ray, to severe multilobar disease with high mortality. Consider testing patients with severe or disseminated
Nocardia for an immune system disorder (eg HIV).
Except in immunocompetent patients with localised cutaneous disease (in whom imaging should be considered on
a case-by-case basis), chest X-ray and brain computed tomography (CT) or magnetic resonance imaging (MRI)
(both with contrast) are recommended to assess for pulmonary and neurological disease.
Diagnosis of nocardiosis
Diagnosis is based on culture of the pathogen. If nocardiosis is suspected, ask the laboratory to look for branching
Gram-positive bacilli on microscopy and culture of skin swabs, pus and sputum. There are multiple species of
Nocardia and species identification is increasingly based on molecular sequencing.
Within the Nocardia genus and even within individual species there is diversity in antimicrobial susceptibility, so
susceptibility testing is essential to guide directed treatment. Although there is also regional variation in
susceptibility, most isolates are susceptible to trimethoprim+sulfamethoxazole.
Treatment of nocardiosis
Approach to management of nocardiosis
Treatment of nocardiosis consists of an initial phase followed by an eradication phase. Comparative studies to
guide antimicrobial therapy are lacking for both choice and duration of therapy. Expert advice is essential when
managing patients with nocardiosis.
Nocardiosis cases can be divided into three categories based on patient factors, severity, and site of disease; see
Box 2.9.
Nocardiosis disease categories for treatment (Box 2.9)
Nocardiosis cases can be divided into three categories based on patient factors, severity, and site of disease:
Mild disease: nonsevere disease in immunocompetent patients with localised cutaneous disease.
Moderate disease: nonsevere disease in:
immunocompetent patients with more extensive cutaneous disease

immunocompromised patients with cutaneous disease (including those with immune compromise caused
by a chronic medical condition such as diabetes, chronic kidney disease or hazardous alcohol use)
any patient with mild or moderate pulmonary disease.
Severe disease: including CNS disease with brain abscess, disseminated disease and severe pneumonia.
Mild disease
For initial empirical therapy of nocardiosis in patients with mild disease (see Box 2.9), use:

When susceptibility is known, continue therapy with trimethoprim+sulfamethoxazole or an alternative

antimicrobial to which the organism is confirmed susceptible. The total duration of therapy is 3 months (including
eradication), or longer if there is a slow response to therapy.
Unless the isolate is resistant, drug desensitisation is recommended for patients who are hypersensitive to
trimethoprim+sulfamethoxazole—seek expert advice. If there is resistance to trimethoprim+sulfamethoxazole,
or if the patient is hypersensitive and desensitisation cannot be performed, alternative options for therapy include
amoxicillin+clavulanate, minocycline, linezolid or moxifloxacin, depending on susceptibility—seek expert advice.
Moderate disease
For initial empirical therapy of nocardiosis in patients with moderate disease (see Box 2.9), use:

PLUS EITHER
OR
1 linezolid 600 mg orally, 12-hourly (child younger than 12 years: 10 mg/kg up to 600 mg
orally, 8-hourly).
Modify therapy based on the results of species identification and susceptibility tests, if possible. When
susceptibility is known, continue therapy with two antimicrobials to which the organism is susceptible to
complete a duration of at least 2 weeks, or longer if there is a slow response. Unless the isolate is resistant, drug
desensitisation is recommended for patients who are hypersensitive to trimethoprim+sulfamethoxazole—seek
expert advice.
Follow initial two-drug therapy with oral eradication therapy using a single drug, to complete a total duration
(initial + eradication therapy) of 3 to 12 months, depending on clinical response. If susceptible, use:

160+800 mg) orally, 12-hourly for up to 12 months’ total duration (initial + eradication
therapy).
If there is resistance to trimethoprim+sulfamethoxazole, or if the patient is hypersensitive and desensitisation

cannot be performed, alternative options for oral eradication therapy include amoxicillin+clavulanate,
minocycline, linezolid or moxifloxacin, depending on susceptibility—seek expert advice.
Severe disease
For initial empirical therapy of severe nocardiosis (see Box 2.9), use three drugs until results of susceptibility
tests are available. If either trimethoprim+sulfamethoxazole or linezolid is contraindicated or not tolerated, seek
expert advice for empirical therapy. If the patient is hypersensitive to trimethoprim+sulfamethoxazole, drug
desensitisation is recommended—seek expert advice.
For initial empirical therapy of nocardiosis in patients with severe disease, use:

320+1600 mg) intravenously or orally, 12-hourly
PLUS
linezolid 600 mg intravenously or orally, 12-hourly (child younger than 12 years: 10

mg/kg up to 600 mg intravenously or orally, 8-hourly)
PLUS EITHER
1 amikacin (adult and child) 20 mg/kg intravenously, daily or amikacin (adult and
child) 10 mg/kg intravenously, 12-hourly. Monitor plasma concentration from the
first dose—see Principles of aminoglycoside use for dosage adjustment and
principles of use
OR
1 imipenem 500 mg (child: 15 mg/kg up to 500 mg) intravenously, 6-hourly [Note 1]
OR
2 meropenem 2 g (child: 40 mg/kg up to 2 g) intravenously, 8-hourly.
Meropenem has a lower risk of seizures than imipenem, but there are less published data to support its use for
nocardiosis. Isolates may be resistant to meropenem but susceptible to imipenem.
Modify therapy based on the results of species identification and susceptibility testing, if possible. When
susceptibility is known, continue therapy with two antimicrobials to which the organism is susceptible for 3
weeks, or up to 6 weeks for CNS disease and in immunocompromised patients.
Follow initial therapy with oral eradication therapy for up to 12 months’ total duration (initial + eradication
therapy). Patients who remain immunocompromised may require maintenance therapy indefinitely—seek expert
advice. For eradication therapy, if susceptible, use:

160+800 mg) orally, 12-hourly for up to 12 months’ total duration (initial + eradication
therapy).
If there is resistance to trimethoprim+sulfamethoxazole, or if the patient is hypersensitive and desensitisation

cannot be performed, alternative options for oral eradication therapy include amoxicillin+clavulanate,
minocycline, linezolid or moxifloxacin, depending on susceptibility.
Note 1: Imipenem is only available in combination with cilastatin. Dose expressed as imipenem component only.
Key references
Ford AC, Peyrin-Biroulet L. Opportunistic infections with anti-tumor necrosis factor-alpha therapy in inflammatory
bowel disease: meta-analysis of randomized controlled trials. Am J Gastroenterol 2013;108(8):1268–76.
Jodlowski TZ, Melnychuk I, Conry J. Linezolid for the treatment of Nocardia spp. infections. Ann Pharmacother
2007;41(10):1694–9.
Lalitha P, Srinivasan M, Rajaraman R, Ravindran M, Mascarenhas J, Priya JL, et al. Nocardia keratitis: clinical course
and effect of corticosteroids. Am J Ophthalmol 2012;154(6):934–9 e1.
McGuinness SL, Whiting SE, Baird R, Currie BJ, Ralph AP, Anstey NM, et al. Nocardiosis in the tropical Northern
Territory of Australia, 1997-2014. Open Forum Infect Dis 2016;3(4):ofw208.
Moylett EH, Pacheco SE, Brown-Elliott BA, Perry TR, Buescher ES, Birmingham MC, et al. Clinical experience with
linezolid for the treatment of nocardia infection. Clin Infect Dis 2003;36(3):313–8.
Ntziora F, Falagas ME. Linezolid for the treatment of patients with central nervous system infection. Ann Pharmacother
2007;41(2):296–308.
Pasciak M, Dacko W, Sikora J, Gurlaga D, Pawlik K, Miekisiak G, et al. Creation of an in-house matrix-assisted laser
desorption ionization-time of flight mass spectrometry Corynebacterineae database overcomes difficulties in
identification of Nocardia farcinica clinical isolates. J Clin Microbiol 2015;53(8):2611–21.
Sorrell TC, Mitchell DH, Iredell JR, Chen SC. Nocardia species [Section N. 254]. In: Bennett JE, Dolin R, Blaser MJ.
Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 8th ed. London: Elsevier Health
Sciences; 2014.
Nontuberculous mycobacterial infections
Introduction to nontuberculous mycobacterial infections
Nontuberculous mycobacteria (NTM) are environmental organisms that occasionally cause respiratory, cutaneous
or disseminated infection; less frequently, they cause infection at other sites. Person-to-person transmission is rare,
with the exception of Mycobacterium abscessus in some patient groups (eg cystic fibrosis).
This topic covers the more common nontuberculous mycobacterial infections:
Mycobacterium avium complex (MAC) infection

Mycobacterium kansasii infection
Infection with rapidly growing mycobacteria (M. abscessus, M. chelonae and M. fortuitum)
Mycobacterium ulcerans infection (Buruli ulcer)
Mycobacterium marinum infection
Mycobacterium leprae infection.
For detailed information on the diagnosis, treatment and prevention of nontuberculous mycobacterial infections,
refer to specific guidelines [Note 1].
Note 1: Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and
prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175(4):367-416. [URL]
Haworth CS, Banks J, Capstick T, Fisher AJ, Gorsuch T, Laurenson IF, et al. British Thoracic Society guidelines for the management of non-
tuberculous mycobacterial pulmonary disease (NTM-PD). Thorax 2017;72(Suppl 2):ii1-ii64. [URL]
Diagnosis of nontuberculous mycobacterial infections

Isolation of nontuberculous mycobacteria from a single sputum sample is not sufficient for diagnosis of respiratory
infection, because this may simply reflect colonisation. Diagnosis in a symptomatic patient requires all of the
following:
at least two positive cultures from sputum, or at least one positive culture from bronchial lavage
compatible radiological findings and evidence of progression
exclusion of other diagnoses.
As nontuberculous mycobacteria are found in tap water, patients should avoid rinsing their mouths or drinking
water immediately before sputum sample collection.
Approach to managing nontuberculous mycobacterial infections

Assessing the need for treatment
Patients with nontuberculous mycobacterial infections should be managed by an expert. Not all cases require
treatment; the need for treatment is in part guided by the organism identified.
Mycobacterium fortuitum and Mycobacterium chelonae are more commonly associated with skin and soft tissue
infections, while Mycobacterium abscessus is usually a respiratory pathogen but may cause soft tissue and
prosthetic material infection. Mycobacterium avium complex infection is usually seen in people with underlying
lung disease, or as a bronchiectatic and nodular disease in postmenopausal women.
For respiratory infection, a period of observation and serial imaging is often required to determine the need for
treatment. In patients with significant lung disease (eg chronic obstructive pulmonary disease), it may not be clear
whether nontuberculous mycobacteria identified in sputum are contributing to symptoms. In these patients,
optimise management of the lung disease before determining the need for antibiotics. However, early antibiotic
treatment without a period of observation may be appropriate for patients with cavitary disease or a high burden of
infection (eg suggested by smear positivity).
Respiratory nontuberculous mycobacterial disease

Adjunctive management of respiratory nontuberculous mycobacterial disease may include smoking cessation,
reflux management, dietary review for malnutrition, and chest clearance by a physiotherapist if there is associated
bronchiectasis. Patients with significant comorbid lung disease may benefit from pulmonary rehabilitation.

Manifestations of Mycobacterium avium complex infection
Mycobacterium avium complex (MAC) causes:
cervical lymphadenitis—more common in children; seek expert paediatric advice

pulmonary disease, occurring in several forms
cavitary and fibrotic upper lobe disease closely resembling tuberculosis—often in older men with pre-
existing respiratory disease such as chronic obstructive pulmonary disease
progressive bronchiectasis with productive cough, and interstitial or nodular shadowing identified by
chest imaging—most common in older women without pre-existing respiratory disease (Lady
Windermere syndrome)
hypersensitivity pneumonitis—usually follows exposure to aerosols generated by spas that are
colonised with nontuberculous mycobacteria (‘hot tub lung’) (see Hypersensitivity pneumonitis).
Antibiotic treatment is usually not required
disseminated disease—occurs in immunocompromised patients, notably those with HIV infection who have
a low CD4 cell count (see Disseminated Mycobacterium avium complex infection below).
Some patients who have Mycobacterium avium complex identified by culture of sputum do not need to be treated
—see Diagnosis of nontuberculous mycobacterial infections and Approach to managing nontuberculous
mycobacterial infections. Clinical assessment by an expert is required.
Pulmonary Mycobacterium avium complex disease
Introduction
Published data to inform the treatment of pulmonary Mycobacterium avium complex disease are limited. If
treatment is indicated, a combination of three drugs is required for the entire treatment course. Test sputum
regularly for mycobacteria while the patient is being treated. The duration of treatment depends on clinical,
microbiological and radiological responses, with treatment continued for at least 12 months from the time the
patient’s sputum first becomes culture-negative. The usual duration of treatment is 18 to 24 months.
Clarithromycin susceptibility testing of Mycobacterium avium complex isolates is recommended in patients who
do not respond to treatment with macrolide-containing regimens. Except for macrolides, there is poor correlation
between Mycobacterium avium complex in vitro drug susceptibility and clinical response to treatment. For
management of resistant organisms, severe disease or a poor response to initial treatment, see here.
A daily or intermittent (three-times-weekly) treatment regimen can be used. An intermittent regimen is not
recommended for patients with cavitary disease, moderate or severe disease (eg multilobar disease), those who
have been previously treated for Mycobacterium avium complex, and those who are immunocompromised.
Daily treatment regimen
For daily treatment of pulmonary Mycobacterium avium complex infection, a three-drug regimen (including a
macrolide, ethambutol and a rifamycin) is required; use:
1 azithromycin 250 mg (child: 5 mg/kg up to 250 mg) orally, daily [Note 2] [Note 3]
OR
1 clarithromycin 500 mg (adult less than 50 kg or older than 70 years: 250 mg; child: 12.5
mg/kg up to 500 mg) orally, 12-hourly
ethambutol (adult and child) 15 mg/kg orally, daily [Note 4]
PLUS EITHER
1 rifampicin 600 mg (adult less than 50 kg: 450 mg; child 50 kg or more: 600 mg; child less
than 50 kg: 15 mg/kg up to 450 mg) orally, daily
OR
2 rifabutin 300 mg (child: 5 mg/kg up to 300 mg) orally, daily.
Staged introduction of the drugs at 1-week intervals is prudent in the elderly, to make it easier to attribute adverse
effects to a particular drug. Gradually introduce the macrolide over 1 to 2 weeks, then add ethambutol, followed by
the rifamycin. Adverse effects of therapy, particularly nausea, may require dose reduction or a trial of evening
dosing. The macrolide and ethambutol are likely more important in the treatment of Mycobacterium avium
complex than rifampicin, and rifampicin is sometimes omitted or substituted with another drug if it causes
troublesome adverse effects. Clofazimine has been used as an alternative to one of the other drugs in the event of
adverse effects.
Monitor vision because ethambutol can cause visual adverse effects (see Monitoring tuberculosis therapy).
Note 2: At the time of writing, azithromycin is not available on the Pharmaceutical Benefits Scheme (PBS) for this indication. See the PBS website
for current information [URL].
Note 3: A higher azithromycin dosage (500 mg orally, daily) can be considered for cavitary disease.
Note 4: An oral liquid formulation of ethambutol is not commercially available; for formulation options for children or people with swallowing
Intermittent (three-times-weekly) treatment regimen
An intermittent regimen is not recommended for patients with cavitary disease, moderate or severe disease (eg
multilobar disease), those who have previously been treated for pulmonary Mycobacterium avium complex, and
those who are immunocompromised.
If intermittent treatment of pulmonary Mycobacterium avium complex infection is appropriate, a three-drug

regimen (including a macrolide, ethambutol and rifampicin) is required; use:
1 azithromycin 500 mg (child: 10 mg/kg up to 500 mg) orally, 3 times weekly [Note 5]
OR
1 clarithromycin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 12-hourly (ie two doses
per day) on 3 days per week
ethambutol (adult and child) 25 mg/kg orally, 3 times weekly [Note 6]
PLUS
rifampicin (adult and child) 15 mg/kg up to 600 mg orally, 3 times weekly.
Note 5: At the time of writing, azithromycin is not available on the Pharmaceutical Benefits Scheme (PBS) for this indication. See the PBS website
for current information [URL].
Resistant organisms, severe disease and poor response to initial treatment
Patients infected with a macrolide-resistant isolate require an alternative regimen—seek expert advice. Treatment
options may include amikacin for the first 2 months of treatment (daily or three times weekly).
Therapeutic options for patients with severe disease or a poor response to initial treatment include the addition of
an aminoglycoside, clofazimine or interferon gamma.
Surgical resection of focal disease or a solitary nodule or cavity is sometimes indicated.
For more information on managing macrolide-resistant and severe pulmonary Mycobacterium avium complex
infections (including amikacin regimens and monitoring), see the British Thoracic Society Guidelines for the
Management of Non-tuberculous Mycobacterial Pulmonary Disease (NTM-PD) (2017) [URL].
Disseminated Mycobacterium avium complex infection
Disseminated Mycobacterium avium complex infection occurs most commonly in immunocompromised patients,
notably those with advanced HIV infection. It is common for patients with advanced HIV infection to have other
opportunistic infections in addition to disseminated Mycobacterium avium complex infection.
For primary treatment of disseminated Mycobacterium avium complex infection in adults, a three-drug regimen
(including a macrolide, ethambutol and rifabutin) is required; use:
1 clarithromycin 500 mg orally, 12-hourly
OR
2 azithromycin 500 mg orally, daily [Note 7]
ethambutol 15 mg/kg orally, daily
PLUS
rifabutin 300 mg orally, daily.
Patients with undiagnosed HIV infection may present initially with M. avium complex infection. In patients who
need to be started on therapy for HIV, see Mycobacterium avium complex (MAC) infection in adults with HIV
infection for advice on starting antiretroviral therapy.
If starting treatment for M. avium complex infection in patients taking antiretroviral therapy for HIV infection,
check for potential drug interactions when prescribing antibiotics (see Antiretroviral drug interactions).
Maintenance therapy (secondary prophylaxis) for disseminated Mycobacterium avium complex disease in patients
with HIV infection is the same as primary treatment; two or three drugs are used according to tolerance and drug
interactions. For patients on antiretroviral therapy with a suppressed HIV viral load, maintenance therapy can be
stopped when the CD4 count has been more than 100 cells/microlitre for 6 months or more, and the patient has
completed 12 months or more of treatment for Mycobacterium avium complex and has no residual signs or
symptoms.
Note 7: An azithromycin dosage of 600 mg orally, daily is used in some centres.

For general information on nontuberculous mycobacterial infections, see Diagnosis of nontuberculous
mycobacterial infections and Approach to managing nontuberculous mycobacterial infections.
Mycobacterium kansasii causes a chronic pulmonary infection that resembles tuberculosis. Pyrazinamide
resistance is universal. Rifampicin is the mainstay of treatment if the isolate is susceptible. For rifampicin-
susceptible isolates, use:
isoniazid 300 mg (child: 10 mg/kg up to 300 mg) orally, daily [Note 8] [Note 9]
PLUS
rifampicin 600 mg (adult less than 50 kg: 450 mg; child 50 kg or more: 600 mg; child less
than 50 kg: 15 mg/kg up to 450 mg) orally, daily
PLUS
ethambutol (adult and child) 15 mg/kg orally, daily [Note 10].
Treatment duration is usually 18 months; however, continue treatment until the patient’s sputum is culture-negative
for at least 12 months.
For detailed information on the management of M. kansasii pulmonary infections, see the British Thoracic Society
Guidelines for the Management of Non-tuberculous Mycobacterial Pulmonary Disease (NTM-PD) [URL].
Note 8: An oral liquid formulation of isoniazid is not commercially available; for formulation options for children or people with swallowing
Note 9: In patients who are at risk of peripheral neuropathy, administer pyridoxine (adult: 25 mg; child: 6.25 to 12.5 mg) orally, with each dose of
isoniazid.
Infection with rapidly growing mycobacteria (M. abscessus, M. chelonae

and M. fortuitum)
Overview of rapidly growing mycobacteria
For general information on nontuberculous mycobacterial infections, see Diagnosis of nontuberculous
mycobacterial infections and Approach to managing nontuberculous mycobacterial infections.
Mycobacterium abscessus, Mycobacterium chelonae and Mycobacterium fortuitum are rapidly growing
mycobacteria that cause skin and soft tissue and respiratory infections, infections of prosthetic material, and
infections associated with contact lens use and ocular surgery (especially M. chelonae with laser in situ
keratomileusis [LASIK]). Occasionally these organisms cause disseminated infection.
For detail on M. abscessus pulmonary disease, see Mycobacterium abscessus pulmonary disease.
In the majority of patients with M. chelonae or M. fortuitum identified on culture of respiratory samples, the
organisms are transient or not contributing to the patient’s symptoms, and treatment is not required. Patients with
repeated positive cultures and persistent respiratory symptoms not responding to other treatments are more likely
to need treatment.
Treatment is complex; it depends on the site of infection, and is guided by the results of susceptibility testing.
Adjunctive surgery may be required.
If treatment is required for M. fortuitum, use a combination of two oral drugs with demonstrated in vitro
susceptibility—options usually include doxycycline, ciprofloxacin or trimethoprim+sulfamethoxazole. Macrolides
are not first-line treatment because all isolates have inducible erythromycin methylase (erm) genes, which can
produce macrolide resistance despite initial in vitro susceptibility.
For respiratory disease caused by M. chelonae or M. fortuitum, continue treatment until the patient’s sputum is
culture-negative for at least 12 months.
For severe skin and soft tissue infection caused by rapidly growing mycobacteria, the minimum duration of
treatment is 4 months. For bone infection, 6 months of treatment is recommended. A longer duration of treatment
is usually required in immunocompromised patients.
Mycobacterium abscessus pulmonary disease

Pulmonary disease caused by Mycobacterium abscessus is difficult to treat and of emerging importance,
particularly in patients with cystic fibrosis. If M. abscessus is identified in sputum or bronchoscopic samples, close
follow-up is required. Although patients may spontaneously clear M. abscessus, it should not be dismissed as a
coloniser.
The M. abscessus complex can be further speciated into M. abscessus subspecies abscessus, M. abscessus
subspecies bolletii, and M. abscessus subspecies massiliense. If possible, the subspecies should be determined
because this can influence treatment choice—M. abscessus subsp. massiliense is more likely to be macrolide-
susceptible, with higher rates of treatment success. Testing for inducible macrolide resistance should be done on all
M. abscessus isolates by undertaking extended incubation of isolates in the presence of clarithromycin; inducible
resistance may predict treatment failure.
The decision to treat can be complex and as with other nontuberculous mycobacteria will be guided by symptoms,
progressive changes on CT scan, and recurrent isolation by culture. Cavitary disease suggests a high burden of
infection and supports early treatment initiation.
There have been no clinical trials to guide drug selection, so recommendations are based on pharmacokinetic and
pharmacodynamic studies, potential adverse effects, and the goals of therapy (eg to obtain microbiological cure, to
target symptoms such as haemoptysis or cough). Patients often require multiple treatment courses.
Treatment consists of an initial phase followed by a continuation phase. The initial phase comprises a combination
drug regimen; for example, oral azithromycin and clofazimine, plus intravenous amikacin and one or two other
parenteral drugs such as cefoxitin, imipenem or tigecycline. The duration of the initial phase is 2 to 12 weeks,
depending on the goals of therapy and tolerability of treatment. The continuation phase should include nebulised
amikacin, oral azithromycin and clofazimine, and potentially other oral agents (eg linezolid, moxifloxacin,
minocycline) based on susceptibility test results and tolerability. The duration of the continuation phase is usually
at least 6 months, but may extend beyond 12 months. Seek expert advice.
In carefully selected patients with limited focal disease, surgical resection with perioperative combination drug
therapy is often curative.
For detailed information on the management of M. abscessus pulmonary infections, see the British Thoracic
Society Guidelines for the Management of Non-tuberculous Mycobacterial Pulmonary Disease (NTM-PD) [URL].

Clinical presentation
Mycobacterium ulcerans infection (also known as Buruli, Bairnsdale or Daintree ulcer) is geographically
restricted, occurring in coastal Victoria, Far North Queensland and occasionally the Capricorn coast of
Queensland.
Skin and soft tissue infection caused by M. ulcerans usually begins as a painless dermal papule or subcutaneous
nodule, which breaks down over weeks to months to form a necrotic ulcer with undermined edges. The necrosis
may extend several centimetres beyond the edge of the surface lesion.
M. ulcerans less commonly presents as an atypical cellulitis involving part or all of a limb, or as a plaque without
an ulcer.
Diagnosis
Diagnosis requires clinical suspicion in the presence of a history of travel to or residence in an endemic area. The
median incubation period is 4.5 months.
Rapid and accurate diagnosis can be made directly from tests of a swab run around the undermined edge of an
ulcer. It is important to order the correct tests—M. ulcerans-specific polymerase chain reaction (PCR), smear and
culture. Many lesions are smear-positive; culture results may take several weeks.
In cases presenting without a defined ulcer (eg atypical cellulitis, oedema, plaque), the diagnosis is suggested by
history of exposure to an endemic area and failure to respond to usual empirical treatment. If M. ulcerans infection
is suspected, perform a biopsy or fine-needle aspirate for testing. Clearly record the possibility of M. ulcerans on
the test request form—M. ulcerans-specific PCR is very likely to be positive, and histology is characteristic.
Treatment
In Australia, many cases of M. ulcerans infection are managed with oral antibiotics alone. Surgery may be
required for extensive disease as an adjunct to antibiotics.
A recommended antibiotic regimen for M. ulcerans infection is:
rifampicin (adult and child) 10 mg/kg up to 600 mg orally, daily for 8 weeks
PLUS
clarithromycin 500 mg (child: 7.5 mg/kg up to 500 mg) orally, 12-hourly for 8 weeks.
Other regimens that have been used are rifampicin plus either moxifloxacin or ciprofloxacin. For patients who
cannot take rifampicin, an alternative regimen is moxifloxacin plus clarithromycin. Intravenous amikacin is
reserved for severe cases and is rarely used.
Clinical deterioration during antibiotic treatment can be caused by a paradoxical reaction to treatment rather than
antibiotic failure.
Surgery may be required in some patients. The procedure consists of excision of the ulcer and either primary
closure or grafting; adjunctive antibiotic treatment reduces the need for wide excision and allows preservation of
deep structures. Although small lesions can be cured with resection alone, relapse may occur if antibiotics are not
used. With larger lesions, antibiotics and surgery are often used sequentially, with 4 to 8 weeks of antibiotics used
before excision.
Conservative surgical debridement of necrotic tissue is likely to facilitate healing (see Surgical
wound debridement). Repeated debridement may be needed.
Healing of M. ulcerans lesions is slow and may continue for up to 12 months after completion of antibiotic therapy
if skin defects are large, particularly when the diagnosis has been delayed. Inform patients that the ulcer will
continue to heal after antibiotic therapy is stopped.
Inform patients that the ulcer will continue to heal after antibiotic therapy is stopped.
Adjuvant heat therapy may reduce the risk of relapse after resection for patients who cannot have antibiotic
therapy. A small case series from Africa found that direct application of heat to the ulcer for several hours each day
for up to 8 weeks reduced relapse [Note 11].
Note 11: Vogel M, Bayi PF, Ruf MT, Bratschi MW, Bolz M, Um Boock A, et al. Local heat application for the treatment of Buruli ulcer: results of a
phase II open label single center non comparative clinical trial. Clin Infect Dis 2016;62(3):342-50. [URL]

Mycobacterium marinum causes localised papular or nodular skin lesions following exposure to fresh or salt water
(fish-tank or swimming-pool granuloma). Diagnosis is often made by biopsy. Consider sporotrichosis (a
lymphocutaneous infection caused by Sporothrix schenckii) as a differential diagnosis.
Seek expert advice about the management of M. marinum infection. Antibiotic therapy is not required if a single
lesion is successfully excised.
There are no randomised controlled trials comparing treatment regimens. A number of drugs have in vitro efficacy,
including clarithromycin, ethambutol, rifampicin, doxycycline, trimethoprim+sulfamethoxazole and moxifloxacin;
these are often used in combination. The optimal duration of therapy is not known, but treatment is recommended
for 1 to 2 months after the resolution of all lesions (typically 3 to 4 months in total). Perform susceptibility testing
if treatment failure occurs.
Surgical excision or debridement (especially for closed spaces of the hand) may be indicated.
Mycobacterium leprae infection

Detailed consideration of Hansen disease (Mycobacterium leprae infection or leprosy) is beyond the scope of these
guidelines—seek expert advice. Leprosy should be included in the differential diagnosis of hypopigmented patches
on the skin, particularly if the patient experiences diminished or altered sensation.
Key references
Introduction to nontuberculous mycobacterial infections
Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement:
diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med
2007;175(4):367–416.
Haworth CS, Banks J, Capstick T, Fisher AJ, Gorsuch T, Laurenson IF, et al. British Thoracic Society guidelines for the
management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). Thorax 2017;72(Suppl 2):ii1–ii64.
Approach to managing nontuberculous mycobacterial infections
Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann JL, Nick JA, et al. US Cystic Fibrosis Foundation and European
Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in
individuals with cystic fibrosis: executive summary. Thorax 2016;71(1):88–90.
Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement:
diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med
2007;175(4):367–416.
Corti M, Palmero D. Mycobacterium avium complex infection in HIV/AIDS patients. Expert Rev Anti Infect Ther
2008;6(3):351–63.
Jeong BH, Jeon K, Park HY, Moon SM, Kim SY, Lee SY, et al. Peak plasma concentration of azithromycin and
treatment responses in Mycobacterium avium complex lung disease. Antimicrob Agents Chemother 2016;60(10):6076–
83.
Shimomura H, Andachi S, Aono T, Kigure A, Yamamoto Y, Miyajima A, et al. Serum concentrations of clarithromycin
and rifampicin in pulmonary Mycobacterium avium complex disease: long-term changes due to drug interactions and
their association with clinical outcomes. J Pharm Health Care Sci 2015;1:32.
Infection with rapidly growing mycobacteria (M. abscessus, M. chelonae and M. fortuitum)
Mukherjee V, Bender WS, Egan JP, 3rd. Inhaled antibiotics for refractory nontuberculous mycobacteria and non-cystic
fibrosis bronchiectasis and the significance of Mycobacterium abscessus subsp. abscessus isolation during M. avium
complex lung disease therapy. Am J Respir Crit Care Med 2015;192(1):106–8.
Park J, Cho J, Lee CH, Han SK, Yim JJ. Progression and treatment outcomes of lung disease caused by
Mycobacterium abscessus and Mycobacterium massiliense. Clin Infect Dis 2017;64(3):301–308.
Zhang Z, Lu J, Liu M, Wang Y, Zhao Y, Pang Y. In vitro activity of clarithromycin in combination with other antimicrobial
agents against Mycobacterium abscessus and Mycobacterium massiliense. Int J Antimicrob Agents 2017;49(3):383–6.
Aboagye SY, Asare P, Otchere ID, Koka E, Mensah GE, Yirenya-Tawiah D, et al. Environmental and behavioral drivers
of Buruli ulcer disease in selected communities along the Densu river basin of Ghana: A case-control study. Am J Trop
Med Hyg 2017;96(5):1076–83.
Aiga H, Amano T, Cairncross S, Adomako J, Nanas OK, Coleman S. Assessing water-related risk factors for Buruli
ulcer: a case-control study in Ghana. Am J Trop Med Hyg 2004;71(4):387–92.
Friedman ND, Athan E, Walton AL, O'Brien DP. Increasing experience with primary oral medical therapy for
Mycobacterium ulcerans disease in an Australian cohort. Antimicrob Agents Chemother 2016;60(5):2692–5.
O'Brien DP, Friedman ND, Cowan R, Pollard J, McDonald A, Callan P, et al. Mycobacterium ulcerans in the elderly:
More severe disease and suboptimal outcomes. PLoS Negl Trop Dis 2015;9(12):e0004253.
O'Brien DP, Jenkin G, Buntine J, Steffen CM, McDonald A, Horne S, et al. Treatment and prevention of Mycobacterium
ulcerans infection (Buruli ulcer) in Australia: guideline update. Med J Aust 2014;200(5):267–70.
Vogel M, Bayi PF, Ruf MT, Bratschi MW, Bolz M, Um Boock A, et al. Local heat application for the treatment of Buruli
ulcer: Results of a phase II open label single center non comparative clinical trial. Clin Infect Dis 2016;62(3):342–50.
Johnson MG, Stout JE. Twenty-eight cases of Mycobacterium marinum infection: retrospective case series and
literature review. Infection 2015;43(6):655–62.
Malaria
Aetiology of malaria
Malaria is caused by Plasmodium parasites that are transmitted to humans through the bites of infected
mosquitoes. Of the five Plasmodium species that infect humans (P. falciparum, P. vivax, P. knowlesi, P. malariae
and P. ovale), P. falciparum and P. knowlesi are the most pathogenic and P. falciparum is the most resistant to
standard antimalarials. P. knowlesi is increasingly a cause of malaria in parts of Southeast Asia; it has a similar
appearance on microscopy to P. falciparum (ring stages) or P. malariae (mature stages).
Diagnosis of malaria
Consider malaria in patients with a febrile illness who have visited a malarious area, particularly within the
preceding year. While malaria usually occurs within a few weeks of infection, disease can occasionally be delayed
for many months. For patients with suspected malaria, send a blood sample in an EDTA tube to an appropriate
laboratory for examination, including thick and thin blood films.
A single negative blood film or negative antigen test does not exclude the diagnosis of malaria, particularly if the
patient has taken antimalarials recently. Some antibiotics commonly used by travellers (eg
trimethoprim+sulfamethoxazole, tetracyclines, quinolones) have antimalarial activity that can modify or suppress
malaria symptoms, and make diagnosis by blood film more difficult.
Assessment of malaria severity

Malaria is classified as uncomplicated or severe/complicated. Therapy for malaria is based on severity of illness.
Determine the parasite count in all patients with P. falciparum malaria, regardless of clinical presentation or
severity.
Uncomplicated malaria is defined as symptomatic malaria and a positive parasitological test result (microscopy
or rapid diagnostic test), without features of severe malaria. It is treated with oral therapy, if tolerated (see
Treatment of uncomplicated malaria).
Severe malaria is indicated by one or more of the following features:
a blood parasite count more than 100 000/microlitre (more than 2% of red blood cells parasitised)
impaired consciousness
jaundice
oliguria
respiratory distress
severe anaemia
hypoglycaemia
vomiting
clinical acidosis or metabolic acidosis on blood biochemistry
acute kidney injury.
Urgently treat patients who have severe malaria with intravenous therapy—see Treatment of severe malaria.
Urgently treat patients who have severe malaria with intravenous therapy.
Treatment of uncomplicated malaria

General principles
Uncomplicated malaria is treated with oral therapy. However, if the patient has any features of severe malaria, or is
unable to tolerate oral therapy, treat as for severe malaria and seek expert advice.
If the patient is unable to tolerate oral therapy, treat as for severe malaria and seek expert advice.
Patients with uncomplicated malaria caused by Plasmodium falciparum or Plasmodium knowlesi are at risk of
rapid deterioration—start treatment as soon as possible. Initiate treatment in hospital and monitor for deterioration.
Artemether+lumefantrine (an artemisinin-based combination) is the treatment of choice for uncomplicated malaria,
including in pregnant women after the first trimester of pregnancy. For uncomplicated malaria in the first trimester
of pregnancy, use atovaquone+proguanil or seek expert advice. Do not use atovaquone+proguanil to treat malaria
if it was used for prophylaxis.
Do not use atovaquone+proguanil to treat malaria if it was used for prophylaxis.
Standard treatment for uncomplicated malaria
Treatment regimens for uncomplicated malaria are shown below. For patients with P. falciparum malaria, see also
Additional considerations for P. falciparum. For patients with P. vivax or P. ovale malaria, see also Additional
considerations for P. vivax and P. ovale.
Use:
1 artemether+lumefantrine tablets 20+120 mg, to be taken with fatty food or full-fat milk
for a total of six doses [Note 1]
adult and child more than 34 kg: 4 tablets orally, at 0, 8, 24, 36, 48
and 60 hours
child 5 to 14 kg: 1 tablet orally, at 0, 8, 24, 36, 48 and 60 hours
child 15 to 24 kg: 2 tablets orally, at 0, 8, 24, 36, 48 and 60 hours
OR
2 atovaquone+proguanil tablets 250+100 mg (adult formulation), to be taken with fatty

food or full-fat milk
adult and child more than 40 kg: 4 tablets orally, daily for 3 days
child 11 to 20 kg: 1 tablet orally, daily for 3 days
child 21 to 30 kg: 2 tablets orally, daily for 3 days
OR the combination of
3 quinine sulfate 600 mg (adult less than 50 kg: 450 mg) (child: 10 mg/kg up to 600 mg)
orally, 8-hourly for 7 days [Note 2]
PLUS EITHER
doxycycline orally, 12-hourly for 7 days (which can start after day 1 of quinine therapy)
adult: 100 mg
OR (for pregnant women or children younger than 8 years)
Monitor parasite count daily until negative.
Perform full blood count and malaria microscopy at 7 and 28 days after completion of therapy, to assess for
recrudescence of malaria parasites.
Note 1: Recurrent Plasmodium malariae has occurred after artemether+lumefantrine therapy. In these patients,
consider therapy with chloroquine or hydroxychloroquine—seek expert advice. Chloroquine is not registered in
Australia but is available via the Special Access Scheme.
Note 2: Both quinine sulfate and quinine bisulfate are available as 300 mg tablets. Quinine sulfate 600 mg is
approximately equivalent to quinine bisulfate 900 mg. Although the Australian Therapeutic Goods
Administration (TGA) lists quinine as Category D in pregnancy, quinine has been used extensively in pregnant
women to treat P. falciparum malaria.
Additional considerations for P. falciparum

Seek expert advice for patients with malaria caused by P. falciparum (either alone or with other species) acquired
from the Greater Mekong Subregion (Thailand, Vietnam, Cambodia, Laos and Myanmar) who respond slowly to
artemether+lumefantrine—that is, persisting parasitaemia after 72 hours of therapy. Reduced efficacy of
artemisinin-based combination therapy against P. falciparum has been reported in this region (but at the time of
writing, not other malaria species). Options include:
extending artemether+lumefantrine duration by 2 days (ie standard regimen extended by four doses;
additional doses given at 72, 84, 96 and 108 hours) or
switching to oral atovaquone+proguanil for 3 days (see dosage above) or
switching to quinine sulfate plus either doxycycline or clindamycin for 7 days (see dosage above).
For patients with malaria caused by P. falciparum who are being treated in malaria-receptive regions of northern
Australia [Note 3], a single dose of primaquine is recommended. Primaquine eliminates the transmissible stages of
P. falciparum, preventing the transfer of parasites from human hosts to mosquitoes. Primaquine can cause severe
haemolysis in patients who are glucose-6-phosphate dehydrogenase (G6PD) deficient—if the patient is G6PD
deficient, seek expert advice. Once G6PD deficiency has been excluded, add to the standard treatment regimen for
uncomplicated malaria:
primaquine 15 mg (child over 6 months: 0.25 mg/kg up to 15 mg) orally, as a single dose
[Note 4].
Note 3: Malaria-receptive regions of northern Australia are regions north of 19°S latitude. This represents a line
from just below Broome on the west coast, through Tennant Creek in the Northern Territory, to just above
Townsville on the east coast.
Note 4: Do not use primaquine in pregnant women, infants younger than 6 months and breastfeeding women
with infants under 6 months—seek expert advice.
Additional considerations for P. vivax and P. ovale
P. vivax and P. ovale can exist as dormant parasites (hypnozoites) in the liver that can reactivate to cause a relapse
of malaria. The treatment regimens for uncomplicated malaria (see above) do not eliminate hypnozoites, so
concurrent treatment with primaquine (for P. vivax or P. ovale) or tafenoquine (for P. vivax) is required to eliminate
dormant liver parasites.
Primaquine and tafenoquine [Note 5] can cause severe haemolysis in patients who are glucose-6-phosphate
dehydrogenase (G6PD) deficient—if the patient is G6PD deficient, seek expert advice.
For P. vivax infection, once G6PD deficiency has been excluded, add to the standard treatment regimen for
primaquine 30 mg (child over 6 months: 0.5 mg/kg up to 30 mg) orally, daily, or if nausea
occurs 15 mg (child over 6 months: 0.25 mg/kg up to 15 mg) orally, 12-hourly. Treat for
14 days or, in adults more than 70 kg, until a total cumulative dose of 6 mg/kg is reached
[Note 6] [Note 7].
For P. ovale infection, once G6PD deficiency has been excluded, add to the standard treatment regimen for
primaquine 15 mg (child over 6 months: 0.25 mg/kg up to 15 mg) orally, daily for 14 days
[Note 7].
If a relapse of malaria occurs despite treatment with primaquine or tafenoquine, seek expert advice.
Note 5: Tafenoquine is registered in Australia for radical cure of P. vivax malaria. While currently available
G6PD tests can be used to assess safety of the daily primaquine regimen, they do not reliably identify the level of
G6PD activity required for safe use of tafenoquine. Seek expert advice.
Note 6: Evidence suggests that relapses of malaria caused by P. vivax are more common if primaquine is not
used, or if the total cumulative dose of primaquine is less than 6 mg/kg, especially when the infection has been
acquired in Indonesia, Timor-Leste or Pacific Island countries. Adults who weigh more than 70 kg require
treatment for 15 days or longer to reach a cumulative dose of 6 mg/kg.
Note 7: Do not use primaquine in pregnant women, infants younger than 6 months and breastfeeding women
with infants under 6 months—seek expert advice.
Treatment of severe malaria

Standard treatment for severe malaria
Severe malaria is usually caused by Plasmodium falciparum, but may also be caused by other Plasmodium species.
Urgent treatment of malaria is essential if the patient has any features of severe malaria (see Assessment of
malaria severity).
Start intravenous therapy for severe malaria as soon as possible and seek expert advice on further management.
Intravenous antimalarial therapy is mandatory for severe malaria. Start therapy as soon as possible and seek expert
advice on further management. Artesunate is the treatment of choice for severe malaria, including in pregnant
women, when the benefits outweigh the harms in all trimesters. Use (but see below for advice on patients returning
from the Greater Mekong Subregion):
1 artesunate (adult and child more than 20 kg, including pregnant women in any trimester)
2.4 mg/kg (child up to 20 kg: 3 mg/kg) intravenously, on admission and repeat at 12 hours
and 24 hours, then once daily until the patient has clinically improved and can tolerate
oral therapy [Note 8]
OR (if parenteral artesunate is not immediately available)
2 quinine dihydrochloride (adult and child)
loading dose: 20 mg/kg intravenously over 4 hours [Note 9]
followed by (starting 4 hours after the loading dose is completed): 10 mg/kg intravenously over 4 hours, 8-hourly
until the patient has clinically improved and can tolerate oral therapy [Note 10] [Note 11].
Seek expert advice for patients with severe P. falciparum malaria acquired in the Greater Mekong Subregion
(Thailand, Vietnam, Cambodia, Laos and Myanmar), where the prevalence of artemisinin resistance is increasing.
Combination therapy with intravenous artesunate plus intravenous quinine is now recommended for these patients.
Do not delay therapy if only one of the two intravenous drugs is immediately available—start treatment with one
drug and request urgent shipment of the other.
Check a drug information reference source before administering intravenous quinine because there are important
monitoring and safety considerations. Measure blood pressure and blood glucose concentration regularly (because
quinine stimulates insulin secretion and can cause hypoglycaemia). Cardiac monitoring is also necessary. If
treatment with intravenous quinine continues for longer than 48 hours, dosage adjustment may be necessary,
especially in patients with kidney impairment (see Table 2.80)—seek expert advice.
Monitor parasite count at least twice daily until clinically stable, and then daily until negative.
There are other important considerations when treating severe malaria.
Adjunctive therapy with ceftriaxone and paracetamol is recommended—see Adjunctive therapy for severe
malaria.
Switch to oral antimalarial treatment when the patient has clinically improved and can tolerate oral therapy
—see Intravenous to oral switch for severe malaria.
Treatment with primaquine (or tafenoquine for P. vivax) concurrently with oral antimalarial therapy is
indicated in cases of P. vivax and P. ovale infection, and in some cases of P. falciparum infection—see
Additional considerations for P. vivax and P. ovale or Additional considerations for P. falciparum.
Note 8: Intravenous artesunate is not registered for use in Australia but is available in many Australian hospitals
for immediate use, via the Special Access Scheme. Notify the Therapeutic Goods Administration (TGA) within
28 days of use.
Note 9: The intravenous loading dose of quinine is not required if the patient has received 3 or more doses of
quinine or quinidine in the last 48 hours, or mefloquine prophylaxis in the last 24 hours, or a treatment dose of
mefloquine in the last 3 days.
Note 10: To calculate the maintenance dose of quinine in obese patients, use ideal body weight (for adults, see
Table 2.79 or Ideal body weight calculator).
Note 11: Although the Australian Therapeutic Goods Administration (TGA) lists quinine as Category D in
pregnancy, quinine has been used extensively in pregnant women to treat P. falciparum malaria.
Adjunctive therapy for severe malaria

In addition to antimalarial therapy, ceftriaxone and paracetamol are recommended for severe malaria.
Bacteraemia is common in severe malaria; collect blood samples for culture in patients with severe malaria and
start pre-emptive treatment with ceftriaxone:
ceftriaxone 2 g (child: 50 mg/kg up to 2 g) intravenously, daily for 2 days then reassess

based on blood culture results.
To reduce the risk of haemolytic acute kidney injury, use:
paracetamol 1 g (child 15 mg/kg up to 1 g) orally or enterally, 6-hourly for 72 hours.
Intravenous to oral switch for severe malaria

Switch from intravenous to oral antimalarial treatment when the patient has clinically improved and can tolerate
oral therapy.
Regardless of which intravenous therapy was given, use:
1 artemether+lumefantrine tablets 20+120 mg, to be taken with fatty food or full-fat milk
for a total of six doses
adult and child more than 34 kg: 4 tablets orally, at 0, 8, 24, 36, 48
and 60 hours
child 5 to 14 kg: 1 tablet orally, at 0, 8, 24, 36, 48 and 60 hours
OR
2 atovaquone+proguanil tablets 250+100 mg (adult formulation), to be taken with fatty

food or full-fat milk
adult and child more than 40 kg: 4 tablets orally daily for 3 days
child 11 to 20 kg: 1 tablet orally, daily for 3 days

OR the combination of
3 quinine sulfate 600 mg (adult less than 50 kg: 450 mg) (child: 10 mg/kg up to 600 mg)
PLUS EITHER
doxycycline orally, 12-hourly for 7 days

adult: 100 mg
OR (for pregnant women or children younger than 8 years)
To assess for delayed haemolysis from the artemisinin therapy and for recrudescence of malaria parasites, perform
full blood count and malaria microscopy at 7, 14, 21 and 28 days after completion of oral therapy for severe
malaria.
Note 12: Although the Australian Therapeutic Goods Administration (TGA) lists quinine as Category D in
pregnancy, quinine has been used extensively in pregnant women to treat P. falciparum malaria.
Prophylaxis of malaria
Introduction
Malaria prophylaxis is complicated by the development of multidrug-resistant strains of Plasmodium falciparum
throughout the world, particularly in Southeast Asia.
Recommendations for malaria prophylaxis from different sources vary considerably. For specific geographical
locations, useful information about the risk of malaria, drug resistance and antimalarial prophylaxis is available
from:
Centers for Disease Control and Prevention (CDC). CDC Health information for international travel (Yellow
book) 2018. [URL]
World Health Organization (WHO). International travel and health. [URL]
Alternatively, individualised advice can be obtained from travel medicine clinics and other expert advisory
services. This approach is strongly recommended for children, pregnant women, people staying in malaria-
endemic regions for longer than 8 weeks, people with complex travel itineraries, and people travelling to high-risk
areas.
Expert advice is strongly recommended for children, pregnant women, people staying in malaria-endemic regions for longer than
8 weeks, people with complex travel itineraries, and people travelling to high-risk areas.
Vector avoidance
Simple measures give significant protection and minimise the potential for mosquito bites, such as:
applying effective insect repellent and using other insecticide products (eg mosquito coils or vaporising
mats)
wearing light-coloured long trousers and long-sleeved shirts in the evening
sleeping in screened accommodation or using mosquito nets, which can be pyrethroid impregnated
avoiding outside activities between dusk and dawn
avoiding perfume and aftershave.
Antimalarial prophylaxis
Indications for prophylaxis
No antimalarial prophylaxis regimen is guaranteed to prevent malaria. Consequently, when prescribing

prophylaxis, the risk of disease and the efficacy of the drug(s) must be balanced against the potential for drug
toxicity. Consider the following factors when assessing the risk of acquiring malaria:
country and area to be visited

time of year
duration of visit
type of activities planned.
In some areas of malaria-endemic countries, including many major cities and tourist resorts, the risk of malaria is
low and prophylaxis is not required.
Consider malaria prophylaxis for migrants from malarious areas who return there to visit family and friends,
because the risk of malaria is often underappreciated by these individuals.
Malaria in pregnant women or patients with asplenia or hyposplenism is potentially serious, so it is strongly
recommended that these individuals do not travel to malarious areas, especially areas in which drug-resistant P.
falciparum is present.
Advise travellers to malarious areas that antimalarial prophylaxis is not always effective and they must seek urgent
medical attention if they develop a fever while travelling or after returning.
Fever in travellers to malarious areas requires urgent medical attention.
Prophylaxis for children is difficult. Doxycycline prophylaxis is not recommended for children younger than 8
years, and mefloquine is not approved for paediatric use in Australia (though it has been widely used).
Recommendations for prophylaxis
Do not use mefloquine for prophylaxis in the Greater Mekong Subregion (Thailand, Vietnam, Cambodia, Laos and
Myanmar), due to mefloquine resistance.
For prophylaxis of malaria, use:
1 atovaquone+proguanil tablets 250+100 mg (adult formulation)
adult and child more than 40 kg: 1 tablet orally with fatty food or full-
fat milk, daily (starting 1 to 2 days before entering, and continuing for
7 days after leaving, the malarious area)
atovaquone+proguanil tablets 62.5+25 mg (paediatric formulation)

child 11 to 20 kg: 1 tablet; 21 to 30 kg: 2 tablets; 31 to 40 kg: 3 tablets
orally with fatty food or full-fat milk, daily (starting 1 to 2 days before
entering, and continuing for 7 days after leaving, the malarious area)
OR
1 doxycycline orally, daily (starting 1 to 2 days before entering, and continuing for 4 weeks
after leaving, the malarious area)
adult: 100 mg

OR (in areas without mefloquine resistance)
1 mefloquine 250 mg (child 5 to 15 kg: 62.5 mg [= 1/4 tablet]; 16 to 30 kg: 125 mg [= 1/2
tablet]; 31 to 45 kg: 187.5 mg [= 3/4 tablet]; over 45 kg: 250 mg [= 1 tablet]) orally, once
weekly (starting 2 to 3 weeks before entering, and continuing for 4 weeks after leaving,
the malarious area) [Note 13].
Unlike atovaquone+proguanil, doxycycline and mefloquine are not sufficiently effective against the primary liver
stages of malaria, so it is recommended that prophylaxis with these drugs is continued for 4 weeks after leaving the
malarious area.
Note 13: Avoid mefloquine for prophylaxis in people with epilepsy or a history of psychiatric disorders.
Stand-by emergency treatment for malaria

Travellers who choose not to use antimalarial prophylaxis can be given a stand-by course of
artemether+lumefantrine or atovaquone+proguanil to use if a febrile illness occurs and medical care is unlikely to
be available within 24 hours (see Treatment of uncomplicated malaria for dosages). Travellers should be advised to
seek medical attention, even if emergency treatment is taken, because there are many possible causes of febrile
illness.
In many countries, travellers can purchase antimalarial drugs without a prescription, but they should be warned
that counterfeit products are common.
Key references
Abreha T, Hwang J, Thriemer K, Tadesse Y, Girma S, Melaku Z, et al. Comparison of artemether-lumefantrine and
chloroquine with and without primaquine for the treatment of Plasmodium vivax infection in Ethiopia: A randomized
controlled trial. PLoS Med 2017;14(5):e1002299.
Amaratunga C, Lim P, Suon S, Sreng S, Mao S, Sopha C, et al. Dihydroartemisinin-piperaquine resistance in

Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis 2016;16(3):357–
65.
Aung NM, Kaung M, Kyi TT, Kyaw MP, Min M, Htet ZW, et al. The safety of a conservative fluid replacement strategy
in adults hospitalised with malaria. PLoS One 2015;10(11):e0143062.
Ballard SB, Salinger A, Arguin PM, Desai M, Tan KR. Updated CDC recommendations for using artemether-
lumefantrine for the treatment of uncomplicated malaria in pregnant women in the United States. MMWR Morb Mortal
Wkly Rep 2018;67(14):424–31.
Barber BE, Grigg MJ, William T, Yeo TW, Anstey NM. The treatment of Plasmodium knowlesi malaria. Trends Parasitol
2017;33(3):242–53.
Centers for Disease Control and Prevention (CDC). CDC Yellow Book 2018: health information for international travel.
New York: Oxford University Press; 2017. https://wwwnc.cdc.gov/travel/yellowbook/2018/table-of-contents
Centers for Disease Control and Prevention (CDC). Malaria Treatment (United States) [guidelines for clinicians].
Atlanta, GA: CDC; Last updated: February 28, 2017. https://www.cdc.gov/malaria/diagnosis_treatment/treatment.html
Centers for Disease Control and Prevention (CDC). Part 3: Alternatives for Pregnant Women and Treatment of Severe
Malaria. In: Treatment of Malaria: Guidelines For Clinicians (United States). Atlanta, GA: CDC; Last updated: July 15,
2013. https://www.cdc.gov/malaria/diagnosis_treatment/clinicians3.html
Chavada R, Hui SH, O'Connor S, Akima S, Gosbell IB. Post-artesunate delayed haemolysis in severe imported
Plasmodium falciparum malaria. Med J Aust 2015;203(9):364.
Dellicour S, Sevene E, McGready R, Tinto H, Mosha D, Manyando C, et al. First-trimester artemisinin derivatives and
quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational
studies. PLoS Med 2017;14(5):e1002290.
Eick-Cost AA, Hu Z, Rohrbeck P, Clark LL. Neuropsychiatric outcomes after mefloquine exposure among U.S. Military
service members. Am J Trop Med Hyg 2017;96(1):159–66.
Grigg MJ, William T, Menon J, Dhanaraj P, Barber BE, Wilkes CS, et al. Artesunate-mefloquine versus chloroquine for
treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW): an open-label, randomised
controlled trial. Lancet Infect Dis 2016;16(2):180–8.
Hanson J, Anstey NM, Bihari D, White NJ, Day NP, Dondorp AM. The fluid management of adults with severe malaria.
Crit Care 2014;18(6):642.
Hemming-Schroeder E, Lo E. Evidence of a hard selective sweep for artemisinin resistant Plasmodium falciparum.
Lancet Infect Dis 2017;17(5):462–3.
Imwong M, Suwannasin K, Kunasol C, Sutawong K, Mayxay M, Rekol H, et al. The spread of artemisinin-resistant
Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study. Lancet Infect
Dis 2017;17(5):491–7.
Kakuru A, Jagannathan P, Muhindo MK, Natureeba P, Awori P, Nakalembe M, et al. Dihydroartemisinin-piperaquine for
the prevention of malaria in pregnancy. N Engl J Med 2016;374(10):928–39.
Llanos-Cuentas A, Lacerda MV, Rueangweerayut R, Krudsood S, Gupta SK, Kochar SK, et al. Tafenoquine plus
chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre,
double-blind, randomised, phase 2b dose-selection study. Lancet 2014;383(9922):1049–58.
Moore KA, Simpson JA, Paw MK, Pimanpanarak M, Wiladphaingern J, Rijken MJ, et al. Safety of artemisinins in first
trimester of prospectively followed pregnancies: an observational study. Lancet Infect Dis 2016;16(5):576–83.
Nyein PP, Aung NM, Kyi TT, Htet ZW, Anstey NM, Kyi MM, et al. High frequency of clinically significant bacteremia in
adults hospitalized with falciparum malaria. Open Forum Infect Dis 2016;3(1):ofw028.
Phyo AP, Win KK, Thu AM, Swe LL, Htike H, Beau C, et al. Poor response to artesunate treatment in two patients with
severe malaria on the Thai-Myanmar border. Malar J 2018;17(1):30.
Plewes K, Kingston HWF, Ghose A, Wattanakul T, Hassan MMU, Haider MS, et al. Acetaminophen as a renoprotective
adjunctive treatment in patients with severe and moderately severe falciparum malaria: A randomized, controlled,
open-label trial. Clin Infect Dis 2018.
Pregact Study Group, Pekyi D, Ampromfi AA, Tinto H, Traore-Coulibaly M, Tahita MC, et al. Four artemisinin-based
treatments in african pregnant women with malaria. N Engl J Med 2016;374(10):913–27.
Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ. Global extent of chloroquine-resistant Plasmodium
vivax: a systematic review and meta-analysis. Lancet Infect Dis 2014;14(10):982–91.
Rutledge GG, Marr I, Huang GKL, Auburn S, Marfurt J, Sanders M, et al. Genomic characterization of recrudescent
Plasmodium malariae after treatment with artemether/lumefantrine. Emerg Infect Dis 2017;23(8):1300–7.
Spring MD, Lin JT, Manning JE, Vanachayangkul P, Somethy S, Bun R, et al. Dihydroartemisinin-piperaquine failure
associated with a triple mutant including kelch13 C580Y in Cambodia: an observational cohort study. Lancet Infect Dis
2015;15(6):683–91.
Tun KM, Imwong M, Lwin KM, Win AA, Hlaing TM, Hlaing T, et al. Spread of artemisinin-resistant Plasmodium
falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect Dis 2015;15(4):415–21.
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Gastrointestinal helminths (worms)
Dog hookworm infection
Eosinophilic enterocolitis caused by Ancylostoma caninum (dog hookworm) in humans can be treated with
albendazole or mebendazole, or with endoscopic removal of the parasite. Use:
1 albendazole 400 mg (child 10 kg or less: 200 mg) orally, as a single dose
OR
2 mebendazole 100 mg (child 10 kg or less: 50 mg) orally, 12-hourly for 3 days.
A. caninum occasionally causes cutaneous larva migrans, although this is classically and more commonly caused
by Ancylostoma braziliense (cat and dog hookworm); both types respond to a single dose of oral ivermectin (see
Cutaneous larva migrans).
Hookworm infection
To treat hookworm (Ancylostoma duodenale or Necator americanus) infection, use:
OR
2 mebendazole 100 mg (child 10 kg or less: 50 mg) orally, 12-hourly for 3 days
OR
3 pyrantel (adult and child) 10 mg/kg up to 1 g orally, daily for 3 days.
Roundworm infection
To treat roundworm (Ascaris lumbricoides) infection, use:
OR
2 mebendazole 100 mg (child 10 kg or less: 50 mg) orally, 12-hourly for 3 days
OR
3 pyrantel (adult and child) 10 mg/kg up to 1 g orally, as a single dose (repeat after 7 days if
heavy infection).
Threadworm infection
Threadworm (or pinworm) (Enterobius vermicularis) infection is not usually associated with co-infection with
other helminths.
To treat Enterobius vermicularis, use:
mebendazole 100 mg (child 10 kg or less: 50 mg) orally, as a single dose

1
OR
1 pyrantel (adult and child) 10 mg/kg up to 1 g orally, as a single dose
OR
1 albendazole 400 mg (child 10 kg or less: 200 mg) orally, as a single dose.
Mebendazole, pyrantel and albendazole are equally effective in the treatment of Enterobius vermicularis, but
albendazole has a broader spectrum and is only available with a prescription.
Due to the frequency of reinfection and autoinfection, consider repeating the dose after 2 weeks. Treat household
contacts and carers at the same time to reduce the risk of reinfection. Provide advice on hygiene measures to
reduce the risk of reinfection and spread of infection: wash hands regularly, avoid scratching around the anus, keep
fingernails short, take a shower or bath daily, and wash clothing, towels and bed linen in hot water.
Strongyloidiasis
Management of strongyloidiasis in immunocompetent patients
To treat strongyloidiasis (Strongyloides stercoralis infection) in immunocompetent patients, use:
1 ivermectin (adult and child 15 kg or more) 200 micrograms/kg orally with fatty food, as a
single dose; repeat after 7 to 14 days
OR
2 albendazole 400 mg (child 10 kg or less: 200 mg) orally with fatty food, 12-hourly for 3
days; repeat course after 7 to 14 days.
Management of strongyloidiasis in immunocompromised patients

For information on primary prophylaxis and pre-emptive treatment of Strongyloides stercoralis in
immunocompromised adults, see Strongyloides stercoralis prophylaxis in immunocompromised adults without
HIV infection.
Immunocompromised patients can develop hyperinfection or disseminated strongyloidiasis syndrome, which can
be fatal. Patients at risk include those receiving high-dose or prolonged corticosteroids (eg prednisolone 20 mg
daily or more [or equivalent, see Table 2.45] for more than 2 weeks) or other potent immunosuppressive drugs (eg
used for chemotherapy or following organ transplant), or who have human T-lymphotropic virus type 1 infection,
haematological malignancy or advanced HIV infection.
In immunocompromised patients with uncomplicated strongyloidiasis, use:
ivermectin (adult and child 15 kg or more) 200 micrograms/kg orally with fatty food, on
days 1, 2, 15 and 16.
Immunocompromised patients with hyperinfection or disseminated strongyloidiasis syndrome need longer

courses of therapy, together with reduction of immunosuppression therapy if possible. There is limited evidence on
optimal treatment—seek expert advice. The duration of treatment is based on clinical response. A regimen that has
been used is:
ivermectin (adult and child 15 kg or more) 200 micrograms/kg orally or enterally with
fatty food, daily until symptoms resolve and stool or sputum microscopy demonstrates
clearance of larvae
FOLLOWED BY TWO FURTHER DOSES:
ivermectin (adult and child 15 kg or more) 200 micrograms/kg orally or enterally with
fatty food, daily on days 7 and 8 after completion of daily therapy.
In patients who are not improving clinically or who are not absorbing enteral feeds, consider administering
ivermectin subcutaneously [Note 1] instead of via the oral or enteral route (using the same dosage as above),
continued until microscopy demonstrates clearance of larvae.
Patients who remain immunocompromised require follow-up clinical assessment and serology to check for relapse.
Following treatment of strongyloidiasis, immunocompromised patients who live in or visit a Strongyloides-

endemic region (eg remote Aboriginal and Torres Strait Islander communities) should receive ongoing
prophylaxis:
ivermectin (adult and child 15 kg or more) 200 micrograms/kg orally with fatty food, once
every 3 months while the patient remains immunocompromised and continues to live in or
visit an endemic area.
For immunocompromised children weighing less than 15 kg, seek expert advice.
Note 1: A veterinary formulation of ivermectin injection has occasionally been used for patients who do not respond to oral ivermectin. Use of the
veterinary product in humans requires approval; the approval process varies between states and territories.
Tapeworm infection
Manifestations of Taenia infection
Taenia infection may be caused by Taenia solium (pork tapeworm) or Taenia saginata (beef tapeworm). Both can
cause gastrointestinal infection, while T. solium can also cause tissue cysticercosis, including neurocysticercosis. T.
solium cysticercosis results from ingestion of eggs that have been shed by another human with gastrointestinal
pork tapeworm infection, or from autoingestion of eggs.
Gastrointestinal taeniasis
To treat gastrointestinal taeniasis caused by pork tapeworm or beef tapeworm, use:
1 praziquantel (adult and child) 10 mg/kg orally, as a single dose
OR
2 niclosamide 2 g (child: 50 mg/kg up to 2 g) orally, as a single dose [Note 2].
When praziquantel is used to treat pork tapeworm there is a risk of seizures from occult neurocysticercosis (see
below); however, this is uncommon.
Note 2: Niclosamide is not registered for use in Australia but is available via the Special Access Scheme.
Neurocysticercosis
Patients with brain cysts (neurocysticercosis) often present with seizures requiring antiepileptic therapy. In patients
with active cysts, systematic reviews found that the use of albendazole with or without concomitant corticosteroids
reduces long-term seizure frequency and the number of active lesions. There is insufficient evidence on the
efficacy of corticosteroids alone, and consensus is now that albendazole together with corticosteroids is the
preferred therapy. A small randomised controlled trial supports the addition of praziquantel to albendazole and
corticosteroids [Note 3]; this combination is recommended for patients with more than two viable parenchymal
cysticerci [Note 4]. Patients with calcified cysts but no active cysts do not require cysticidal drug therapy. Seek
expert advice.
Note 3: Garcia HH, Gonzales I, Lescano AG, Bustos JA, Zimic M, Escalante D, et al. Efficacy of combined antiparasitic therapy with praziquantel and
albendazole for neurocysticercosis: a double-blind, randomised controlled trial. Lancet Infect Dis 2014;14(8):687-95. [URL]
Note 4: White AC, Jr., Coyle CM, Rajshekhar V, Singh G, Hauser WA, Mohanty A, et al. Diagnosis and treatment of neurocysticercosis: 2017 Clinical
practice guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH).
Clin Infect Dis 2018;66(8):1159-63. [URL]
Dwarf tapeworm infection
Dwarf tapeworm (Hymenolepis nana) infection is usually asymptomatic, but heavy infections may cause
abdominal pain and diarrhoea. Use:
praziquantel (adult and child) 25 mg/kg orally, as a single dose (repeat after 7 days if
heavy infection).
Whipworm infection
To treat whipworm (Trichuris trichiura) infection, use:
1 albendazole 400 mg (child 10 kg or less: 200 mg) orally, daily for 3 days
OR
2 mebendazole 100 mg (child 10 kg or less: 50 mg) orally, 12-hourly for 3 days.
Treatment with albendazole or mebendazole reduces worm burden but is often not curative, and reinfection is
common in communities where whipworm is endemic. Worm burden correlates with associated morbidity, such as
anaemia, gastrointestinal disturbance, stunted growth and, rarely, rectal prolapse. Community deworming
programs and housing and hygiene initiatives are important public health measures for reducing whipworm
infection morbidity.
Community deworming programs

Age-targeted anthelmintic therapy in communities with high rates of intestinal helminth infection improves
nutrition and growth. In selected Aboriginal and Torres Strait Islander communities where such infections are
endemic, for children between 6 months and 12 years, use:
albendazole 400 mg (child 10 kg or less: 200 mg) orally, as a single dose once a year.
Key references
Dog hookworm infection
Schuster A, Lesshafft H, Reichert F, Talhari S, de Oliveira SG, Ignatius R, et al. Hookworm-related cutaneous larva
migrans in northern Brazil: resolution of clinical pathology after a single dose of ivermectin. Clin Infect Dis
2013;57(8):1155–7.
Hookworm infection
Davies J, Majumdar SS, Forbes RT, Smith P, Currie BJ, Baird RW. Hookworm in the Northern Territory: down but not
out. Med J Aust 2013;198(5):278–81.
Strongyloidiasis
Buonfrate D, Requena-Mendez A, Angheben A, Munoz J, Gobbi F, Van Den Ende J, et al. Severe strongyloidiasis: a
systematic review of case reports. BMC Infect Dis 2013;13:78.
Chiodini PL, Reid AJ, Wiselka MJ, Firmin R, Foweraker J. Parenteral ivermectin in Strongyloides hyperinfection.
Lancet 2000;355(9197):43–4.
Grein JD, Mathisen GE, Donovan S, Fleckenstein L. Serum ivermectin levels after enteral and subcutaneous
administration for Strongyloides hyperinfection: a case report. Scand J Infect Dis 2010;42(3):234–6.
Gupta S, Jain A, Fanning TV, Couriel DR, Jimenez CA, Eapen GA. An unusual cause of alveolar hemorrhage post
hematopoietic stem cell transplantation: a case report. BMC Cancer 2006;6:87.
Hauber HP, Galle J, Chiodini PL, Rupp J, Birke R, Vollmer E, et al. Fatal outcome of a hyperinfection syndrome
despite successful eradication of Strongyloides with subcutaneous ivermectin. Infection 2005;33(5-6):383–6.
Henriquez-Camacho C, Gotuzzo E, Echevarria J, White AC, Jr., Terashima A, Samalvides F, et al. Ivermectin versus
albendazole or thiabendazole for Strongyloides stercoralis infection. Cochrane Database Syst Rev 2016;
(1):CD007745.
Huston JM, Eachempati SR, Rodney JR, Cayci C, Fusco D, Mathew M, et al. Treatment of Strongyloides stercoralis
hyperinfection-associated septic shock and acute respiratory distress syndrome with drotrecogin alfa (activated) in a
renal transplant recipient. Transpl Infect Dis 2009;11(3):277–80.
Keiser PB, Nutman TB. Strongyloides stercoralis in the Immunocompromised Population. Clin Microbiol Rev
2004;17(1):208–17.
Leung V, Al-Rawahi GN, Grant J, Fleckenstein L, Bowie W. Case report: failure of subcutaneous ivermectin in treating
Strongyloides hyperinfection. Am J Trop Med Hyg 2008;79(6):853–5.
Marty FM, Lowry CM, Rodriguez M, Milner DA, Pieciak WS, Sinha A, et al. Treatment of human disseminated
strongyloidiasis with a parenteral veterinary formulation of ivermectin. Clin Infect Dis 2005;41(1):e5–8.
Pacanowski J, Santos MD, Roux A, C LEM, Guillot J, Lavarde V, et al. Subcutaneous ivermectin as a safe salvage
therapy in Strongyloides stercoralis hyperinfection syndrome: a case report. Am J Trop Med Hyg 2005;73(1):122–4.
Satou T, Koga M, Koike K, Tada I, Nikaido T. Nemaidal activities of thiabendazole and ivermectin against the larvae of
Strongyloides ratti and S. venezuelensis. Vet Parasitol 2001;99(4):311–22.
Turner SA, Maclean JD, Fleckenstein L, Greenaway C. Parenteral administration of ivermectin in a patient with
disseminated strongyloidiasis. Am J Trop Med Hyg 2005;73(5):911–4.
Tapeworm infection
Baird RA, Wiebe S, Zunt JR, Halperin JJ, Gronseth G, Roos KL. Evidence-based guideline: treatment of parenchymal
neurocysticercosis: report of the Guideline Development Subcommittee of the American Academy of Neurology.
Neurology 2013;80(15):1424–9.
Garcia HH, Gonzales I, Lescano AG, Bustos JA, Pretell EJ, Saavedra H, et al. Enhanced steroid dosing reduces
seizures during antiparasitic treatment for cysticercosis and early after. Epilepsia 2014;55(9):1452–9.
Garcia HH, Gonzales I, Lescano AG, Bustos JA, Zimic M, Escalante D, et al. Efficacy of combined antiparasitic
therapy with praziquantel and albendazole for neurocysticercosis: a double-blind, randomised controlled trial. Lancet
Infect Dis 2014;14(8):687–95.
Romo ML, Wyka K, Carpio A, Leslie D, Andrews H, Bagiella E, et al. The effect of albendazole treatment on seizure
outcomes in patients with symptomatic neurocysticercosis. Trans R Soc Trop Med Hyg 2015;109(11):738–46.
Sharma M, Singh T, Mathew A. Antiepileptic drugs for seizure control in people with neurocysticercosis. Cochrane
White AC, Jr., Coyle CM, Rajshekhar V, Singh G, Hauser WA, Mohanty A, et al. Diagnosis and treatment of
neurocysticercosis: 2017 Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the
American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis 2018;66(8):1159–63.
Zammarchi L, Strohmeyer M, Bartalesi F, Bruno E, Munoz J, Buonfrate D, et al. Epidemiology and management of
cysticercosis and Taenia solium taeniasis in Europe, systematic review 1990-2011. PLoS One 2013;8(7):e69537.
Zhao BC, Jiang HY, Ma WY, Jin DD, Li HM, Lu H, et al. Albendazole and Corticosteroids for the Treatment of Solitary
Cysticercus Granuloma: A Network Meta-analysis. PLoS Negl Trop Dis 2016;10(2):e0004418.
Whipworm infection
Crowe AL, Smith P, Ward L, Currie BJ, Baird R. Decreasing prevalence of Trichuris trichiura (whipworm) in the
Northern Territory from 2002 to 2012. Med J Aust 2014;200(5):286–9.
Community deworming programs

Adegnika AA, Zinsou JF, Issifou S, Ateba-Ngoa U, Kassa RF, Feugap EN, et al. Randomized, controlled, assessor-
blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides,
trichuris trichiura, and hookworm infection. Antimicrob Agents Chemother 2014;58(5):2535–40.
Awasthi S, Peto R, Read S, Richards SM, Pande V, Bundy D, et al. Population deworming every 6 months with
albendazole in 1 million pre-school children in North India: DEVTA, a cluster-randomised trial. Lancet
2013;381(9876):1478–86.
Croke K, Hicks JH, Hsu E, Kremer MR, Miguel EA. Does mass deworming affect child nutrition? meta-analysis, cost-
effectiveness, and statistical power. Washington, D.C.: The World Bank; 2016.
http://documents.worldbank.org/curated/en/926411482169164466/Does-mass-deworming-affect-child-nutrition-meta-
analysis-cost-effectiveness-and-statistical-power
Ebenezer R, Gunawardena K, Kumarendran B, Pathmeswaran A, Jukes MC, Drake LJ, et al. Cluster-randomised trial
of the impact of school-based deworming and iron supplementation on the cognitive abilities of schoolchildren in Sri
Lanka's plantation sector. Trop Med Int Health 2013;18(8):942–51.
Joseph SA, Casapia M, Montresor A, Rahme E, Ward BJ, Marquis GS, et al. The Effect of Deworming on Growth in
One-Year-Old Children Living in a Soil-Transmitted Helminth-Endemic Area of Peru: A Randomized Controlled Trial.
PLoS Negl Trop Dis 2015;9(10):e0004020.
Kepha S, Mwandawiro CS, Anderson RM, Pullan RL, Nuwaha F, Cano J, et al. Impact of single annual treatment and
four-monthly treatment for hookworm and Ascaris lumbricoides, and factors associated with residual infection among
Kenyan school children. Infect Dis Poverty 2017;6(1):30.
Kremer M, Croke K. More evidence on the effects of deworming: What lessons can we learn? Am J. Trop Med Hyg,
2017;96(6):1265–6.
Levecke B, Montresor A, Albonico M, Ame SM, Behnke JM, Bethony JM, et al. Assessment of anthelmintic efficacy of
mebendazole in school children in six countries where soil-transmitted helminths are endemic. PLoS Negl Trop Dis
2014;8(10):e3204.
Liu C, Lu L, Zhang L, Luo R, Sylvia S, Medina A, et al. Effect of Deworming on Indices of Health, Cognition, and
Education Among Schoolchildren in Rural China: A Cluster-Randomized Controlled Trial. Am J Trop Med Hyg
2017;96(6):1478–89.
Salam RA, Haider BA, Humayun Q, Bhutta ZA. Effect of administration of antihelminthics for soil-transmitted helminths
during pregnancy. Cochrane Database Syst Rev 2015;(6):CD005547.
Speich B, Moser W, Ali SM, Ame SM, Albonico M, Hattendorf J, et al. Efficacy and reinfection with soil-transmitted
helminths 18-weeks post-treatment with albendazole-ivermectin, albendazole-mebendazole, albendazole-oxantel
pamoate and mebendazole. Parasit Vectors 2016;9:123.
Taylor-Robinson DC, Maayan N, Soares-Weiser K, Donegan S, Garner P. Deworming drugs for soil-transmitted
intestinal worms in children: effects on nutritional indicators, haemoglobin, and school performance. Cochrane
Yap P, Du ZW, Wu FW, Jiang JY, Chen R, Zhou XN, et al. Rapid re-infection with soil-transmitted helminths after triple-
dose albendazole treatment of school-aged children in Yunnan, People's Republic of China. Am J Trop Med Hyg
2013;89(1):23–31.
Gastrointestinal protozoa
Pathogenicity of gastrointestinal protozoa
Although pathogenic gastrointestinal protozoa can cause chronic infectious diarrhoea, most chronic diarrhoea is
due to a noninfectious cause.
Most chronic diarrhoea has a noninfectious cause.
Protozoa that are human gastrointestinal pathogens include Giardia intestinalis, Entamoeba histolytica,
Cyclospora cayetanensis, Cystoisospora (Isospora) belli, Cryptosporidium species and microsporidia.
Nonpathogenic commensal protozoa are found as commonly in asymptomatic people as they are in people with
symptoms—treatment for these organisms is ineffective and unnecessary.
The pathogenicity of Blastocystis hominis and Dientamoeba fragilis has not been established.
Faecal testing for parasites (which includes protozoa) is indicated in patients with abdominal symptoms (eg
abdominal pain, diarrhoea) for more than 2 weeks. Faecal parasite testing is not indicated for nonspecific
symptoms (eg fatigue) when the patient does not have abdominal symptoms.
Blastocystis hominis carriage

Until recently, Blastocystis hominis was detected only by faecal microscopy. Due to the introduction of multiplex
polymerase chain reaction (mPCR) faecal testing in Australia, which is more sensitive, it has become evident that
carriage of B. hominis is much more common than previously thought. However, the pathogenicity of this
organism has not been established [Note 1].
The pathogenicity of Blastocystis hominis has not been established.
A positive mPCR result should be interpreted with care—B. hominis is commonly detected in asymptomatic
individuals, and when B. hominis is identified in a symptomatic patient, symptoms are more likely to have an
alternative cause.
In patients with persistent abdominal symptoms (eg abdominal pain, diarrhoea) and B. hominis carriage, it is
important to investigate for other causes (eg irritable bowel syndrome, inflammatory bowel disease, malabsorption
syndromes, colon cancer, Clostridium difficile infection, enteric bacterial infection, HIV-related opportunistic
infections, Tropheryma whipplei infection [Whipple disease])—consider referral to a gastroenterologist.
The use of antimicrobial therapy for B. hominis is controversial and is not supported by good quality evidence.
However, in symptomatic patients in whom other causes have been excluded, treatment may be considered—seek
advice from an infectious diseases physician.
Repeat courses of antibiotics and retesting are not indicated.
Note 1: For more information, see the Royal College of Pathologists of Australasia position statement Faecal
pathogen testing by PCR and the detection of Dientamoeba fragilis and Blastocystis species [URL].
Cryptosporidium species infection

In immunocompetent patients, infection with Cryptosporidium species (cryptosporidiosis) usually causes an acute
self-limiting gastroenteritis, so antimicrobial treatment is not usually indicated.
In immunocompromised patients (eg advanced HIV infection, organ transplant, hypogammaglobulinaemia, IgA
deficiency, potent immunosuppressive therapy), cryptosporidiosis may be prolonged or severe. It responds best to
an improvement in the patient’s immune status. In patients with HIV infection, antiretroviral therapy with immune
reconstitution reduces the duration and severity of gastroenteritis. For patients with a new diagnosis of HIV, see
Cryptosporidium species gastroenteritis in adults with HIV infection for information on starting antiretroviral
therapy.
Clinical trials have not shown a clinical benefit for using antimicrobials to treat cryptosporidiosis in
immunocompromised patients. Fluid and electrolyte replacement and antimotility drugs are the mainstay of
treatment (see Supportive management of acute gastroenteritis). However, for persistent, severe cryptosporidial
diarrhoea, particularly in an immunocompromised patient, consider:
nitazoxanide 500 mg (child 1 to 3 years: 100 mg; 4 to 11 years: 200 mg) orally, 12-hourly
for 3 days [Note 2].
If starting treatment for cryptosporidiosis in patients taking antiretroviral therapy for HIV infection, check for
potential drug interactions when prescribing antiprotozoal drugs (see Antiretroviral drug interactions).
Cyclospora cayetanensis infection

Clinical features of Cyclospora cayetanensis gastroenteritis (cyclosporiasis) resemble cryptosporidiosis.
To treat Cyclospora cayetanensis gastroenteritis, use:

Treat for 7 days in immunocompetent patients or 14 days in immunocompromised patients.
For patients hypersensitive to trimethoprim+sulfamethoxazole, either ciprofloxacin or nitazoxanide can be

used.
If starting treatment for cyclosporiasis in patients taking antiretroviral therapy for HIV infection, check for
potential drug interactions when prescribing antibiotics (see Antiretroviral drug interactions).
Secondary prophylaxis may be needed in immunocompromised patients to prevent relapse; refer to an infectious
diseases physician.
In patients with a new diagnosis of HIV, see Cyclospora cayetanensis gastroenteritis in adults with HIV
infection for information on starting antiretroviral therapy.
Cystoisospora (Isospora) belli infection

Cystoisospora (Isospora) belli, similarly to Cryptosporidium, causes a self-limiting gastroenteritis in
immunocompetent patients—antimicrobial therapy is not usually indicated.
In people with advanced HIV infection, and rarely in other immunocompromised patients (eg organ transplant,
haematological malignancy, tumour necrosis factor (TNF) inhibitor recipients, human T-lymphotropic virus type 1
infection), C. belli causes chronic diarrhoea.
Trimethoprim+sulfamethoxazole is the drug of choice to treat C. belli infections. In patients who are
hypersensitive to trimethoprim+sulfamethoxazole, consider drug desensitisation.
For primary treatment of symptomatic patients with C. belli infection, particularly if immunocompromised, use:

160+800 mg) orally or intravenously, 12-hourly for 7 days.
For patients hypersensitive to trimethoprim+sulfamethoxazole, use:
ciprofloxacin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 12-hourly for 7 days [Note
3] [Note 4].
If starting treatment for C. belli infection in patients taking antiretroviral therapy for HIV infection, check for
potential drug interactions when prescribing antibiotics (see Antiretroviral drug interactions).
For maintenance therapy (secondary prophylaxis), use:

160+800 mg) orally, 3 times weekly.
For maintenance therapy in patients hypersensitive to trimethoprim+sulfamethoxazole, use:

ciprofloxacin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 3 times weekly [Note 3]
[Note 4].
In patients with HIV infection with a suppressed viral load, stop maintenance therapy when there is no evidence of
active C. belli infection and the CD4 count is more than 200 cells/microlitre for 6 months or more. In patients
receiving immunosuppressive therapy temporarily, stop maintenance therapy 6 months after immunosuppressive
therapy is completed.
In patients with a new diagnosis of HIV, see Cystoisospora (Isospora) belli gastroenteritis in adults with HIV
infection for information on starting antiretroviral therapy.
Dientamoeba fragilis carriage

Until recently, Dientamoeba fragilis was detected only by faecal microscopy. Due to the introduction of multiplex
polymerase chain reaction (mPCR) faecal testing in Australia, which is more sensitive, it has become evident that
carriage of D. fragilis is much more common than previously thought. However, the pathogenicity of this
organism has not been established [Note 5].
The pathogenicity of Dientamoeba fragilis has not been established.
A positive mPCR result should be interpreted with care—D. fragilis is commonly detected in asymptomatic
individuals, and when D. fragilis is identified in a symptomatic patient, symptoms are more likely to have an
alternative cause. If D. fragilis is identified by mPCR and the patient has significant abdominal symptoms (eg
abdominal pain, diarrhoea), follow-up faecal microscopy is recommended.
In patients with persistent symptoms and D. fragilis carriage, it is important to investigate for other causes (eg
irritable bowel syndrome, inflammatory bowel disease, malabsorption syndromes, colon cancer, Clostridium
difficile infection, enteric bacterial infection, HIV-related opportunistic infections, Tropheryma whipplei infection
[Whipple disease])—consider referral to a gastroenterologist.
The use of antimicrobial therapy for D. fragilis is controversial. A randomised controlled trial of metronidazole for
treatment of D. fragilis in children showed no benefit [Note 6]. However, treatment may be considered in
symptomatic patients in whom D. fragilis has been identified on faecal microscopy or who have eosinophilia, and
where other causes have been excluded—seek advice from an infectious diseases physician.
Repeat courses of antibiotics and retesting are not indicated.
Note 5: For more information, see the Royal College of Pathologists of Australasia position statement Faecal
pathogen testing by PCR and the detection of Dientamoeba fragilis and Blastocystis species [URL].
Note 6: Roser D, Simonsen J, Stensvold CR, Olsen KE, Bytzer P, Nielsen HV, et al. Metronidazole therapy for
treating dientamoebiasis in children is not associated with better clinical outcomes: a randomized, double-
blinded and placebo-controlled clinical trial. Clin Infect Dis 2014;58(12):1692-9. [URL]
Entamoeba histolytica infection (amoebiasis)

Entamoeba species
The pathogenic species Entamoeba histolytica is identical on microscopy to the nonpathogenic species Entamoeba
dispar and Entamoeba moshkovskii, but they can be differentiated by antigen detection and nucleic acid
amplification testing (eg polymerase chain reaction [PCR]).
Asymptomatic carriage of Entamoeba histolytica

Treatment of asymptomatic carriage of Entamoeba histolytica (with a luminal agent only) is recommended to
minimise transmission and the risk of developing invasive disease. Use:
paromomycin 500 mg (child: 10 mg/kg up to 500 mg) orally, 8-hourly for 7 days [Note 7].
Invasive amoebiasis
For acute amoebic colitis (dysentery), use:
1 tinidazole 2 g (child: 50 mg/kg up to 2 g) orally, daily for 3 days [Note 8]
OR
2 metronidazole 600 mg (child: 15 mg/kg up to 600 mg) orally, 8-hourly for 7 days.
For severe amoebic colitis (eg frequent blood-stained stools, perforation, peritonitis or toxic megacolon), use:
1 tinidazole 2 g (child: 50 mg/kg up to 2 g) orally, daily for 5 days [Note 8]
OR
2 metronidazole 800 mg (child: 15 mg/kg up to 800 mg) orally, 8-hourly for 7 days
OR (if the patient is unable to tolerate oral therapy)
2 metronidazole 750 mg (child: 15 mg/kg up to 750 mg) intravenously, 8-hourly for 7 days.
Patients with suspected or proven peritonitis or toxic megacolon should also receive antimicrobial therapy for
peritonitis (see Peritonitis due to perforated viscus).
Once treatment of invasive amoebiasis is completed, follow with a luminal agent to eradicate cysts and prevent
relapse. Use:
paromomycin 500 mg (child: 10 mg/kg up to 500 mg) orally, 8-hourly for 7 days [Note 9].
For information on amoebic liver abscess, see Liver abscess.
Note 8: If tinidazole dosing is difficult in children, use metronidazole instead.
Giardia intestinalis infection (giardiasis)

Giardia intestinalis (also known as Giardia lamblia or Giardia duodenalis) is the most common protozoal cause of
chronic diarrhoea.
Treatment of immunocompetent patients with asymptomatic Giardia intestinalis carriage is usually not necessary.
Treatment of immunocompetent patients with asymptomatic G. intestinalis carriage is usually not necessary. For
symptomatic patients, use:
1 tinidazole 2 g (child: 50 mg/kg up to 2 g) orally, as a single dose [Note 10]
OR
2 metronidazole 2 g (child: 30 mg/kg up to 2 g) orally, daily for 3 days

OR
2 metronidazole 400 mg (child: 10 mg/kg up to 400 mg) orally, 8-hourly for 5 days.
In pregnant patients, discuss the harms and benefits of therapy. If treatment is necessary, metronidazole or
paromomycin can be used. While paromomycin has traditionally been preferred in pregnancy, especially in the
first trimester, there is evidence and clinical experience to support the use of metronidazole throughout pregnancy.
If metronidazole is used, prescribe the divided-dose regimen above (8-hourly).
Symptom recurrence after treatment may be caused by postinfection lactose intolerance (see Transient lactose
intolerance), reinfection or drug resistance. Metronidazole-resistant G. intestinalis is cross-resistant to tinidazole,
but nitazoxanide is likely to remain effective [Note 11]. Alternative drugs that can be used in the setting of drug
resistance are albendazole, mebendazole and paromomycin [Note 12]—refer to an infectious diseases physician.
Note 10: If tinidazole dosing is difficult in children, use metronidazole instead.
Microsporidia infection
Microsporidia species (eg Encephalitozoon [Septata] intestinalis, Enterocytozoon bieneusi) can be associated with
self-limiting diarrhoea in immunocompetent patients. Treatment is not usually indicated.
In immunocompromised patients, particularly those with advanced HIV infection (and occasionally in organ
transplant), microsporidial infection can cause chronic diarrhoea, and rarely, involve other organs.
For primary treatment of E. intestinalis and other Encephalitozoon species (excluding E. bieneusi) in
immunocompromised adults, use:
albendazole 400 mg orally with fatty food, 12-hourly for 21 days.
If starting treatment for microsporidia species infection in patients taking antiretroviral therapy for HIV infection,
check for potential drug interactions when prescribing albendazole (see Antiretroviral drug interactions).
In adults who have a relapse of infection caused by Encephalitozoon species, use maintenance therapy:
albendazole 400 mg orally with fatty food, 12-hourly.
In patients with HIV infection on antiretroviral therapy with a suppressed HIV viral load, stop maintenance
therapy when the CD4 count is more than 200 cells/microlitre for 6 months or more.
For treatment of E. bieneusi and other microsporidial infections in immunocompromised patients, seek expert
advice.
In patients with a new diagnosis of HIV, see Microsporidia species gastroenteritis in adults with HIV infection for
information on starting antiretroviral therapy.
Key references
Blastocystis hominis carriage
Bowen AC, Sheorey H, Bryant PA, Robson J, Burgner DP. Polymerase chain reaction testing for faecal parasites: risks
and alternatives. Med J Aust 2016;204(7):262.
Byrne S, Robson JM. Advances in molecular diagnosis of parasitic enteropathogens. Pathology 2015;47(3):234–42.
El Safadi D, Gaayeb L, Meloni D, Cian A, Poirier P, Wawrzyniak I, et al. Children of Senegal river basin show the
highest prevalence of blastocystis sp ever observed worldwide. BMC Infect Dis 2014;14:164.
Moghaddam DD, Ghadirian E, Azami M. Blastocystis hominis and the evaluation of efficacy of metronidazole and
trimethoprim/sulfamethoxazole. Parasitol Res 2005;96(4):273–5.
Nigro L, Larocca L, Massarelli L, Patamia I, Minniti S, Palermo F, et al. A placebo-controlled treatment trial of
Blastocystis hominis infection with metronidazole. J Travel Med 2003;10(2):128–30.
Roberts T, Ellis J, Harkness J, Marriott D, Stark D. Treatment failure in patients with chronic Blastocystis infection. J
Med Microbiol 2014;63(Pt 2):252–7.
Roberts T, Stark D, Harkness J, Ellis J. Update on the pathogenic potential and treatment options for Blastocystis sp.
Gut Pathog 2014;6:17.
Rossignol JF, Kabil SM, Said M, Samir H, Younis AM. Effect of nitazoxanide in persistent diarrhea and enteritis
associated with Blastocystis hominis. Clin Gastroenterol Hepatol 2005;3(10):987–91.
Royal College of Pathologists of Australasia. Guideline: Faecal pathogen testing by PCR and the detection of
Dientamoeba fragilis and Blastocystis species. 2015;(6/2015). http://www.rcpa.edu.au/Library/College-
Policies/Guidelines/Faecal-pathogen-testing-by-PCR.aspx
Stensvold CR, Clark CG. Current status of Blastocystis: A personal view. Parasitol Int 2016;65(6 Pt B):763–71.
Yakoob J, Jafri W, Jafri N, Islam M, Asim Beg M. In vitro susceptibility of Blastocystis hominis isolated from patients
with irritable bowel syndrome. Br J Biomed Sci 2004;61(2):75–7.
Cryptosporidium species infection
Hussien SM, Abdella OH, Abu-Hashim AH, Aboshiesha GA, Taha MA, El-Shemy AS, et al. Comparative study
between the effect of nitazoxanide and paromomycine in treatment of cryptosporidiosis in hospitalized children. J Egypt
Soc Parasitol 2013;43(2):463–70.
Dientamoeba fragilis carriage
Bowen AC, Sheorey H, Bryant PA, Robson J, Burgner DP. Polymerase chain reaction testing for faecal parasites: risks
and alternatives. Med J Aust 2016;204(7):262.
Byrne S, Robson JM. Advances in molecular diagnosis of parasitic enteropathogens. Pathology 2015;47(3):234–42.
Gray TJ, Kwan YL, Phan T, Robertson G, Cheong EY, Gottlieb T. Dientamoeba fragilis: a family cluster of disease
associated with marked peripheral eosinophilia. Clin Infect Dis 2013;57(6):845–8.
Roser D, Simonsen J, Nielsen HV, Stensvold CR, Molbak K. Dientamoeba fragilis in Denmark: epidemiological
experience derived from four years of routine real-time PCR. Eur J Clin Microbiol Infect Dis 2013;32(10):1303–10.
Roser D, Simonsen J, Stensvold CR, Olsen KE, Bytzer P, Nielsen HV, et al. Metronidazole therapy for treating
dientamoebiasis in children is not associated with better clinical outcomes: a randomized, double-blinded and placebo-
controlled clinical trial. Clin Infect Dis 2014;58(12):1692–9.
Royal College of Pathologists of Australasia. Guideline: Faecal pathogen testing by PCR and the detection of
Dientamoeba fragilis and Blastocystis species. 2015;(6/2015). http://www.rcpa.edu.au/Library/College-
Policies/Guidelines/Faecal-pathogen-testing-by-PCR.aspx
Stark D, Barratt J, Chan D, Ellis JT. Dientamoeba fragilis, the Neglected Trichomonad of the Human Bowel. Clin
Microbiol Rev 2016;29(3):553–80.
Giardia intestinalis infection (giardiasis)
Escobedo AA, Ballesteros J, Gonzalez-Fraile E, Almirall P. A meta-analysis of the efficacy of albendazole compared
with tinidazole as treatments for Giardia infections in children. Acta Trop 2016;153:120–7.
Sheehy O, Santos F, Ferreira E, Berard A. The use of metronidazole during pregnancy: a review of evidence. Curr
Drug Saf 2015;10(2):170–9.
Filariasis
Filariasis
Filariasis is transmitted by the bite of some species of mosquitoes, flies and midges. There are eight
recognised nematode causes of human filariasis. The most important are: Wuchereria bancrofti, Brugia malayi
and Brugia timori, which cause lymphatic filariasis; Onchocerca volvulus, which causes river blindness; and
Loa loa, which causes loaiasis. Mansonella perstans, Mansonella ozzardi and Mansonella streptocerca also
infect humans.
Filariasis is not endemic in Australia. Chronic long-term exposure to the parasites is usually necessary for
infection, particularly for lymphatic filariasis, so disease is rare in travellers returning from a short trip to an
endemic area. Mass drug administration programs are reducing, and in some circumstances eliminating,
filariasis and onchocerciasis in endemic regions.
Each infection has a unique presentation and management approach—seek expert advice. Treatment is usually
with albendazole, ivermectin, diethylcarbamazine [Note 1] or doxycycline, sometimes in combination.
Note 1: Diethylcarbamazine is not registered for use in Australia but is available via the Special Access Scheme.
Key references
Debrah AY, Specht S, Klarmann-Schulz U, Batsa L, Mand S, Marfo-Debrekyei Y, et al. Doxycycline leads to
sterility and enhanced killing of female Onchocerca volvulus worms in an area with persistent microfilaridermia
after repeated ivermectin treatment: a randomized, placebo-controlled, double-blind trial. Clin Infect Dis
2015;61(4):517–26.
Kar SK, Dwibedi B, Kerketa AS, Maharana A, Panda SS, Mohanty PC, et al. A randomized controlled trial of
increased dose and frequency of albendazole with standard dose DEC for treatment of Wuchereria bancrofti
microfilaremics in Odisha, India. PLoS Negl Trop Dis 2015;9(3):e0003583.
Tafatatha TT, Ngwira BM, Taegtmeyer M, Phiri AJ, Wilson TP, Banda LG, et al. Randomised controlled clinical trial
of increased dose and frequency of albendazole and ivermectin on Wuchereria bancrofti microfilarial clearance in
northern Malawi. Trans R Soc Trop Med Hyg 2015;109(6):393–9.
Thomsen EK, Sanuku N, Baea M, Satofan S, Maki E, Lombore B, et al. Efficacy, safety, and pharmacokinetics of
coadministered diethylcarbamazine, albendazole, and ivermectin for treatment of Bancroftian filariasis. Clin Infect
Dis 2016;62(3):334–41.
Hydatid disease
Hydatid disease
Hydatid disease is caused by the Echinococcus species of tapeworm. Dogs are the definitive host for
Echinococcus granulosus; foxes are the definitive host for Echinococcus multilocularis (which is not
endemic in Australia but is occasionally diagnosed in migrants). Large cysts can form in humans following
exposure to tapeworm eggs; these are usually in the liver, but can occur in the lung, brain, bone or muscle.
Treatment of asymptomatic E. granulosus infection may not be required, but monitor cysts for continued
growth.
If treatment of hydatid disease is required, seek expert advice.
If treatment of cystic disease is required, seek expert advice. Options include open or laparoscopic surgery,
ultrasound-guided percutaneous drainage (such as the PAIR technique for liver cysts [puncture, aspiration,
injection of a protoscolicidal agent such as hypertonic saline or ethanol, then re-aspiration after at least 15
minutes]) or antimicrobial therapy. Surgery is usually the treatment of choice for symptomatic disease
because it is associated with the lowest recurrence rates, especially for liver cysts.
For both surgery and percutaneous drainage (eg PAIR), adjunctive albendazole is recommended; use:
albendazole 400 mg (child older than 6 years: 7.5 mg/kg up to 400 mg) orally with
fatty food, 12-hourly, starting 1 week before and continuing for 4 weeks after surgery
or PAIR.
Small pulmonary lesions may respond to albendazole alone.
Complicated disease where surgery has failed or is not possible may require more prolonged albendazole.
Ensure monitoring for adverse effects is performed in patients on prolonged albendazole therapy—consult a
comprehensive source of drug information for more information.
Praziquantel followed by albendazole is used if cysts are spilled during surgery or trauma. Praziquantel can
also be used with albendazole before surgery and in complicated hydatid disease.
Alveolar hydatid disease (so-called because of the characteristic budding appearance of the cysts) is caused
by E. multilocularis. Management is complex—seek expert advice.
Key references
Akhan O, Salik AE, Ciftci T, Akinci D, Islim F, Akpinar B. Comparison of long-term results of percutaneous
treatment techniques for hepatic cystic echinococcosis types 2 and 3b. AJR Am J Roentgenol 2017;208(4):878–
84.
Akhan O, Yildiz AE, Akinci D, Yildiz BD, Ciftci T. Is the adjuvant albendazole treatment really needed with PAIR in
the management of liver hydatid cysts? A prospective, randomized trial with short-term follow-up results.
Cardiovasc Intervent Radiol 2014;37(6):1568–74.
Chen X, Cen C, Xie H, Zhou L, Wen H, Zheng S. The comparison of 2 new promising weapons for the treatment
of hydatid cyst disease: PAIR and laparoscopic therapy. Surg Laparosc Endosc Percutan Tech 2015;25(4):358–
62.
Gomez IGC, Lopez-Andujar R, Belda Ibanez T, Ramia Angel JM, Moya Herraiz A, Orbis Castellanos F, et al.
Review of the treatment of liver hydatid cysts. World J Gastroenterol 2015;21(1):124–31.
O'Hern JA, Cooley L. A description of human hydatid disease in Tasmania in the post-eradication era. Med J
Aust 2013;199(2):117–20.
Liver flukes
Liver flukes
The liver flukes that infect humans are Fasciola hepatica, Clonorchis sinensis and Opisthorchis viverrini.
To treat F. hepatica, use:
triclabendazole (adult and child) 10 mg/kg orally, daily for 2 days [Note 1].
If triclabendazole is not available, seek expert advice; treatment options include bithionol and nitazoxanide
[Note 2].
To treat C. sinensis or O. viverrini, use:
praziquantel (adult and child) 25 mg/kg orally, 8-hourly for 2 days.
Note 1: Triclabendazole is not registered for use in Australia but is available via the Special Access Scheme.
Note 2: Bithionol and nitazoxanide are not registered for use in Australia but are available via the Special Access Scheme.
Key references
Villegas F, Angles R, Barrientos R, Barrios G, Valero MA, Hamed K, et al. Administration of triclabendazole is safe
and effective in controlling fascioliasis in an endemic community of the Bolivian Altiplano. PLoS Negl Trop Dis
2012;6(8):e1720.
Schistosomiasis
Schistosomiasis
The diagnosis of schistosomiasis (bilharziasis) is confirmed by the identification of eggs in stool, urine or
biopsy samples. If infection is suspected (eg in travellers from endemic areas), serology may assist diagnosis,
but interpretation of results can be difficult—seek expert advice.
For chronic infection with Schistosoma haematobium, Schistosoma japonicum, Schistosoma mansoni and
Schistosoma mekongi, use:
praziquantel (adult and child) 20 mg/kg orally, for two doses, given 4 hours apart.
Further treatment courses may be required in patients who have inadequate response to initial treatment.
Acute schistosomiasis syndrome (Katayama fever) occurs 3 to 8 weeks after infection and is a systemic
hypersensitivity reaction to schistosome antigens and circulating immune complexes. Treatment includes
prednis(ol)one followed by praziquantel. Seek expert advice.
For information about swimmers’ itch, see Cercarial dermatitis.
Key references
Andrade G, Bertsch DJ, Gazzinelli A, King CH. Decline in infection-related morbidities following drug-mediated
reductions in the intensity of Schistosoma infection: A systematic review and meta-analysis. PLoS Negl Trop Dis
2017;11(2):e0005372.
Mutapi F, Maizels R, Fenwick A, Woolhouse M. Human schistosomiasis in the post mass drug administration era.
Lancet Infect Dis 2017;17(2):e42–e8.
Olveda RM, Acosta LP, Tallo V, Baltazar PI, Lesiguez JL, Estanislao GG, et al. Efficacy and safety of
praziquantel for the treatment of human schistosomiasis during pregnancy: a phase 2, randomised, double-blind,
placebo-controlled trial. Lancet Infect Dis 2016;16(2):199–208.
Zwang J, Olliaro PL. Clinical efficacy and tolerability of praziquantel for intestinal and urinary schistosomiasis-a
meta-analysis of comparative and non-comparative clinical trials. PLoS Negl Trop Dis 2014;8(11):e3286.
Prophylaxis for preterm prelabour rupture of
membranes
Approach to prophylaxis for PPROM
Preterm prelabour rupture of membranes (PPROM) (ie membrane rupture before 37 weeks’ gestation and before
the onset of uterine contractions) is the commonest cause of preterm birth. Antibiotic prophylaxis for PPROM
prolongs pregnancy and reduces maternal and neonatal morbidity. However, antibiotic prophylaxis for PPROM
does not appear to reduce perinatal mortality or improve longer-term outcomes. The use of antibiotic prophylaxis
in preterm labour in the absence of membrane rupture is not supported by evidence.
PPROM may be preceded by infection. For women with PPROM, exclude urinary tract infection and sexually
transmitted infections (eg Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis) and screen for
Streptococcus agalactiae (group B streptococcus) carriage (if this has not already occurred).
For PPROM with suspected or confirmed intra-amniotic infection (chorioamnionitis) (ie fever [38°C or more]
with other clinical manifestations such as uterine tenderness and purulent amniotic fluid), treat as for intra-
amniotic infection (chorioamnionitis).
For PPROM without suspected or confirmed intra-amniotic infection (chorioamnionitis):
If delivery is imminent or gestational age is more than 36 weeks, PPROM prophylaxis is not required. If
indicated, give prophylaxis for group B streptococcus—see Prevention of neonatal Streptococcus agalactiae
(group B streptococcus) disease.
If delivery is not imminently planned and gestational age is at or before 36 weeks, give PPROM
prophylaxis.
Regimens for prophylaxis for PPROM

The optimal antibiotic regimen for prophylaxis for preterm prelabour rupture of membranes (PPROM) is
uncertain. A suitable regimen is:
1 amoxicillin 2 g intravenously, 6-hourly for 48 hours, followed by amoxicillin 250 mg

orally, 8-hourly for a total of 7 days (intravenous + oral) or until delivery (whichever is
sooner)
OR
1 ampicillin 2 g intravenously, 6-hourly for 48 hours, followed by amoxicillin 250 mg

orally, 8-hourly for a total of 7 days (intravenous + oral) or until delivery (whichever is
sooner)
1 erythromycin (base) 250 mg orally, 6-hourly for 7 days or until delivery (whichever is
sooner)
OR
1 erythromycin (ethyl succinate) 400 mg orally, 6-hourly for 7 days or until delivery
(whichever is sooner).
Some centres use oral erythromycin (at the dosage above) as monotherapy for 10 days, based on a large
randomised controlled trial [Note 1]. However, the methodology of the study has been criticised; the reduction in
neonatal morbidity found with monotherapy may have been due to chance.
For patients hypersensitive to penicillins, give erythromycin as a single drug for 10 days.
If labour starts during or after the completion of PPROM prophylaxis, give prophylaxis for Streptococcus
agalactiae (group B streptococcus) if indicated—see Prevention of neonatal Streptococcus agalactiae (group B
streptococcus) disease.
If the patient is undergoing caesarean section, surgical prophylaxis is also required (see here for regimens).
Note 1: Kenyon SL, Taylor DJ, Tarnow-Mordi W, Group OC. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the
ORACLE I randomised trial. ORACLE Collaborative Group. Lancet 2001;357(9261):979-88. [URL]
Key references
Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 188: Prelabor rupture of membranes. Obstet
Gynecol 2018;131(1):e1–e14.
Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev 2013;
(12):CD001058.
Kenyon SL, Taylor DJ, Tarnow-Mordi W, Group OC. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal
membranes: the ORACLE I randomised trial. ORACLE Collaborative Group. Lancet 2001;357(9261):979–88.
Wojcieszek AM, Stock OM, Flenady V. Antibiotics for prelabour rupture of membranes at or near term. Cochrane
Women’s Health Committee, The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
(RANZCOG). Prophylactic antibiotics in obstetrics and gynaecology. Melbourne: RANZCOG; Reviewed 2016.
https://www.ranzcog.edu.au/Statements-Guidelines
World Health Organization (WHO). WHO recommendations for prevention and treatment of maternal peripartum
infections. Geneva: WHO; 2015.
http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/peripartum-infections-guidelines/en/
Yeung SW, Sahota DS, Leung TY. Comparison of the effect of penicillins versus erythromycin in preventing neonatal
group B streptococcus infection in active carriers following preterm prelabor rupture of membranes. Taiwan J Obstet
Gynecol 2014;53(2):210–4.
Yudin MH, van Schalkwyk J, Van Eyk N. No. 233-Antibiotic therapy in preterm premature rupture of the membranes. J
Obstet Gynaecol Can 2017;39(9):e207–e12.
Prevention of neonatal Streptococcus agalactiae
(group B streptococcus) disease
Approach to preventing neonatal GBS disease
Streptococcus agalactiae (group B streptococcus [GBS]) is a commensal organism of the gastrointestinal and
genital tracts in up to 30% of healthy women of childbearing age. Other than in pregnancy, it is generally an
incidental finding.
The use of benzylpenicillin or ampicillin prophylaxis for pregnant women colonised with group B
streptococcus reduces the risk of mother-to-child transmission and, therefore, the risk of early-onset neonatal
group B streptococcus infection. However, the approach to identifying women colonised with group B
streptococcus varies between centres; risk-based and screening approaches are used. If screening is
undertaken, carriage is best predicted by antenatal screening at 35 to 37 weeks’ gestation or 3 to 5 weeks
before the anticipated delivery date.
Antibiotic prophylaxis for group B streptococcus is indicated for the following situations:
invasive group B streptococcal disease in a neonate from a previous pregnancy

group B streptococcus identified during the current pregnancy by:
screening by culture or nucleic acid amplification testing (NAAT) (eg polymerase chain reaction
[PCR]) of either vaginal or anorectal swabs
culture of urine sample
intrapartum nucleic acid amplification testing
unknown antepartum group B streptococcal status (investigations not performed, results incomplete or
not available) and any of the following:
intrapartum fever (38°C or more)
preterm onset of labour (before 37 weeks’ gestation)
prolonged rupture of membranes (18 hours or longer).
Antibiotic prophylaxis for group B streptococcus is not indicated for women with intact membranes
undergoing a caesarean section, irrespective of their group B streptococcal status, provided that labour has
not started. However, surgical prophylaxis is indicated—see here for regimens.
Prophylaxis regimens for neonatal GBS disease

If indicated, start antibiotic prophylaxis for group B streptococcus (GBS) on admission to hospital for labour,
induction of labour or rupture of membranes. Ideally, start prophylaxis at least 4 hours before delivery.
Evidence to guide dosing is limited; however, the recommended regimen is:
benzylpenicillin 3 g intravenously for the first dose, then 1.8 g intravenously, 4-hourly
until delivery.
cefazolin 2 g intravenously, 8-hourly until delivery.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, if the group B
streptococcus isolate is susceptible to clindamycin, use:
clindamycin 600 mg intravenously, 8-hourly until delivery.
If the group B streptococcus isolate is resistant to clindamycin or the results of susceptibility testing are not
available, use:
vancomycin intravenously, until delivery; see Principles of vancomycin use for dosage
and principles of use.
Patients undergoing caesarean section require surgical prophylaxis (see here for regimens). If the group B
streptococcus prophylaxis regimen has an appropriate spectrum of activity for surgical prophylaxis,
additional surgical prophylaxis is not required. However, adjust the timing of the dose to achieve adequate
plasma and tissue concentrations at the time of surgical incision and for the duration of the procedure. See
also Surgical antibiotic prophylaxis for patients receiving treatment for established infection.
If intra-amniotic infection (chorioamnionitis) is suspected or confirmed (ie fever [38°C or more] with other
clinical manifestations such as uterine tenderness and purulent amniotic fluid), stop prophylaxis and treat as
for intra-amniotic infection.
Management of neonates at risk of early-onset neonatal GBS sepsis

Neonates with maternal risk factors for early-onset neonatal group B streptococcal (GBS) sepsis require close
observation for signs of sepsis and septic shock during the first 48 hours of life (irrespective of whether
intrapartum antibiotic prophylaxis was given)—see Early recognition of sepsis or septic shock in neonates,
infants and children for definitions. For further information, see the Australasian Society for Infectious
Diseases (ASID) guideline Management of Perinatal Infections [URL].
For the treatment of term neonates (gestational age 37 weeks or older) with early-onset sepsis or septic
shock, see Empirical for early-onset sepsis or septic shock in neonates, source not apparent.
For treatment of preterm neonates (gestational age younger than 37 weeks) with sepsis and septic shock,
seek expert advice.
Key references
https://www.safetyandquality.gov.au/antimicrobial-use-and-resistance-in-australia/resources-page/
Hughes RG, Brocklehurst P, Steer PJ, Heath P, Stenson BM, on behalf of the Royal College of Obstetricians and
Gynaecologists. Prevention of early-onset neonatal group B streptococcal disease: Green-top Guideline No. 36.
BJOG 2017;124(12):e280–e305.
Ohlsson A, Shah VS. Intrapartum antibiotics for known maternal group B streptococcal colonization. Cochrane
Palasanthiran P, Starr M, Jones C, Giles M, editors. Management of perinatal infections. Sydney: Australasian
Society for Infectious Diseases; 2014. http://www.asid.net.au/resources/clinical-guidelines
Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG), Women's Health
Committee. Maternal group B streptococcus in pregnancy: screening and management [C-Obs 19]. Melbourne:
RANZCOG; 2003 [reviewed 2016]. https://www.ranzcog.edu.au/Statements-Guidelines
Verani JR, McGee L, Schrag SJ, National Center for Immunization Respiratory Diseases, Centers for Disease
Control and Prevention (CDC). Prevention of perinatal group B streptococcal disease: revised guidelines from
CDC, 2010. MMWR Recomm Rep 2010;59(RR-10):1–36.
http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/peripartum-infections-guidelines/en
Intra-amniotic infection (chorioamnionitis)
Introduction to intra-amniotic infection
Intra-amniotic infection (previously called chorioamnionitis) is an infection involving the amniotic fluid, placenta,
fetus, fetal membranes or decidua. Most intra-amniotic infections are polymicrobial and caused by ascending
cervicovaginal organisms (eg Streptococcus agalactiae [group B streptococcus], Enterobacteriaceae). Genital
mycoplasmas are commonly isolated from patients with intra-amniotic infection, but the clinical significance of
these organisms is uncertain. Rarely, intra-amniotic infection may arise from haematogenous spread of organisms
from a maternal bacteraemia (eg Listeria monocytogenes [Note 1]) or as a direct result of an invasive procedure
(eg amniocentesis).
Women with intra-amniotic infections often present with nonspecific signs of infection. Suspect intra-amniotic
infection in a pregnant woman with any of the following features:
fever (38°C or more) and ruptured membranes

fever during labour (intrapartum fever), even if membranes are intact
uterine tenderness
purulent amniotic fluid.
If intra-amniotic infection is suspected, early consultation with an obstetrician is required for appropriate
assessment and management. Complications of intra-amniotic infection include preterm labour and delivery,
postpartum uterine atony with haemorrhage, maternal infections including endometritis, and neonatal morbidity
and mortality related to prematurity and neonatal sepsis.
Note 1: For information about the management of perinatal listeriosis, see the Australasian Society for
Infectious Diseases (ASID) guideline Management of Perinatal Infections [URL].
Empirical therapy for intra-amniotic infection

Patients with intra-amniotic infection can present with sepsis or septic shock (see Early recognition of sepsis or
septic shock in adults for definitions). For patients with sepsis or septic shock, start antibiotic therapy within 1
hour of presentation to medical care or, for ward-based patients, development of sepsis or septic shock,
immediately after appropriate samples are taken for culture. For nonantibiotic management of sepsis or septic
shock, see Early intervention for sepsis or septic shock.
Patients undergoing caesarean section require surgical prophylaxis (see here for regimens). If the intra-amniotic
infection treatment regimen has an appropriate spectrum of activity for prophylaxis, additional surgical
prophylaxis is not required. However, adjust the timing of the dose to achieve adequate plasma and tissue
concentrations at the time of surgical incision and for the duration of the procedure. See also Surgical antibiotic
prophylaxis for patients receiving treatment for established infection.
For empirical therapy of suspected or confirmed intra-amniotic infection, as a two-drug regimen, use:

aminoglycoside use for subsequent dosing [Note 3] [Note 4] and see Maternal postpartum
management and duration of therapy
and see Maternal postpartum management and duration of therapy
PLUS EITHER
1 amoxicillin 2 g intravenously, 6-hourly; see Maternal postpartum management and

duration of therapy
OR
1 ampicillin 2 g intravenously, 6-hourly; see Maternal postpartum management and duration

of therapy.
If the results of culture and susceptibility testing are not available by 72 hours and empirical therapy is still
required, stop the gentamicin-containing regimen and seek expert advice.
regimen, use:

PLUS
care support, use 6-hourly dosing. See Maternal postpartum management and duration of
therapy
PLUS
metronidazole 500 mg intravenously, 12-hourly; see Maternal postpartum management

and duration of therapy.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, if the group B streptococcus
isolate is susceptible to clindamycin, as a two-drug regimen, use:

PLUS
clindamycin 600 mg intravenously, 8-hourly; see Maternal postpartum management and

isolate is resistant to clindamycin, or if the group B streptococcus status (or susceptibility) is unknown, in the
above regimen replace clindamycin with the combination of:
intensive care support. See Maternal postpartum management and duration of therapy
PLUS
metronidazole 500 mg intravenously, 12-hourly; see Maternal postpartum management

calculate the dose.
function.
Maternal postpartum management and duration of therapy

Following vaginal delivery, provided that there are no features of sepsis, stop antibiotic therapy for intra-amniotic
infection. Further antibiotic therapy is not routinely required because the risk of postpartum endometritis is low.
Following caesarean delivery, provided that there are no features of sepsis, give one additional dose of each of the
antibiotics started preoperatively, and then stop therapy. If metronidazole or clindamycin was not in the
preoperative regimen, add:
metronidazole 500 mg intravenously, as a single dose, after umbilical cord clamping.
Consider continuing intravenous antibiotics for up to 24 hours following caesarean delivery for patients at
increased risk of postpartum endometritis (eg obese patients, patients with prolonged labour or ruptured
membranes).
There is no evidence that oral antibiotic therapy is beneficial after the discontinuation of intravenous therapy.
If the patient develops fever (38°C or more) and endometritis is suspected, see Empirical therapy for postpartum
endometritis.
Management of neonates born to mothers with intra-amniotic infection

Neonates born to mothers with intra-amniotic infection are at increased risk of early-onset sepsis. Following birth,
closely observe neonates born to mothers with intrapartum fever (ie 38°C or more during labour), or suspected or
confirmed intra-amniotic infection. Some neonates at increased risk of early-onset sepsis require presumptive
antibiotic therapy. For women with intrapartum fever, or suspected or confirmed intra-amniotic infection, seek
advice from a paediatrician as soon as possible to ensure appropriate postnatal management of the neonate.
In the absence of signs of sepsis or septic shock, term (gestational age 37 weeks’ or older) and late-preterm
(gestational age 34 to 36.6 weeks) neonates born to mothers with intrapartum fever or suspected intra-amniotic
infection do not routinely need antibiotic therapy, but should be closely observed.
Consider performing investigations (eg full blood count, blood culture) and starting presumptive antibiotic therapy
for:
preterm neonates with a gestational age less than 34 weeks born to mothers with intrapartum fever or
suspected intra-amniotic infection
neonates of any gestational age born to mothers with confirmed intra-amniotic infection.
For presumptive antibiotic therapy of preterm neonates (gestational age younger than 37 weeks) or the treatment of
early-onset sepsis or septic shock in preterm neonates, seek expert advice.
For presumptive antibiotic therapy of term neonates or the treatment of early-onset sepsis or septic shock in term
neonates, see Empirical regimens for early-onset sepsis or septic shock in neonates, source not apparent.
Key references
Chapman E, Reveiz L, Illanes E, Bonfill Cosp X. Antibiotic regimens for management of intra-amniotic infection.
Committee on Obstetric Practice. Committee Opinion No. 712: Intrapartum management of intraamniotic infection.
Obstet Gynecol 2017;130(2):e95–e101.
Johnson CT, Farzin A, Burd I. Current management and long-term outcomes following chorioamnionitis. Obstet
Gynecol Clin North Am 2014;41(4):649–69.
Tita ATN, Andrews WW. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol 2010;37(2):339–54.
World Health Organization. WHO recommendations for prevention and treatment of maternal peripartum infections.
2015. https://www.ncbi.nlm.nih.gov/books/NBK327079/
Prophylaxis for repair of obstetric anal sphincter
injuries
Prophylaxis for repair of obstetric anal sphincter injuries
Give a single preprocedural dose of antibiotic(s) before the repair of an obstetric anal sphincter injury (OASIS)
(including third- or fourth-degree perineal tears). Use:
cefazolin 2 g intravenously, as early as possible; redosing may be required (see Duration

of surgical antibiotic prophylaxis). Do not give additional intravenous doses once the
procedure is completed
PLUS
metronidazole 500 mg intravenously, as early as possible; redosing may be required (see

Duration of surgical antibiotic prophylaxis). Do not give additional intravenous doses once
the procedure is completed.
As an alternative, cefoxitin may be used as a single drug; however, its activity against anaerobes is inferior to the
regimen above and it requires frequent redosing (every 2 hours). Use:
cefoxitin 2 g intravenously, as early as possible; redosing may be required (see Duration of

surgical antibiotic prophylaxis). Do not give additional intravenous doses once the
procedure is completed.
regimens above.
clindamycin 600 mg intravenously, as early as possible; redosing may be required (see

Duration of surgical antibiotic prophylaxis). Do not give additional intravenous doses once
the procedure is completed.
The role of postoperative antibiotic therapy following anal sphincter repair is unclear, but is recommended because
infection in this setting carries a high risk of anal incontinence and fistula formation. Use:
Use:
cefalexin 500 mg orally, 6-hourly for 5 days
PLUS
PLUS
There is no evidence to recommend maternal antibiotic prophylaxis for other indications following vaginal
delivery.
Key references
Aigmueller T, Umek W, Elenskaia K, Frudinger A, Pfeifer J, Helmer H, et al. Guidelines for the management of third
and fourth degree perineal tears after vaginal birth from the Austrian Urogynecology Working Group. Int Urogynecol J
2013;24(4):553–8.
Auckland District Health Board (ADHB). Perineal tears - third and fourth degree (OASIS). Auckland: ADHB; 2017.
http://nationalwomenshealth.adhb.govt.nz/health-professionals/policies-guidelines
Buppasiri P, Lumbiganon P, Thinkhamrop J, Thinkhamrop B. Antibiotic prophylaxis for third- and fourth-degree perineal
tear during vaginal birth. Cochrane Database Syst Rev 2014;(10):CD005125.
Chibueze EC, Parsons AJ, Ota E, Swa T, Oladapo OT, Mori R. Prophylactic antibiotics for manual removal of retained
placenta during vaginal birth: a systematic review of observational studies and meta-analysis. BMC Pregnancy
Childbirth 2015;15:313.
Chongsomchai C, Lumbiganon P, Laopaiboon M. Prophylactic antibiotics for manual removal of retained placenta in
vaginal birth. Cochrane Database Syst Rev 2014;(10):CD004904.
Duggal N, Mercado C, Daniels K, Bujor A, Caughey AB, El-Sayed YY. Antibiotic prophylaxis for prevention of
postpartum perineal wound complications: a randomized controlled trial. Obstet Gynecol 2008;111(6):1268–73.
Royal College of Obstetricians and Gynaecologists (RCOG). Third- and fourth-degree perineal tears, management
[Green-top Guideline no. 29]. 3rd ed. London: RCOG; 2015. https://www.rcog.org.uk/en/guidelines-research-
services/guidelines/gtg29/
Safrai M, Kabiri D, Haj-Yahya R, Reuveni-Salzman A, Lipschuetz M, Ezra Y. The effect of prophylactic antibiotic
treatment for manual removal of the placenta on frequency of postpartum endometritis. Int J Gynaecol Obstet
2017;139(1):45–9.
Women’s Health Committee, The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
(RANZCOG). Prophylactic antibiotics in obstetrics and gynaecology. Melbourne: RANZCOG; Reviewed 2016.
https://www.ranzcog.edu.au/Statements-Guidelines
http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/peripartum-infections-guidelines/en/
Postpartum endometritis
Introduction to postpartum endometritis
Postpartum endometritis is an infection of the pregnancy endometrium following delivery. The infection may
extend into the myometrium and parametrium, and progress beyond the uterus, causing peritonitis and pelvic
thrombophlebitis.
Postpartum endometritis is usually a polymicrobial infection, most commonly involving ascending cervicovaginal
organisms. Rarely, patients who are critically ill with sepsis or septic shock may have infection caused by
Clostridium species or Streptococcus pyogenes (group A streptococcus). Late-onset endometritis (occurring more
than 7 days after delivery) suggests Chlamydia trachomatis infection.
Postpartum endometritis typically presents with fever (38°C or more), lower abdominal pain and uterine
tenderness. Purulent vaginal discharge may be present.
The majority of endometritis cases present within the first week after delivery, but approximately 15% of cases
present between 1 and 6 weeks postpartum. Late presentations are often less severe and may present as late
postpartum haemorrhage. If postpartum endometritis is suspected, refer to an obstetrician for appropriate
assessment and management.
For the management of endometritis unrelated to pregnancy, see Pelvic inflammatory disease and postprocedural
pelvic infection.
Empirical therapy for postpartum endometritis

Nonsevere postpartum endometritis
Postpartum endometritis is considered nonsevere if the infection is localised and the patient does not have fever or
other systemic features.
For treatment of nonsevere postpartum endometritis, use:
PLUS
Severe postpartum endometritis
Empirical antibiotic therapy for severe postpartum endometritis
Postpartum endometritis is considered severe if the infection is associated with systemic features, sepsis or septic
shock (see Early recognition of sepsis or septic shock in adults for definitions).
for ward-based patients, development of sepsis or septic shock, immediately after appropriate samples are taken
shock.
Rarely, patients who are critically ill may have infection caused by Streptococcus pyogenes or Clostridium species;
see Streptococcus pyogenes bloodstream infections, including toxic shock syndrome and Clostridial necrotising
skin and soft tissue infection.
For treatment of severe postpartum endometritis, as a three-drug regimen, use:

duration of therapy for severe postpartum endometritis
and see Modification and duration of therapy for severe postpartum endometritis
PLUS

for severe postpartum endometritis
PLUS EITHER

severe postpartum endometritis
OR
1 ampicillin 2 g intravenously, 6-hourly; see Modification and duration of therapy for severe
postpartum endometritis.
regimen, use:

PLUS
care support, use 6-hourly dosing. See Modification and duration of therapy for severe
postpartum endometritis
PLUS

for severe postpartum endometritis.
isolate is susceptible to clindamycin, as a two-drug regimen, use:

PLUS
clindamycin 600 mg intravenously, 8-hourly; see Modification and duration of therapy for
severe postpartum endometritis.
isolate is resistant to clindamycin, or if the group B streptococcus status (or susceptibility) is unknown, in the
above regimen replace clindamycin with the combination of:
intensive care support. See Modification and duration of therapy for severe postpartum
endometritis
PLUS

for severe postpartum endometritis.
calculate the dose.
function.
Modification and duration of therapy for severe postpartum endometritis
Modify therapy based on the results of culture and susceptibility testing (if possible), and clinical response. If
results of susceptibility testing are not available by 72 hours and empirical intravenous therapy is still required,
stop the gentamicin-containing regimen and seek expert advice.
For uncomplicated infections, continue intravenous antibiotic therapy for at least 24 to 48 hours after the
resolution of leucocytosis and clinical signs and symptoms (ie fever, uterine tenderness, purulent vaginal
discharge), and then stop antibiotic therapy. Oral antibiotic therapy is not required.
For complicated infection (eg abscess, bacteraemia), a longer course of intravenous therapy may be required
followed by a switch to oral therapy once the patient is clinically stable (see Guidance
for antimicrobial intravenous to oral switch). If the results of susceptibility testing are not available and oral
continuation therapy is appropriate, use oral amoxicillin+clavulanate (as for nonsevere postpartum endometritis).
Key references
antimicrobiaeml use and resistance in human health. Sydney: ACSQHC; 2017.
Chebbo A, Tan S, Kassis C, Tamura L, Carlson RW. Maternal sepsis and septic shock. Crit Care Clin 2016;32(1):119–
35.
Dalton E, Castillo E. Post partum infections: A review for the non-OBGYN. Obstet Med 2014;7(3):98–102.
Mackeen AD, Packard RE, Ota E, Speer L. Antibiotic regimens for postpartum endometritis. Cochrane Database Syst
Rev 2015;(2):CD001067.
Meaney-Delman D, Bartlett LA, Gravett MG, Jamieson DJ. Oral and intramuscular treatment options for early
postpartum endometritis in low-resource settings: a systematic review. Obstet Gynecol 2015;125(4):789–800.
World Health Organization. WHO recommendations for prevention and treatment of maternal peripartum infections.
2015. https://www.ncbi.nlm.nih.gov/books/NBK327079/
Neonatal herpes simplex infection
Neonatal herpes simplex infection
In neonates, infection with herpes simplex virus (HSV) can present with isolated skin or mucous membrane
lesions, encephalitis, pneumonitis or disseminated infection. Management is complex and expert advice is
required. If expert advice is not available immediately, see Figure 2.5 for initial management of neonates
suspected to have or who are at risk of acquiring herpes simplex virus infection.
If treatment for neonatal herpes simplex infection is required, use:
aciclovir 20 mg/kg intravenously, 8-hourly.
The duration of treatment depends on the clinical presentation. Disease affecting the skin, eyes and mouth requires
14 days of intravenous therapy. At least 21 days of intravenous therapy is required for neonates with disseminated
disease or encephalitis. Treatment for encephalitis should continue until herpes simplex virus is no longer detected
in the cerebrospinal fluid—seek expert advice.
The role and duration of therapy in high-risk asymptomatic neonates has not been fully established. The risk to the
neonate is related to whether the mother’s herpes simplex virus infection is primary and within 6 to 10 weeks of
delivery (higher risk) or recurrent (much lower risk). Examples of higher-risk asymptomatic neonates include:
neonates with negative herpes simplex virus polymerase chain reaction (PCR) tests, but who are born either
via vaginal tract or caesarean section to mothers with primary herpes simplex virus active genital lesions at
the time of delivery
neonates with positive herpes simplex virus PCR swabs (from the conjunctiva, mouth and nasopharynx, or
rectum) who are born to mothers with a history of recurrent herpes simplex virus infection.
Some experts recommend 10 days of antiviral therapy (as above) for these infants.
Oral aciclovir should not be used for initial treatment of herpes simplex virus infection in neonates. However,
there is evidence for oral suppressive therapy (after completion of the intravenous treatment course) to prevent
neurological recurrence following encephalitis in neonates. Suppressive therapy with oral aciclovir can also be
considered in preterm neonates (to prevent early reactivation of disease) and in term neonates who have skin, eye
or mouth lesions (to prevent cutaneous recurrence). Suppressive therapy is usually continued for at least 6 months.
Seek expert advice.
After successful treatment, monitor all infants closely for recurrence of herpes simplex virus infection. If
recurrence occurs, seek expert advice.
For more comprehensive information, see the Australasian Society for Infectious Diseases (ASID) guidelines
Management of Perinatal Infections [URL].
Initial management of neonates suspected to have, or born to mothers with, herpes simplex
virus (HSV) infection (Figure 2.5)
CSF = cerebrospinal fluid; HSV = herpes simplex virus; PCR = polymerase chain reaction
Adapted with permission from Palasanthiran P, Starr M, Jones C, Giles M, editors. Management of perinatal infection. Sydney: Australasian Society
for Infectious Diseases; 2014. [URL]
Key references
Septic abortion
Septic abortion
Septic abortion is an infection of the upper genital tract following either spontaneous abortion (miscarriage)
or induced (surgical, unsafe, or rarely, medical) abortion; it is uncommon in developed countries. Infection
may spread, causing bacteraemia.
Septic abortion is usually a polymicrobial infection, most commonly involving ascending cervicovaginal
organisms, particularly anaerobic bacteria. Patients who are critically ill with sepsis or septic shock may have
infection caused by Clostridium species or Streptococcus pyogenes (group A streptococcus).
Clinical presentation is variable but usually includes fever (38°C or more) and uterine bleeding. Abdominal
pain may be present and the uterus is usually only mildly tender.
Investigate suspected cases of suspected septic abortion with an endocervical swab for:
nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]) for
Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium
microscopy, culture and susceptibility testing.
Perform an ultrasound to exclude the presence of retained products of conception.
Collect blood samples for culture and susceptibility testing for patients in hospital.
If septic abortion is suspected, refer to an obstetrician or gynaecologist for appropriate assessment and
management.
For empirical therapy of septic abortion, treat as for postpartum endometritis.
Key references
Eschenbach DA. Treating spontaneous and induced septic abortions. Obstet Gynecol 2015;125(5):1042–8.
Udoh A, Effa EE, Oduwole O, Okusanya BO, Okafo O. Antibiotics for treating septic abortion. Cochrane
Principles of surgical antibiotic prophylaxis
Introduction to surgical antibiotic prophylaxis
One-third to one-half of antibiotic use in hospitals is for surgical antibiotic prophylaxis (the use of antibiotics to
prevent postoperative infection). Inappropriate prescribing of surgical antimicrobial prophylaxis remains high,
especially with respect to timing and duration.
Principles for appropriate prescribing of surgical antibiotic prophylaxis are outlined in Box 2.10 (below). For
discussion of the role of prophylaxis, including the recommended regimens, for specific procedures, see Surgical
antibiotic prophylaxis for specific procedures.
Principles for appropriate prescribing of surgical antibiotic prophylaxis (Box 2.10)
Do not use surgical antibiotic prophylaxis unless there is a clear indication for its use (see Indications for
surgical antibiotic prophylaxis and the recommendations for specific procedures).
Antibiotic choice may need to be modified according to patient factors, including the presence of
infection, recent antimicrobial use, colonisation with multidrug-resistant bacteria, prolonged
hospitalisation or the presence of prostheses. See Antibiotic selection for surgical prophylaxis.
Cefazolin is more effective than vancomycin in preventing postoperative infections caused by methicillin-
susceptible Staphylococcus aureus (MSSA). See here for the role of vancomycin prophylaxis.
S. aureus carriage increases the risk of postoperative infection; preoperative screening and targeted
decolonisation may be warranted. See Preventing postoperative infections caused by S. aureus.
Surgical antibiotic prophylaxis must be administered before surgical incision. For short-acting antibiotics,
such as cefazolin, the dose should be administered no more than 60 minutes before incision. For
antibiotics that are not short acting, the dose should be administered no more than 120 minutes before
incision. See Timing of surgical antibiotic prophylaxis.
A single preoperative dose of antibiotic(s) is sufficient for the significant majority of procedures. In
specific circumstances, a repeat intraoperative dose may also be necessary. See Duration of surgical
antibiotic prophylaxis.
For a small minority of procedures, there are inadequate data to show that a single dose of prophylaxis is
as effective as 24 hours of prophylaxis. For these procedures, postoperative doses can be considered but
prophylaxis should not continue beyond 24 hours. See Duration of surgical antibiotic prophylaxis.
Do not extend the duration of antibiotic prophylaxis because the patient has a urinary or intravascular
catheter, or surgical drain, in situ.
Appropriate surgical antibiotic prophylaxis has been conclusively shown to reduce the rate of superficial
incisional, deep incisional, and organ/space surgical site infections, as well as postoperative pneumonia and
urinary tract infection.
Adherence to the principles in these guidelines maximises the potential benefit of surgical antibiotic prophylaxis
while minimising potential harms, including the development of drug-resistant pathogens.
Indications for surgical antibiotic prophylaxis

When is surgical antibiotic prophylaxis indicated?
Postoperative infection can complicate any surgical procedure; however, the potential benefits of preventing
postoperative infection with surgical antibiotic prophylaxis must be balanced against the potential harms of
antimicrobial use (eg diarrhoea, rash, bacterial resistance; see also Types of adverse effects of antimicrobials).
Many procedures do not require prophylaxis.
The recommendations for surgical antibiotic prophylaxis for specific procedures are informed, when possible, by
evidence that prophylaxis is beneficial for the relevant procedure. In general, surgical antibiotic prophylaxis is
indicated if there is a significant risk of postoperative infection (eg colonic resection) or if postoperative infection
would have serious consequences (eg infection associated with a prosthetic implant), even when such infection is
uncommon.
Surgical antibiotic prophylaxis for patients with a pre-existing joint prosthesis

Although surgical procedures can result in incidental bacteraemia, there is a low risk of seeding of the joint
prosthesis and subsequent infection. Accumulated evidence supports the same approach to surgical antibiotic
prophylaxis for patients with and without a pre-existing joint prosthesis; neither the indication for prophylaxis nor
the choice of antibiotic regimen is altered by the presence of a joint prosthesis. This is true even for procedures that
commonly cause bacteraemia (eg tooth extractions, periodontal procedures, cystoscopy, insertion of an indwelling
urinary catheter, perforating dermatological procedures). The potential adverse effects outweigh the potential
benefits of prophylaxis [Note 1].
Only give surgical antibiotic prophylaxis to patients with a pre-existing joint prosthesis if prophylaxis is indicated for the
procedure.
Note 1: For a detailed discussion of prevention of prosthetic joint infection in patients undergoing dental procedures, see the American Dental
Association Council on Scientific Affairs evidence-based guideline on prevention of orthopaedic implant infection in patients undergoing dental
procedures, available here.
Surgical antibiotic prophylaxis for patients with a pre-existing breast implant
Neither the indication for prophylaxis nor the choice of antibiotic regimen is altered by the presence of a breast
implant; therefore, the same approach to surgical antibiotic prophylaxis should be taken for patients with and
without a pre-existing breast implant.
Only give surgical antibiotic prophylaxis to patients with a pre-existing breast implant if prophylaxis is indicated for the
procedure.
Surgical antibiotic prophylaxis for patients with specific cardiac conditions
Antibiotics for the prevention of endocarditis may be needed for patients with specific cardiac conditions (see Box
2.12) who are undergoing a surgical procedure, even if surgical antibiotic prophylaxis is not indicated (eg
tonsillectomy, adenoidectomy). See here for the approach to endocarditis prophylaxis.
If prophylaxis is recommended to prevent enterococcal endocarditis and cefazolin is used for surgical antibiotic
prophylaxis, additional infective endocarditis prophylaxis is required because cephalosporins are generally
ineffective against enterococci. See Endocarditis prophylaxis for genitourinary and gastrointestinal tract
procedures for add-on recommendations (eg amoxicillin, ampicillin, vancomycin).
However, if prophylaxis is indicated to prevent endocarditis caused by viridans streptococci or Staphylococcus

aureus and cefazolin is used for surgical antibiotic prophylaxis, additional infective endocarditis prophylaxis is not
required because cefazolin has adequate activity against these bacteria.
Nonantibiotic measures to prevent postoperative infections

Surgical antibiotic prophylaxis should not be the only strategy used to prevent postoperative infection. The risk of
postoperative infection is reduced by a comprehensive approach to patient management, including optimal
perioperative medical management (eg perioperative glycaemic control), adequate debridement, and good surgical
technique. However, if there are nonmodifiable risk factors (eg excessive soiling, tissue damage), optimal patient
management cannot eliminate the risk of postoperative infection.
Nonantibiotic measures to prevent infection are examined in guidelines issued by the World Health Organization
[Note 2] and Centers for Disease Control and Prevention [Note 3]. See also Prevention of surgical wound
complications.
Note 2: Allegranzi B, Bischoff P, de Jonge S, Kubilay NZ, Zayed B, Gomes SM, et al. New WHO recommendations on preoperative measures for
surgical site infection prevention: an evidence-based global perspective. Lancet Infect Dis 2016;16(12):e276-e87. [URL]
Allegranzi B, Zayed B, Bischoff P, Kubilay NZ, de Jonge S, de Vries F, et al. New WHO recommendations on intraoperative and postoperative
measures for surgical site infection prevention: an evidence-based global perspective. Lancet Infect Dis 2016;16(12):e288-e303. [URL]
Note 3: Berrios-Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, et al. Centers for Disease Control and Prevention Guideline for
the Prevention of Surgical Site Infection, 2017. JAMA Surg 2017. [URL]
Antibiotic selection for surgical prophylaxis

General principles
The prophylactic antibiotic regimens recommended for specific procedures are directed against the organism(s)
most likely to cause postoperative infection. Cefazolin is the preferred drug for the majority of procedures that
require prophylaxis.
The antibiotic regimens may need to be modified according to patient factors (eg presence of infection,
colonisation with multidrug-resistant bacteria) and environmental factors (eg organisms causing infection within
the institution and their susceptibilities).
Most postoperative infections are caused by organisms that already colonise the patient; these may include
multidrug-resistant bacteria when there has been prolonged hospitalisation, recent travel or repeated antibiotic use.
See Preventing postoperative Staphylococcus aureus infections and Preventing postoperative infections caused by
multidrug-resistant Gram-negative bacteria.
There is little evidence that patients colonised with vancomycin-resistant enterococci (VRE) require modified
prophylaxis regimens and the recommendations in these guidelines are appropriate.
Avoid using broad-spectrum antibiotics, including broad-spectrum cephalosporins (eg cefotaxime, ceftriaxone), for
surgical antibiotic prophylaxis.
Avoid using broad-spectrum antibiotics for surgical antibiotic prophylaxis.
For specific advice about the role of gentamicin in surgical antibiotic prophylaxis, see here. For specific advice
about the role of vancomycin and teicoplanin in surgical antibiotic prophylaxis, see here.
Surgical antibiotic prophylaxis for patients receiving treatment for established infection
If the patient is being treated with antibiotic therapy for established infection, it is not necessary to give additional
antibiotic prophylaxis, provided the treatment regimen has activity against the organism(s) most likely to cause
postoperative infection. However, adjust the timing of the treatment dose to achieve adequate plasma and tissue
concentrations at the time of surgical incision and for the duration of the procedure. In general, if more than two
half-lives of the drug have elapsed since the previous dose, an additional dose should be given—seek expert
advice.
Surgical antibiotic prophylaxis for patients with a penicillin or cephalosporin allergy

Cefazolin is the mainstay of surgical antibiotic prophylaxis. It is a beta-lactam antibiotic that shares no common
side-chains with other beta lactams (see Cross-reactivity between beta lactams), and is often tolerated in patients
with a penicillin or cephalosporin allergy.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, cefazolin can be
used. Other cephalosporins may also be appropriate—seek expert advice.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, a non–beta-lactam antibiotic
must be used instead of cefazolin—for alternatives, see the relevant procedure.
Principles of gentamicin use for surgical antibiotic prophylaxis

The Gram-negative spectrum of cefazolin is adequate for most surgical procedures for which Gram-negative
activity is required. However, gentamicin continues to be recommended as prophylaxis for the few procedures
requiring a broader spectrum of Gram-negative activity. Gentamicin is also used as an alternative when cefazolin is
contraindicated.
The risk of gentamicin toxicity is very low when it is given as a single dose for prophylaxis. There are few
absolute contraindications to gentamicin use (see Box 2.42).
There is divergent practice in gentamicin dosing for surgical prophylaxis; doses from 1.5 to 5 mg/kg are used. The
doses recommended in these guidelines are based on extensive clinical experience and the
pharmacokinetic/pharmacodynamic properties of gentamicin.
The appropriate dose depends on the duration of prophylaxis required.
A 2 mg/kg dose is recommended when a short duration (up to 6 hours) of prophylaxis is required because it
provides an adequate tissue concentration for the duration of the procedure.
A 5 mg/kg dose is recommended when a longer duration (up to 24 hours) of prophylaxis may be required
(eg some cardiac procedures). If there is a moderate likelihood that a procedure will continue for longer than
6 hours, consider using a 5 mg/kg dose.
For patients who are obese (eg adults with a body mass index of 30 kg/m2 or more), use adjusted body weight (see
Box 2.46) to calculate the gentamicin dose.
When gentamicin is used for surgical antibiotic prophylaxis, monitoring is not required.
Principles of glycopeptide use for surgical antibiotic prophylaxis
The role of glycopeptides in surgical antibiotic prophylaxis
The glycopeptide antibiotics, vancomycin and teicoplanin, have a limited role in surgical antibiotic prophylaxis
because they are less effective than cefazolin at preventing postoperative methicillin-susceptible Staphylococcus
aureus (MSSA) skin and soft tissue infections. Vancomycin and teicoplanin are also associated with selection of
glycopeptide-resistant organisms (eg vancomycin-resistant enterococci [VRE], vancomycin-intermediate S. aureus
[VISA]).
Glycopeptides are less effective than cefazolin at preventing postoperative infections caused by methicillin-susceptible
Staphylococcus aureus (MSSA).
In some centres, teicoplanin is used as an alternative to vancomycin because, unlike vancomycin, it does not
require a long infusion.
Glycopeptides should not be used for surgical prophylaxis, except for patients:
with severe hypersensitivity (immediate or delayed) to penicillins

at increased risk of postoperative infection caused by methicillin-resistant S. aureus (MRSA).
Glycopeptide use for patients with severe hypersensitivity to penicillins
In patients with severe (immediate or delayed) hypersensitivity to penicillins, vancomycin or teicoplanin is used as
a replacement for cefazolin. If there is a significant risk that the surgical site will be contaminated with Gram-
negative organisms, vancomycin or teicoplanin is given in combination with gentamicin.
In general, vancomycin or teicoplanin is preferred to clindamycin because it has activity against a greater
percentage of S. aureus isolates; however, clindamycin is an alternative for susceptible S. aureus strains, based on
local epidemiology, or recent screening or culture results.
Glycopeptide use for patients at increased risk of postoperative infection caused by MRSA
Consider adding vancomycin or teicoplanin to the prophylactic regimen if there is an increased risk of
postoperative infection with MRSA. This includes:
patients with an increased risk of MRSA infection (see Box 2.31)

patients undergoing prosthetic cardiac valve, joint or vascular surgery if the procedure is a reoperation
(return to theatre or early revision).
Glycopeptide dosing
Use actual body weight to calculate vancomycin doses, even in patients who are overweight or obese. A 15 mg/kg
vancomycin dose is recommended for prophylaxis in these guidelines because therapeutic concentrations only
need to be maintained for the duration of the procedure.
If teicoplanin is used, an appropriate regimen is:
teicoplanin (adult and child) 15 mg/kg up to 800 mg intravenously, within the 120 minutes
before the procedure.
Surgical antibiotic prophylaxis for obese patients

Antibiotic pharmacokinetics are altered in obese patients, so dosage adjustments may be necessary. Weight-based
antimicrobial dosing has not been shown to reduce the incidence of postoperative infection in obese patients.
However, data from small pharmacokinetic studies suggest 2 g doses of cefazolin may result in inadequate tissue
levels in obese patients. Given the safety and low cost of cefazolin, it is reasonable to increase the cefazolin dose
to 3 g in patients who weigh more than 120 kg.
Preventing postoperative Staphylococcus aureus infections
Approach to preventing postoperative S. aureus infections
Staphylococcus aureus carriage increases the risk of postoperative infection. Perioperative decolonisation of
colonised patients reduces postoperative infection following specific surgical procedures.
Consider preoperative screening (for both methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S.
aureus (MRSA) carriage) and decolonisation of colonised patients—see here for specific advice. In patients with
known S. aureus carriage, decolonisation without screening is an alternative approach.
If a patient is colonised with MRSA, vancomycin or teicoplanin is added to the prophylactic regimen.
Screening for S. aureus carriage

For patients undergoing arthroplasty procedures or cardiothoracic procedures involving median sternotomy,
perform preoperative screening and decolonise colonised patients.
There are fewer data to support preoperative screening, and decolonisation of colonised patients, for other surgical
procedures. However, strongly consider screening and decolonising patients undergoing surgical procedures in
which prosthetic material is implanted, because S. aureus is the most common cause of postoperative infection of
prosthetic implants. Also consider screening and decolonising patients undergoing other surgical procedures.
Detection of S. aureus carriage is improved when swabs from multiple sites (eg nose and groin) are cultured,
compared to swabs from the nose alone.
The request for microscopy, culture and susceptibility testing should specify that the sample be screened for both
MSSA and MRSA.
Decolonisation of patients colonised with S. aureus

For perioperative decolonisation of patients colonised with S. aureus, use:
mupirocin 2% nasal ointment inside each nostril, twice daily for 5 days
WITH OR WITHOUT EITHER
for use in showers—an antiseptic wash or soap containing chlorhexidine 2% or 4%; wash
once daily for 5 days. Pay particular attention to areas of hairy skin
OR
for use in baths—60 mL of sodium hypochlorite solution (household bleach) per bathtub
[Note 4]; wash once daily for 5 days.
Dilute sodium hypochlorite (household bleach) is preferred for infants and children because it is well tolerated.
Chlorhexidine-impregnated washcloths, applied the night before and morning of surgery, are an alternative to
bathing or showering with antiseptics.
The optimal timing of perioperative S. aureus decolonisation is not known. While decolonisation must be started
before the procedure, it can be completed after the procedure.
Monitoring for the development of mupirocin resistance is recommended if mupirocin decolonisation is commonly
used.
Note 4: The clinical trial that demonstrated efficacy for this approach used 1/4 of a cup (approximately 60 mL) of 6% sodium hypochlorite solution
(household bleach) per bathtub.
Preventing postoperative infections caused by multidrug-resistant

Gram-negative bacteria
Preoperative screening for faecal carriage of multidrug-resistant Gram-negative bacteria may be considered for
patients undergoing complex gastrointestinal surgery or transrectal prostate biopsy if they have an increased risk of
colonisation with these bacteria (see Box 2.30). Prophylaxis for patients colonised with a multidrug-resistant
Gram-negative bacterium should be guided by the results of susceptibility testing—seek expert advice.
At the time of writing, there are no data to support preoperative decolonisation to reduce or eliminate faecal
carriage of multidrug-resistant Gram-negative bacteria.
Route of administration of surgical antibiotic prophylaxis

Surgical antibiotic prophylaxis is almost always administered intravenously.
Applying antimicrobials (eg ointments, solutions, powders) to the surgical incision to prevent surgical site
infection is not recommended, because there is potential for harm (eg hypersensitivity reactions, bacterial
resistance) and inadequate evidence to support a benefit.
The safety and effectiveness of soaking prosthetic devices in antiseptic or antimicrobial solutions before
implantation has not been established and is not recommended.
Timing of surgical antibiotic prophylaxis

Large trials show that appropriately timed antibiotic prophylaxis is crucial.
Surgical antibiotic prophylaxis must be administered before surgical incision to achieve effective plasma and tissue
concentrations at the time of incision. For short-acting antibiotics, such as cefazolin, the dose should be
administered no more than 60 minutes before surgical incision. For antibiotics that are not short acting, the dose
should be administered no more than 120 minutes before surgical incision.
Surgical antibiotic prophylaxis must be administered before surgical incision.
Vancomycin requires a slow infusion, at a rate not exceeding 10 mg/minute. Shorter infusion times can be used if
tolerated, but should not be less than 60 minutes for a 1 g dose, 90 minutes for a 1.5 g dose or 120 minutes for a 2
g dose. Start the vancomycin infusion within the 120 minutes before surgical incision. It is the consensus view of
the Antibiotic Expert Groups that the infusion should be started at least 15 minutes before incision to ensure
adequate blood and tissue concentrations at the time of incision and allow potential infusion-related toxicity to be
recognised before induction of anaesthesia. The infusion can be completed after surgical incision.
Vancomycin requires a slow infusion but surgical incision can occur before the infusion is completed.
Duration of surgical antibiotic prophylaxis

The World Health Organization [Note 5] and Centers for Disease Control and Prevention [Note 6] advise, on the
basis of meta-analyses, that surgical antibiotic prophylaxis should not be continued postoperatively in any
circumstances. However, it is the consensus view of the Antibiotic Expert Groups that the limitations in the
evidence base warrant a more nuanced approach.
For the vast majority of clean and clean–contaminated procedures, prophylactic antibiotics are not required after the surgical
incision is closed.
Large trials show that a single preoperative dose of surgical antibiotic prophylaxis is sufficient to prevent
postoperative infection for the vast majority of clean and clean–contaminated procedures, and is as effective as
longer courses. Intraoperative redosing may be necessary if:
after prophylaxis is given, there is a significant delay in starting the operation

a short-acting antibiotic is used (eg cefoxitin, cefazolin) and more than two half-lives of the drug have
elapsed since the previous dose
there is excessive blood loss during the procedure (eg in adults, 1.5 litres or more).
Table 2.15 (below) gives suggested redosing intervals for antimicrobials recommended for surgical antibiotic
prophylaxis in these guidelines.
For a small minority of procedures identified throughout these guidelines, there are inadequate data to show that a
single dose of prophylaxis (with or without intraoperative doses) is as effective as 24 hours of prophylaxis. For
these procedures, postoperative doses can be considered but prophylaxis should not continue beyond 24 hours.
With the exception of these procedures, postoperative (intravenous or oral) antibiotics do not provide benefit.
Evidence does not support continuing prophylactic antibiotics until surgical drains or intravascular or urinary
catheters are removed.
Postoperative antibiotics increase the risk of subsequent infections with resistant pathogens and Clostridium
difficile.
Postoperative antibiotics increase the risk of subsequent infections with resistant pathogens and Clostridium difficile.
Suggested intraoperative redosing intervals for antibiotics commonly used for surgical
antibiotic prophylaxis (Table 2.15)
Redosing interval for patients [NB1]

Antimicrobial Drug half-life
[NB2]
benzylpenicillin 1 hour 0.5 hours
cefoxitin 2 hours 0.7 to 1.1 hours
cefazolin 4 hours 1.2 to 2.2 hours
clindamycin 6 hours 2 to 4 hours
gentamicin redosing not required [NB3] 2 to 3 hours
metronidazole 12 hours 6 to 8 hours
teicoplanin redosing not required several days
vancomycin 12 hours 4 to 8 hours
NB1: The redosing interval is the time at which a repeat intraoperative dose is required. The interval is measured from the initial preoperative dose,
rather than the beginning of the operation. For a specific drug, the redosing interval is approximately equivalent to two half-lives.
NB2: The redosing intervals in this table only apply to patients with normal kidney function. For patients with impaired kidney function, seek expert
advice.
NB3: Despite gentamicin’s short half-life, redosing is not required because of its ‘postantibiotic effect’, whereby bacterial killing continues for many
hours after plasma concentration is undetectable.
Note 5: Allegranzi B, Zayed B, Bischoff P, Kubilay NZ, de Jonge S, de Vries F, et al. New WHO recommendations on intraoperative and
postoperative measures for surgical site infection prevention: an evidence-based global perspective. Lancet Infect Dis 2016;16(12):e288-e303. [URL]
Note 6: Berríos-Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, et al. Centers for disease control and prevention guideline for the
prevention of surgical site infection, 2017. JAMA Surgery 2017;152(8):784-91. [URL]
Stratifying surgical wounds based on the level of contamination

The following framework stratifies surgical wounds based on the level of contamination, which influences the
likelihood of infection and need for prophylaxis or treatment.
Centers for Disease Control and Prevention stratification of surgical wounds (Box 2.11)
The United States Centers for Disease Control and Prevention classify wounds, including surgical wounds,
according to the degree of contamination.
Clean surgical wounds are uninfected operative wounds in which no inflammation is encountered and the
respiratory, gastrointestinal, genital or urinary tracts are not entered. In addition, clean wounds are
primarily closed and, if necessary, drained with closed drainage. Operative incisional wounds that follow
nonpenetrating (blunt) trauma should be included in this category if they meet the criteria.
Clean–contaminated surgical wounds are operative wounds in which the respiratory, gastrointestinal,
genital (including female and male reproductive tracts), or urinary tracts are entered under controlled
conditions and without unusual contamination. Specifically, operations involving the biliary tract,
appendix, vagina, and oropharynx are included in this category, provided no evidence of infection or major
break in technique is encountered.
Contaminated surgical wounds occur if there are major breaks in sterile technique (eg open cardiac
massage), there is gross spillage from the gastrointestinal tract, or the incision encounters acute,
nonpurulent inflammation (including necrotic tissue without evidence of purulent discharge). Open, fresh
or accidental wounds are also included in this category.
Dirty or infected wounds are those that involve existing clinical infection or perforated viscera, as well as
old traumatic wounds with retained devitalised tissue. This definition suggests that the organisms causing
postoperative infection were present before the operation [NB1].
NB1: Antibiotic treatment, in addition to prophylaxis, is required for patients having surgery on a dirty or infected wound.
Adapted from National Center for Emerging and Zoonotic Infectious Diseases (U.S.) Division of Healthcare Quality Promotion, National
Healthcare Safety Network. National Healthcare Safety Network (NHSN) patient safety component manual: key terms. Atlanta, GA: Centers for
Disease Control and Prevention; 2018 [URL]
Key references
Antibiotic selection for surgical antibiotic prophylaxis
Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, et al. Clinical practice guidelines for
antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 2013;70(3):195–283 .
Martin C, Bourget P, Alaya M, Sertin A, Atlani C, Ennabli K, et al. Teicoplanin in cardiac surgery: intraoperative
pharmacokinetics and concentrations in cardiac and mediastinal tissues. Antimicrob Agents Chemother
1997;41(5):1150–1155 .
Saleh A, Khanna A, Chagin KM, Klika AK, Johnston D, Barsoum WK. Glycopeptides versus β-lactams for the
prevention of surgical site infections in cardiovascular and orthopedic surgery: a meta-analysis. Ann Surg
2015;261(1):72–80 .
Sollecito TP, Abt E, Lockhart PB, Truelove E, Paumier TM, Tracy SL, et al. The use of prophylactic antibiotics prior to
dental procedures in patients with prosthetic joints: Evidence-based clinical practice guideline for dental practitioners--a
report of the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 2015;146(1):11–16.e8
.
Indications for surgical antibiotic prophylaxis
Berríos-Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, et al. Centers for Disease Control and
Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg 2017;152(8):784–791 .
Sollecito TP, Abt E, Lockhart PB, Truelove E, Paumier TM, Tracy SL, et al. The use of prophylactic antibiotics prior to
dental procedures in patients with prosthetic joints: Evidence-based clinical practice guideline for dental practitioners--a
report of the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 2015;146(1):11–6 e8.
Nonantibiotic measures to prevent postoperative infections
Allegranzi B, Bischoff P, de Jonge S, Kubilay NZ, Zayed B, Gomes SM, et al. New WHO recommendations on
preoperative measures for surgical site infection prevention: an evidence-based global perspective. Lancet Infect Dis
2016;16(12):e276–e87. < >
Allegranzi B, Zayed B, Bischoff P, Kubilay NZ, de Jonge S, de Vries F, et al. New WHO recommendations on
intraoperative and postoperative measures for surgical site infection prevention: an evidence-based global perspective.
Lancet Infect Dis 2016;16(12):e288–e303. < >
Berríos-Torres SI. Evidence-Based update to the U.S. Centers for Disease Control and Prevention and Healthcare
Infection Control Practices Advisory Committee guideline for the prevention of surgical site infection: Developmental
process. Surg Infect (Larchmt) 2016;17(2):256–261 .
Berrios-Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, et al. Centers for Disease Control and
Saginur R, Croteau D, Bergeron MG. Comparative efficacy of teicoplanin and cefazolin for cardiac operation
prophylaxis in 3027 patients. The ESPRIT Group. J Thorac Cardiovasc Surg 2000;120(6):1120–30.
Surgical antibiotic prophylaxis for obese patients
antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 2013;70(3):195–283.
Edmiston CE, Krepel C, Kelly H, Larson J, Andris D, Hennen C, et al. Perioperative antibiotic prophylaxis in the gastric
bypass patient: do we achieve therapeutic levels? Surgery 2004;136(4):738–47.
Preventing postoperative Staphylococcus aureus infections
2016;16(12):e276–e287 .
Preventing postoperative infections caused by multidrug-resistant Gram-negative bacteria
Cussans A, Somani BK, Basarab A, Dudderidge TJ. The role of targeted prophylactic antimicrobial therapy before
transrectal ultrasonography-guided prostate biopsy in reducing infection rates: a systematic review. BJU Int
2016;117(5):725–731 .
Roberts MJ, Williamson DA, Hadway P, Doi SAR, Gardiner RA, Paterson DL. Baseline prevalence of antimicrobial
resistance and subsequent infection following prostate biopsy using empirical or altered prophylaxis: A bias-adjusted
meta-analysis. Int J Antimicrob Agents 2014;43(4):301–9 .
Route of administration of surgical antibiotic prophylaxis
Timing of surgical antibiotic prophylaxis
2016;16(12):e276–e87.
Garey KW, Dao T, Chen H, Amrutkar P, Kumar N, Reiter M, et al. Timing of vancomycin prophylaxis for cardiac
surgery patients and the risk of surgical site infections. J Antimicrob Chemother 2006;58(3):645–650.
Weber WP, Mujagic E, Zwahlen M, Bundi M, Hoffmann H, Soysal SD, et al. Timing of surgical antimicrobial
prophylaxis: a phase 3 randomised controlled trial. Lancet Infect Dis 2017;17(6):605–14.
Duration of surgical antibiotic prophylaxis

Berrios-Torres SI. Evidence-based update to the U.S. Centers for Disease Control and Prevention and Healthcare
Infection Control Practices Advisory Committee guideline for the prevention of surgical site infection: Developmental
Process. Surg Infect (Larchmt) 2016;17(2):256–61 .
Swoboda SM, Merz C, Kostuik J, Trentler B, Lipsett PA. Does intraoperative blood loss affect antibiotic serum and
tissue concentrations? Arch Surg 1996;131(11):1165–72.
Takagane A, Mohri Y, Konishi T, Fukushima R, Noie T, Sueyoshi S, et al. Randomized clinical trial of 24 versus 72 h
antimicrobial prophylaxis in patients undergoing open total gastrectomy for gastric cancer. Br J Surg
2017;104(2):e158–e64.
Tamayo E, Gualis J, Flórez S, Castrodeza J, Eiros Bouza JM, Alvarez FJ. Comparative study of single-dose and 24-
hour multiple-dose antibiotic prophylaxis for cardiac surgery. J Thorac Cardiovasc Surg 2008;136(6):1522–1527
.
Stratifying surgical wounds based on the level of contamination
Surgical antibiotic prophylaxis for specific procedures
Surgical prophylaxis for abdominal surgery
General principles
If peritonitis or an abscess is detected during the procedure or if peritoneal soiling occurs, give the patient an
appropriate course of antibiotic treatment (see Peritonitis due to perforated viscus).
Prophylaxis against enterococcal endocarditis is indicated for patients with specific cardiac conditions (see Box
2.12) who are undergoing abdominal surgery for which surgical antibiotic prophylaxis is required. If the surgical
antibiotic prophylaxis regimen does not include an antibiotic active against enterococci (eg amoxicillin, ampicillin,
vancomycin), see Endocarditis prophylaxis for genitourinary and gastrointestinal tract procedures for appropriate
add-on recommendations.
Prophylaxis against enterococcal endocarditis may also be required for patients with specific cardiac conditions
(see Box 2.12) who are undergoing abdominal surgery for which surgical antibiotic prophylaxis is not required, if
the patient has an established gastrointestinal infection—see Endocarditis prophylaxis for genitourinary and
gastrointestinal tract procedures.
Gastroduodenal and oesophageal surgery
Consider the principles for appropriate prescribing of surgical antibiotic prophylaxis (see Box 2.10) and the
general principles (above) of surgical antibiotic prophylaxis for abdominal surgery. See Table 2.16 for the
recommendations for surgical prophylaxis for gastroduodenal and oesophageal procedures.
Gastroduodenal and oesophageal procedures and their requirement for surgical antibiotic
prophylaxis (Table 2.16)
Procedures Is surgical antibiotic prophylaxis indicated?

endoscopic gastroduodenal and oesophageal procedures NO
ONLY IF the patient has risk factors for postoperative
nonendoscopic gastroduodenal or oesophageal
infection (eg morbid obesity; gastric outlet obstruction;
procedures that do not enter the gastrointestinal tract
reduced gastric acidity or motility; gastrointestinal
lumen (eg antireflux procedures)
bleeding, malignancy or perforation)
nonendoscopic gastroduodenal or oesophageal
YES
procedures that enter the gastrointestinal tract lumen
If prophylaxis is indicated for gastroduodenal and oesophageal surgery, use:
cefazolin 2 g (child: 30 mg/kg up to 2 g) intravenously, within the 60 minutes before

surgical incision; intraoperative redosing may be required (see here). Do not give
additional doses once the procedure is completed.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use cefazolin as
above. See also Surgical antibiotic prophylaxis for patients with a penicillin or cephalosporin allergy.
gentamicin (adult and child) 2 mg/kg intravenously over 3 to 5 minutes, within the 120
minutes before surgical incision [Note 1] [Note 2]; intraoperative redosing is unlikely to
be required (see here). Do not give additional doses once the procedure is completed
PLUS EITHER
1 vancomycin (adult and child) 15 mg/kg intravenously, started within the 120 minutes
before surgical incision (recommended rate 10 mg/minute) [Note 3]; intraoperative
redosing may be required (see here). Do not give additional doses once the procedure is
completed
OR
2 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, within the 120
minutes before surgical incision; intraoperative redosing may be required (see here). Do
not give additional doses once the procedure is completed.
Note 1: If there is at least a moderate likelihood that the procedure will continue for longer than 6 hours,
consider using a 5 mg/kg gentamicin dose.
Note 3: It is the consensus view of the Antibiotic Expert Groups that the vancomycin infusion should be started
at least 15 minutes before surgical incision to ensure adequate blood and tissue concentrations at the time of
incision and allow potential infusion-related toxicity to be recognised before induction of anaesthesia.
Biliary surgery, including laparoscopic surgery

general principles of surgical antibiotic prophylaxis for abdominal surgery. See Table 2.17 for the
recommendations for surgical prophylaxis for biliary surgery, including laparoscopic surgery.
If the patient is being treated with antibiotic therapy for acute cholecystitis, it is not necessary to give additional
antibiotic prophylaxis provided the treatment regimen has activity against the organism(s) most likely to cause
concentrations at the time of surgical incision and for the duration of the procedure. See Surgical antibiotic
Biliary procedures and their requirement for surgical antibiotic prophylaxis (Table 2.17)

ONLY IF the patient has risk factors for postoperative infection (eg older
laparoscopic surgery than 70 years, diabetes, obstructive jaundice, common bile duct stones,
acute cholecystitis, nonfunctioning gallbladder)
YES; however, if the patient is being treated with antibiotic therapy for
open cholecystectomy acute cholecystitis, additional antibiotic prophylaxis may not be required
(see above)
If prophylaxis is indicated for biliary surgery, use:

minutes before surgical incision [Note 4]; intraoperative redosing is unlikely to be
required (see here). Do not give additional doses once the procedure is completed
PLUS EITHER
completed
OR
Small intestinal surgery

recommendations for surgical prophylaxis for small intestinal surgery.
If the patient is being treated with antibiotic therapy for acute intra-abdominal infection (eg peritonitis), it is not
necessary to give additional antibiotic prophylaxis provided the regimen has activity against the organism(s) most
likely to cause postoperative infection. However, adjust the timing of the treatment dose to achieve adequate
plasma and tissue concentrations at the time of surgical incision and for the duration of the procedure. See Surgical
antibiotic prophylaxis for patients receiving treatment for established infection.
Small intestinal procedures and their requirement for surgical antibiotic prophylaxis (Table 2.18)

endoscopic small intestinal procedures NO
nonendoscopic small intestinal procedures YES
The choice of prophylaxis depends on whether the bowel lumen is obstructed.
For prophylaxis for nonendoscopic small intestinal procedures when the small intestine is not obstructed, use:

If the small intestine is obstructed, the prophylactic regimen includes metronidazole for activity against
anaerobes; use:

additional doses once the procedure is completed
PLUS
metronidazole 500 mg (child: 12.5 mg/kg up to 500 mg) intravenously, within the 120
As an alternative when the small intestine is obstructed, cefoxitin may be used as a single drug; however, its
activity against anaerobes is inferior to the regimen above. It also requires frequent redosing (every 2 hours). Use:
cefoxitin 2 g (child: 40 mg/kg up to 2 g) intravenously, within the 60 minutes before

For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, the above regimens
are suitable. See also Surgical antibiotic prophylaxis for patients with a penicillin or cephalosporin allergy.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, whether or not the small
intestine is obstructed, use:
PLUS
Colorectal surgery
recommendations for surgical prophylaxis for colorectal surgery.
If the patient is being treated with antibiotic therapy for acute intra-abdominal infection (eg diverticulitis,
peritonitis), it is not necessary to give additional antibiotic prophylaxis provided the regimen has activity against
the organism(s) most likely to cause postoperative infection. However, adjust the timing of the treatment dose to
achieve adequate plasma and tissue concentrations at the time of surgical incision and for the duration of the
procedure. See Surgical antibiotic prophylaxis for patients receiving treatment for established infection.
Colorectal procedures and their requirement for surgical antibiotic prophylaxis (Table 2.19)

endoscopic colorectal procedures NO
nonendoscopic colorectal procedures YES
For prophylaxis for nonendoscopic colorectal procedures, use:
not give additional doses once the procedure is completed
PLUS

regimen above. It also requires frequent redosing (every 2 hours). Use:

PLUS
required (see here). Do not give additional doses once the procedure is completed.
Oral nonabsorbable antibiotics (eg neomycin), in combination with erythromycin or metronidazole and mechanical
bowel preparation, improved outcomes in elective colorectal resections in some studies.
Consider preoperative screening for faecal carriage of multidrug-resistant Gram-negative bacteria in patients with
an increased likelihood of colonisation with these bacteria (see Box 2.30). Prophylaxis for patients colonised with
a multidrug-resistant Gram-negative bacterium should be guided by the results of susceptibility testing—seek
expert advice.
Appendicectomy
recommendations for surgical prophylaxis for appendicectomy.
If antibiotic treatment for appendicitis has been started preoperatively, it is not necessary to give additional
antibiotic prophylaxis. However, adjust the timing of the treatment dose to achieve adequate plasma and tissue
For patients with acute uncomplicated appendicitis, stop antibiotic therapy immediately after appendicectomy. For
patients with complicated appendicitis (perforated appendicitis or appendiceal abscess), antibiotic therapy is
continued for 5 days after adequate surgical control of the source of infection has been achieved; see Acute
appendicitis for advice on intravenous to oral switch.
Appendicectomy procedures and their requirement for surgical antibiotic prophylaxis (Table
2.20)

YES; however, if the patient is being treated with
all appendicectomy procedures, including laparoscopic
antibiotic therapy for appendicitis, additional antibiotic
appendicectomy
prophylaxis is not required (see above)
If the patient is not receiving antibiotic treatment for appendicitis, for prophylaxis, use:
PLUS


PLUS
Hernia repair
recommendations for surgical prophylaxis for hernia repairs.
Hernia repairs and their requirement for surgical antibiotic prophylaxis (Table 2.21)
hernia repair with or without prosthetic material (mesh) YES [NB1]
NB1: Although surgical antibiotic prophylaxis may not be needed for repairs without prosthetic material, prophylaxis is recommended for all procedures
because it may not be possible to determine preoperatively whether prosthetic material will be used.
The choice of prophylaxis depends on whether entry into the bowel lumen is expected and whether the patient is at
increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31).
For prophylaxis for hernia repairs in which entry into the bowel lumen is not expected, use:

For hernia repairs in which entry into the bowel lumen is expected, the prophylactic regimen includes
metronidazole for activity against anaerobes; use:
PLUS

As an alternative when entry into the bowel lumen is expected, cefoxitin may be used as a single drug; however, its
activity against anaerobes is inferior to the regimen above. It also requires frequent redosing (every 2 hours). Use:

For patients colonised or infected with MRSA, or at increased risk of being colonised or infected with MRSA (see
Box 2.31), add vancomycin to the above regimens:
vancomycin (adult and child) 15 mg/kg intravenously, started within the 120 minutes
completed.
For patients with immediate severe or delayed severe hypersensitivity to penicillins undergoing hernia repair in
which entry into the bowel lumen is not expected, use vancomycin as monotherapy (see dosage above).
For patients with immediate severe or delayed severe hypersensitivity to penicillins undergoing hernia repair in
which entry into the bowel lumen is expected, use:
PLUS
Vancomycin (see dosage above) should be added to metronidazole and gentamicin if the patient is colonised or
infected with MRSA, or at increased risk of being colonised or infected with MRSA (see Box 2.31).
Surgical prophylaxis for assisted reproductive technology and infertility

diagnostic procedures
Consider the principles for appropriate prescribing of surgical antibiotic prophylaxis (see Box 2.10). See Table
2.22 for the indications for surgical prophylaxis for assisted reproductive technology and infertility diagnostic
procedures.
Investigate patients for sexually transmitted infections (STIs):
if they have symptoms of an STI

before a transcervical procedure, including hysterosalpingography and hysterosalpingo-contrast sonography
before a laparoscopic dye test (chromotubation).
If the results of investigations are positive, provide appropriate treatment for the STI to reduce the risk of
postprocedural infective complications; ideally, treatment should be completed before the procedure.
Assisted reproductive technology and infertility diagnostic procedures, and their requirement
for surgical antibiotic prophylaxis (Table 2.22)

ONLY IF the patient has a history of PID or tubal
hysterosalpingography, hysterosalpingo-contrast
dilatation, or tubal damage is noted on visualisation
sonography, laparoscopic dye test (chromotubation)
[NB1]
oocyte retrieval (donor or recipient) NO
PID = pelvic inflammatory disease
NB1: Surgical antibiotic prophylaxis is not required if the patient has been investigated, and treated as indicated, for sexually transmitted infections
If prophylaxis is indicated for patients who have not been investigated, and treated as indicated, for STIs before the
procedure, use:
doxycycline 100 mg orally, 12-hourly for 5 days. The first dose of prophylaxis should be
given before the procedure.
Surgical prophylaxis for breast surgery

2.23 for the recommendations for surgical prophylaxis for breast surgery.
Staphylococcus aureus is the most common cause of postoperative implant infection. For patients undergoing
breast reconstruction or augmentation surgery, consider preoperative screening for methicillin-susceptible and
methicillin-resistant S. aureus carriage. If the results of screening are positive, perform decolonisation.
Breast procedures and their requirement for surgical antibiotic prophylaxis (Table 2.23)

diagnostic excisional biopsy
stand-alone sentinel node biopsy

NO
lumpectomy (with or without needle or wire
localisation)
reduction mammoplasty
simple mastectomy
wide local excision

YES
axillary lymph node clearance
nipple surgery
all repeat or revision procedures

prosthetic breast reconstruction surgery (prosthetic
implant or acellular dermal matrix)
YES [NB1]
autologous breast reconstruction surgery
breast augmentation surgery

NB1: Although a single preoperative dose of surgical antibiotic prophylaxis is expected to be sufficient to prevent postoperative infection following
reconstruction or augmentation surgery, there is insufficient evidence to show that a single dose of prophylaxis is as effective as 24 hours of prophylaxis.
Postoperative doses can be considered but prophylaxis (intravenous or oral) should not continue beyond 24 hours, even in the presence of surgical drains
adjacent to the implant. See also discussion below.
If prophylaxis is indicated for breast surgery, use:
cefazolin 2 g intravenously, within the 60 minutes before surgical incision; intraoperative

completed [Note 11].
For patients colonised or infected with methicillin-resistant S. aureus (MRSA), or at increased risk of being
colonised or infected with MRSA (see Box 2.31), add vancomycin to cefazolin:
vancomycin 15 mg/kg intravenously, started within the 120 minutes before surgical
incision (recommended rate 10 mg/minute) [Note 12]; intraoperative redosing may be
required (see here). Do not give additional doses once the procedure is completed [Note
11].
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use cefazolin, with
or without vancomycin, as above. See also Surgical antibiotic prophylaxis for patients with a penicillin or
cephalosporin allergy.
monotherapy (see dosage above).
For breast reconstruction or augmentation surgery, there is insufficient evidence to show that a single dose of
prophylaxis is as effective as 24 hours of prophylaxis. The need for postoperative doses should be considered on
an individual patient basis; there may be a benefit in patients with risk factors for surgical site infection such as
obesity or prior radiation therapy. Postoperative prophylaxis (intravenous or oral) should not exceed 24 hours, even
in the presence of surgical drains adjacent to the implant. Extended prophylaxis is associated with an increased risk
of adverse effects, including subsequent infection with resistant pathogens and Clostridium difficile.
There is insufficient evidence to support the use of topical antimicrobials or antiseptics to irrigate the surgical
pocket at the time of implantation, and the practice is not recommended.
Note 11: Although a single preoperative dose of surgical antibiotic prophylaxis is expected to be sufficient to
prevent postoperative infection following reconstruction or augmentation surgery, there is insufficient evidence
to show that a single dose of prophylaxis is as effective as 24 hours of prophylaxis. Postoperative doses can be
considered but prophylaxis (intravenous or oral) should not continue beyond 24 hours, even in the presence of
surgical drains adjacent to the implant.
Surgical prophylaxis for burns surgery

Surgical antibiotic prophylaxis is not indicated for the majority of patients with burns undergoing surgical
debridement.
For patients with extensive burns, surgical antibiotic prophylaxis may be considered before aggressive surgical
debridement; however, evidence to support the use of prophylaxis is limited. Antibiotic prophylaxis may also be
considered before split-thickness skin graft procedures for extensive burns, particularly if the burn is heavily
colonised with bacteria. Antibiotic prophylaxis is not indicated for patients with burns who do not require
immediate debridement surgery.
If prophylaxis is prescribed, antibiotic choice should be guided by local epidemiology and the results of recent
culture and susceptibility testing.
Postoperative administration of prophylactic antibiotics (intravenous, oral or topical) is not indicated.
Surgical antibiotic prophylaxis is not required if the patient is already receiving antibiotic therapy for established
infection. However, adjust the timing of the treatment dose to achieve adequate plasma and tissue concentrations at
the time of surgical incision and for the duration of the procedure—seek expert advice.
Surgical prophylaxis for cardiac surgery

General principles and indications
2.24 for the recommendations for surgical prophylaxis for cardiac surgery.
Staphylococcus aureus colonisation increases the risk of postoperative infection. Screen patients before cardiac
surgery for S. aureus carriage (both methicillin-susceptible and methicillin-resistant strains); this is particularly
important for patients undergoing procedures that involve median sternotomy. If the results of screening are
positive, perform decolonisation. Known methicillin-resistant S. aureus (MRSA) carriage should not delay urgent
cardiac surgery.
Cardiopulmonary bypass is commonly used in cardiac surgery. Data from small

pharmacokinetic/pharmacodynamic studies demonstrated altered concentrations of antimicrobials with
cardiopulmonary bypass; however, the clinical relevance of these findings is unclear, and there are limited data to
support alternative dosing strategies when cardiopulmonary bypass is used.
Cardiac procedures and their requirement for surgical antibiotic prophylaxis (Table 2.24)

all cardiac procedures, including valve replacement,
coronary artery bypass surgery, cardiac transplant,
YES [NB1]
transcatheter aortic valve implantation (TAVI) and
insertion of a ventricular assist device
NB1: For cardiac procedures, there are inadequate data to show that a single dose of prophylaxis is as effective as 24 hours of prophylaxis. Postoperative
doses can be considered but prophylaxis (intravenous or oral) should not continue beyond 24 hours, even in the presence of chest drains. See also
discussion in Duration of prophylaxis.
Antibiotic regimens
For prophylaxis for cardiac surgery, use:

surgical incision; intraoperative redosing may be required. See also Duration of
prophylaxis.
For patients colonised or infected with MRSA, or at increased risk of being colonised or infected with MRSA (eg
patients undergoing a prosthetic cardiac valve procedure that is a reoperation [return to theatre or early revision];
see also Box 2.31), add vancomycin to cefazolin:
redosing may be required. See also Duration of prophylaxis.
At the time of writing, the optimal antibiotic regimen for prophylaxis for transcatheter aortic valve implantation
(TAVI) is not known. High rates of postoperative endocarditis (including endocarditis caused by organisms not
susceptible to cefazolin) were reported in a large international cohort [Note 14], but have not been observed in
Australian patients. The antibiotic regimens recommended above may need to be modified according to the
organisms causing infection within the institution and their susceptibility patterns—seek expert advice.
redosing may be required. See also Duration of prophylaxis
PLUS
required (see Duration of prophylaxis).
infection is not recommended because there is potential for harm (eg hypersensitivity reactions, bacterial
Note 14: Regueiro A, Linke A, Latib A, Ihlemann N, Urena M, Walther T, et al. Association between
transcatheter aortic valve replacement and subsequent infective endocarditis and in-hospital death. JAMA
2016;316(10):1083-92. [URL]
Duration of prophylaxis
Because of the long duration of many cardiac procedures, repeat intraoperative doses are often necessary.
Administer a repeat dose if:
after prophylaxis is given, there is a significant delay in starting the operation

cefazolin is used and more than 3 to 4 hours (ie more than two cefazolin half-lives) have elapsed since the
previous dose
there is excessive blood loss during the procedure (eg in adults, 1.5 litres or more).
Data from low-quality studies suggest that postoperative doses of prophylaxis reduce the risk of postoperative
infections following cardiac procedures. While postoperative doses may be considered, prophylaxis should not
continue beyond 24 hours, even in the presence of chest drains. Extended prophylaxis is associated with an
increased risk of adverse effects, including subsequent infection with resistant pathogens and Clostridium difficile.
The optimal duration of prophylaxis for cardiac transplant procedures in which the chest is not primarily closed or
the patient has a chronically infected ventricular assist device is unclear—seek expert advice.
When measuring the time to a repeat intraoperative or postoperative dose, measure the interval from the time of
the previous dose rather than the beginning of the operation. See Table 2.15 for redosing intervals for the
antimicrobials recommended above.
Surgical prophylaxis for ear, nose and throat surgery

2.25 for the recommendations for surgical prophylaxis for ear, nose and throat surgery.
The role of topical antibiotic prophylaxis for insertion of tympanostomy tubes (grommets) is controversial. There
is insufficient evidence to recommend routine use of topical antimicrobial therapy.
Antibiotic prophylaxis should not be given to patients with nasal packing or a tamponade device in situ following
epistaxis.
Ear, nose and throat procedures and their requirement for surgical antibiotic prophylaxis (Table
2.25)
Procedure Is surgical antibiotic prophylaxis indicated?

uncomplicated nose or sinus surgery (including
endoscopic procedures)
uncomplicated ear surgery
otoplasty NO [NB1]
stapedectomy
tonsillectomy
adenoidectomy
major ear surgery
complex septorhinoplasty
revision sinus surgery
laryngectomy (primary or salvage) YES [NB2]
tympanomastoid surgery
hearing implant procedures, including cochlear implant

procedures
NB1: Although surgical antibiotic prophylaxis is not required for tonsillectomy or adenoidectomy, patients with specific cardiac conditions (see Box
2.12) who are undergoing these procedures require antibiotics for the prevention of endocarditis—see Endocarditis prophylaxis for respiratory tract or
ear, nose and throat procedures.
laryngectomy, there is insufficient evidence (especially for salvage laryngectomy) to show that a single dose of prophylaxis is as effective as 24 hours of
prophylaxis. Postoperative doses can be considered but prophylaxis (intravenous or oral) should not continue beyond 24 hours.
Major ear surgery, complex septorhinoplasty, revision sinus surgery, laryngectomy or

tympanomastoid surgery
The recommendations below are appropriate for most patients undergoing major ear surgery, complex
septorhinoplasty, revision sinus surgery, laryngectomy or tympanomastoid surgery. However, if a patient is
undergoing major ear surgery, complex septorhinoplasty or revision sinus surgery, and the procedure is
contaminated or dirty (see Box 2.11) or undertaken in the setting of current or recent infection, the optimal
antibiotic regimen is uncertain. The patient may already be treated with antimicrobial therapy and the prophylaxis
regimens recommended below may require adjustment; the choice of prophylaxis should be guided by recent
culture and susceptibility test results—seek expert advice.
For prophylaxis for major ear surgery, complex septorhinoplasty, laryngectomy or tympanomastoid surgery, use:

additional doses once the procedure is completed [Note 16]
PLUS
not give additional doses once the procedure is completed [Note 16]
PLUS for patients undergoing laryngectomy who are colonised or infected with MRSA or at increased risk of
being colonised or infected with MRSA (see Box 2.31)
redosing may be required (see here) [Note 16].
clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, within the 120 minutes
before surgical incision; intraoperative redosing may be required (see here). Do not give
PLUS for laryngectomy or tympanomastoid surgery

required (see here). Do not give additional doses once the procedure is completed [Note
16].
For patients with immediate severe or delayed severe hypersensitivity to penicillins who are undergoing
laryngectomy and are colonised or infected with methicillin-resistant Staphylococcus aureus (MRSA), or at
increased risk of being colonised or infected with MRSA (see Box 2.31), add vancomycin (see dosage above) to
the above regimen. Vancomycin is not needed if clindamycin is expected to have adequate activity against MRSA
based on local epidemiology or recent MRSA culture results.
prevent postoperative infection following laryngectomy, there is insufficient evidence (especially for salvage
laryngectomy) to show that a single dose of prophylaxis is as effective as 24 hours of prophylaxis. Postoperative
doses can be considered but prophylaxis (intravenous or oral) should not continue beyond 24 hours.
Hearing implant procedures

For prophylaxis for hearing implant procedures, use:

PLUS for patients who are colonised or infected with MRSA or at increased risk of being colonised or infected
with MRSA (see Box 2.31)
completed.
completed.
Surgical prophylaxis for gastrointestinal endoscopic procedures

General principles
There is no evidence to support the use of antibiotic prophylaxis for patients undergoing routine upper or lower
gastrointestinal endoscopy.
2.12) who are undergoing gastrointestinal endoscopic procedures for which surgical antibiotic prophylaxis is
required. If the surgical antibiotic prophylaxis regimen does not include an antibiotic active against enterococci (eg
amoxicillin, ampicillin, vancomycin), see Endocarditis prophylaxis for genitourinary and gastrointestinal tract
procedures for appropriate add-on recommendations.
(see Box 2.12) who are undergoing gastrointestinal endoscopic procedures for which surgical antibiotic
prophylaxis is not required, if the patient has an established gastrointestinal infection—see Endocarditis
prophylaxis for genitourinary and gastrointestinal tract procedures.
Endoscopic retrograde cholangiopancreatography
general principles (above) of surgical antibiotic prophylaxis for gastrointestinal endoscopic procedures. See Table
2.26 for the recommendations for surgical prophylaxis for endoscopic retrograde cholangiopancreatography
(ERCP).
If the patient is being treated with antibiotic therapy for an established infection, it is not necessary to give
additional antibiotic prophylaxis provided the regimen has activity against the organism(s) most likely to cause
Endoscopic retrograde cholangiopancreatography procedures and their requirement for

surgical antibiotic prophylaxis (Table 2.26)

ERCP involving transpapillary or transmural drainage of
YES
pseudocysts
ERCP with evidence of biliary tract obstruction ONLY IF complete biliary drainage may not be achieved
ONLY IF the patient has communicating pancreatic
all other ERCP procedures
cysts or pseudocysts
ERCP = endoscopic retrograde cholangiopancreatography
The choice of prophylaxis for ERCP should be guided by local microbiological data—seek expert advice. In the
absence of local microbiological data, use:
minutes before the procedure [Note 20]; intraoperative redosing is unlikely to be required
(see here). Do not give additional doses once the procedure is completed.
Endoscopic ultrasound
general principles of surgical antibiotic prophylaxis for gastrointestinal endoscopic procedures. See Table 2.27 for
the recommendations for surgical prophylaxis for endoscopic ultrasound procedures.
Endoscopic ultrasound procedures and their requirement for surgical antibiotic prophylaxis
(Table 2.27)

diagnostic EUS
NO
EUS-FNA of solid lesions
EUS-FNA of cystic lesions YES
EUS = endoscopic ultrasound; EUS-FNA= endoscopic ultrasound-guided fine-needle aspiration
If prophylaxis is indicated for endoscopic ultrasound procedures, use:
minutes before the procedure; intraoperative redosing may be required (see here). Do not
give additional doses once the procedure is completed
PLUS EITHER
1 cefazolin 2 g (child: 30 mg/kg up to 2 g) intravenously, within the 60 minutes before the

procedure; intraoperative redosing may be required (see here). Do not give additional
doses once the procedure is completed
OR
2 gentamicin (adult and child) 2 mg/kg intravenously over 3 to 5 minutes, within the 120
cefoxitin 2 g (child: 40 mg/kg up to 2 g) intravenously, within the 60 minutes before the

doses once the procedure is completed.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, use metronidazole plus
gentamicin (as above).
Gastrostomy or jejunostomy tube insertion

general principles of surgical antibiotic prophylaxis for gastrointestinal endoscopic procedures. See Table 2.28 for
the recommendations for surgical prophylaxis for percutaneous gastrostomy or jejunostomy tube insertion.
Percutaneous gastrostomy or jejunostomy tube insertion procedures and their requirement for
surgical antibiotic prophylaxis (Table 2.28)

PEG or PEJ tube insertion YES
PRG or PRJ tube insertion YES
PEG = percutaneous endoscopic gastrostomy; PEJ = percutaneous endoscopic jejunostomy; PRG = percutaneous radiologic gastrostomy; PRJ =
percutaneous radiologic jejunostomy
For prophylaxis for percutaneous gastrostomy or jejunostomy tube insertion, use:

For patients colonised or infected with methicillin-resistant Staphylococcus aureus (MRSA), or at increased risk of
being colonised or infected with MRSA (see Box 2.31), add to cefazolin:
completed.
Surgical prophylaxis for gynaecological surgery
2.29 for the indications for surgical prophylaxis for gynaecological procedures. For recommendations for
prophylaxis for urodynamic studies, see Surgical prophylaxis for urological surgery.
Investigate patients for sexually transmitted infections (STIs):
if they have symptoms of an STI

before insertion of an intrauterine contraceptive device
before a transcervical procedure, including surgical termination of pregnancy and hysteroscopy.
If the results of investigations are positive, provide appropriate treatment for the STI to reduce the risk of
postprocedural infective complications; ideally, treatment should be completed before the procedure.
The benefit of routine prophylaxis for pelvic organ prolapse or stress urinary incontinence procedures has not been
demonstrated in clinical trials. Despite this, it is the consensus view of the Antibiotic Expert Groups that a single
dose of prophylaxis should be used for procedures involving insertion of synthetic material because mesh infection
is associated with poor outcomes.
Infection following medical (pharmacological) termination of pregnancy is rare and usually related to retained
products of conception; antibiotic prophylaxis is not required.
2.12) who are undergoing gynaecological procedures for which surgical antibiotic prophylaxis is required, with the
exception of surgical termination of pregnancy. If the surgical antibiotic prophylaxis regimen does not include an
antibiotic active against enterococci (eg amoxicillin, ampicillin, vancomycin), see Endocarditis prophylaxis for
genitourinary and gastrointestinal tract procedures for appropriate add-on recommendations.
Gynaecological procedures and their requirement for surgical antibiotic prophylaxis (Table 2.29)

laparoscopic procedures that do not enter the bowel or
vagina
hysteroscopy, operative or diagnostic
dilation and curettage, with the exception of surgical

termination of pregnancy
NO
endometrial biopsy or ablation
insertion of an intrauterine device
cervical tissue excision procedure (eg LLETZ, biopsy,

endocervical curettage)
autologous mid-urethral sling procedures

hysterectomy
gynaecological–oncological procedures YES
gynaecological laparotomy procedures

synthetic mid-urethral sling procedures
YES
pelvic organ prolapse procedures
YES if not investigated for sexually transmitted
surgical termination of pregnancy
infections before the procedure
LLETZ = large loop excision of the transformation zone
Hysterectomy, and gynaecological–oncological, other laparotomy, pelvic organ prolapse or

synthetic mid-urethral sling procedures
For prophylaxis for hysterectomy, and gynaecological–oncological, other laparotomy, pelvic organ prolapse or
synthetic mid-urethral sling procedures, use:
completed
PLUS
metronidazole 500 mg intravenously, within the 120 minutes before surgical incision;
intraoperative redosing may be required (see here). Do not give additional doses once the
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, the above regimen is
suitable. See also Surgical antibiotic prophylaxis for patients with a penicillin or cephalosporin allergy.
clindamycin 600 mg intravenously, within the 120 minutes before surgical incision;
PLUS
gentamicin 2 mg/kg intravenously over 3 to 5 minutes, within the 120 minutes before
surgical incision [Note 23]; intraoperative redosing is unlikely to be required (see here).
Do not give additional doses once the procedure is completed.
For premenopausal women with abnormal vaginal flora (including bacterial vaginosis) who did not receive
surgical antibiotic prophylaxis, perioperative treatment with rectal metronidazole reduced the rate of vaginal cuff
infection following abdominal hysterectomy. However, these results have not been replicated in patient cohorts
who received surgical antibiotic prophylaxis with metronidazole. Consequently, routine bacterial vaginosis
screening before hysterectomy cannot be recommended.
calculate the dose.
Surgical termination of pregnancy

Before surgical termination of pregnancy, investigate patients for bacterial vaginosis as well as STIs. If the results
of investigations are positive, provide appropriate treatment for the STI to reduce the risk of postprocedural
infective complications; ideally, treatment should be completed before the procedure.
Surgical antibiotic prophylaxis is not required if the patient has been investigated, and treated as indicated, for
bacterial vaginosis and STIs before the procedure.
For prophylaxis for patients who have not been appropriately investigated before surgical termination of
pregnancy, use:
1 doxycycline 100 mg orally, 60 minutes before the procedure, then 200 mg orally, 90
minutes after the procedure [Note 24]
OR
1 doxycycline 400 mg orally, with food, 10 to 12 hours before the procedure. [Note 25]
An alternative regimen is:
metronidazole 2 g orally, within the 120 minutes before the procedure [Note 26]
PLUS for patients at a higher risk of infection (as below)
azithromycin 1 g orally, within the 120 minutes before the procedure.
Women are at a higher risk of post-termination infection, and require adjunctive azithromycin if a metronidazole-
based regimen is used, if they meet any of the following criteria:
age 20 years or older

three or more sexual partners in the past 12 months
a history of pelvic inflammatory disease or an STI in the past 10 years
clinical evidence of cervicitis
a sexual partner who has other partners, a history of STI, or current or recent STI symptoms.
Some centres use a single preoperative dose of azithromycin (as monotherapy) for prophylaxis for surgical
termination of pregnancy; there are few published data on this approach.
Note 24: Nausea has been reported when doxycycline is administered in the perioperative period; consider
concurrent use of an antiemetic drug (see Nausea and vomiting).
Note 25: Alternatively, doxycycline can be given as a single, large dose (ie 400 mg) 60 minutes before the
procedure; however, nausea is common with this regimen. If a single, large dose is to be administered in the
perioperative period, consider concurrent use of an antiemetic drug (see Nausea and vomiting).
Note 26: Nausea has been reported when metronidazole is administered in the perioperative period; consider
concurrent use of an antiemetic drug (see Nausea and vomiting).
Surgical prophylaxis for head and neck surgery

2.30 for the recommendations for surgical prophylaxis for head and neck surgery.
Head and neck procedures and their requirement for surgical antibiotic prophylaxis (Table 2.30)

thyroidectomy
simple lymph node excision (including submandibular

lymph node excision) NO
parotidectomy
clean procedures (see Box 2.11) not listed below

procedures involving insertion of prosthetic material
clean–contaminated procedures (see Box 2.11) not listed

above
YES [NB1]
extensive neck dissection for malignancy
debulking or reconstructive surgery for malignancy

extensive neck dissection for malignancy, and debulking or reconstructive surgery for malignancy, there is insufficient evidence to show that a single
dose of prophylaxis is as effective as 24 hours of prophylaxis. Postoperative doses can be considered but prophylaxis (intravenous or oral) should not
continue beyond 24 hours.
If prophylaxis is indicated for head and neck procedures, use:

PLUS for incisions through mucosal surfaces
not give additional doses once the procedure is completed [Note 27].
Intravenous amoxicillin+clavulanate has been used as a single drug for prophylaxis for extensive neck dissection
for malignancy, and debulking or reconstructive surgery for malignancy. However, the combination of cefazolin
and metronidazole is preferred because of its narrower spectrum of activity.
or without metronidazole, as above. See also Surgical antibiotic prophylaxis for patients with a penicillin or
PLUS for extensive neck dissection, or debulking or reconstructive surgery
prevent postoperative infection following extensive neck dissection for malignancy, and debulking or
reconstructive surgery for malignancy, there is insufficient evidence to show that a single dose of prophylaxis is
as effective as 24 hours of prophylaxis. Postoperative doses can be considered but prophylaxis (intravenous or
oral) should not continue beyond 24 hours.
Surgical prophylaxis for implantable cardiac device insertion

2.31 for the recommendations for surgical prophylaxis for implantable cardiac device insertion.
Implantable cardiac device insertion procedures and their requirement for surgical antibiotic
prophylaxis (Table 2.31)

insertion of an implantable cardiac device (eg permanent
pacemaker device, cardioverter defibrillator, cardiac YES
resynchronisation device, ventricular assist device)
The choice of prophylaxis for ventricular assist device insertion should be guided by local microbiology and the
optimal duration of prophylaxis is unclear—refer to local protocols or seek expert advice.
For prophylaxis for insertion of other implantable cardiac devices, use:

being colonised or infected with MRSA (see Box 2.31), add vancomycin to cefazolin:
completed.
completed
PLUS
A single preoperative dose of surgical antibiotic prophylaxis is sufficient to prevent postoperative infection.
Postoperative (intravenous or oral) antibiotics do not provide benefit and increase the risk of subsequent infections
with resistant pathogens and Clostridium difficile.
infection is not recommended because there is potential for harm (eg hypersensitivity reactions, bacterial
Surgical prophylaxis for neurosurgery

2.32 for the recommendations for surgical prophylaxis for neurosurgery.
The benefit of routine antibiotic prophylaxis for the insertion of external ventricular drains has not been
demonstrated in clinical trials. Despite this, a single dose of prophylaxis is recommended in these guidelines, in
line with consensus guidelines from the Neurocritical Care Society, because postoperative infection would have
serious consequences [Note 31].
There is no evidence that antibiotic prophylaxis for basilar skull fracture reduces the incidence of meningitis,
mortality or the need for surgical correction. Therefore, antibiotic prophylaxis is not indicated for patients with
cerebrospinal fluid (CSF) leakage following trauma. However, patients with CSF leak should be vaccinated against
Streptococcus pneumoniae to protect against the development of pneumococcal meningitis. See the Australian
Immunisation Handbook for further information.
For neurosurgical spinal procedures, see Surgical prophylaxis for spinal surgery.
Neurosurgery procedures and their requirement for surgical antibiotic prophylaxis (Table 2.32)

intracranial shunt insertion [NB1]
pressure monitor insertion
craniotomy
microsurgery YES
re-exploration procedures
external ventricular drain insertion

NB1: Patients scheduled for insertion of an intracranial shunt should be vaccinated against Streptococcus pneumoniae, ideally before the procedure, to
protect against the development of pneumococcal meningitis. See the Australian Immunisation Handbook for further information.
For prophylaxis for neurosurgery procedures, use:

being colonised or infected with MRSA (see Box 2.31), add vancomycin to cefazolin:
completed.
Ventricular drains that remain in situ do not justify extending the duration of antibiotic prophylaxis
postoperatively. Extended prophylaxis is associated with an increased risk of adverse effects, including subsequent
infection with resistant pathogens and Clostridium difficile.
The rate of shunt infection is reduced when the shunt is impregnated with an antibiotic (clindamycin or
rifampicin), but data are lacking on the risk of selecting resistant organisms.
Note 31: Fried HI, Nathan BR, Rowe AS, Zabramski JM, Andaluz N, Bhimraj A, et al. The insertion and
management of external ventricular drains: an evidence-based consensus statement: a statement for healthcare
professionals from the Neurocritical Care Society. Neurocritical Care 2016;24(1):61-81. [URL]
Surgical prophylaxis for obstetric surgery

2.33 for the indications for surgical prophylaxis for obstetric procedures. For recommendations for prophylaxis for
repair of obstetric anal sphincter injuries (including third- or fourth-degree perineal tears), see Prophylaxis for
repair of obstetric anal sphincter injuries.
Obstetric procedures and their requirement for surgical antibiotic prophylaxis (Table 2.33)

assisted vaginal delivery NO
YES even if the patient is receiving antibiotics for
caesarean section, elective or nonelective
preterm prelabour rupture of membranes [NB1]
NB1: For patients receiving intrapartum prophylaxis against Streptococcus agalactiae or treatment for intra-amniotic infection, additional surgical
antibiotic prophylaxis is required, unless the antibiotic regimen has activity against the organism(s) most likely to cause postoperative infection (eg
cefazolin, clindamycin plus gentamicin) (see Caesarean section, below).
Caesarean section
For patients receiving intrapartum prophylaxis against Streptococcus agalactiae (group B streptococcus) or
treatment for intra-amniotic infection (chorioamnionitis), additional surgical antibiotic prophylaxis is required,
unless the antibiotic regimen has activity against the organism(s) most likely to cause postoperative infections (eg
cefazolin, clindamycin plus gentamicin). Furthermore, adequate plasma and tissue concentrations must be
achieved at the time of surgical incision and for the duration of the procedure. See Surgical antibiotic prophylaxis
for patients receiving treatment for established infection.
Although it has previously been recommended that prophylaxis be given after cord clamping to avoid theoretical
risks to the neonate (eg maternal anaphylaxis), studies have confirmed that administration before surgical incision
results in lower infection rates without compromising the neonate.
For prophylaxis for caesarean section, use:

being colonised or infected with MRSA (see Box 2.31), add vancomycin to the above regimen:
For patients with immediate severe or delayed severe hypersensitivity to penicillins who are neither colonised or
infected with MRSA, nor at increased risk of being colonised or infected with MRSA (see Box 2.31), use:
clindamycin 600 mg intravenously, within the 120 minutes before surgical incision;
PLUS
For patients with immediate severe or delayed severe hypersensitivity to penicillins who are colonised or
infected with MRSA, or at increased risk of being colonised or infected with MRSA (see Box 2.31), use:
PLUS
A randomised controlled trial demonstrated a reduction in postoperative infection when azithromycin was added to
cefazolin for prophylaxis for nonelective caesarean section deliveries [Note 36]. However, this study has
limitations, and there are concerns about possible adverse effects of this regimen, particularly effects on the
neonate. It is not currently recommended for routine practice.
Note 33: Pharmacokinetic studies suggest 2 g doses of cefazolin may result in inadequate tissue levels in obese
patients undergoing obstetric procedures; see Surgical antibiotic prophylaxis for obese patients for a discussion
of cefazolin dosing in obese women undergoing caesarean section.
calculate the dose.
Note 36: Tita AT, Szychowski JM, Boggess K, Saade G, Longo S, Clark E, et al. Adjunctive azithromycin
prophylaxis for cesarean delivery. N Engl J Med 2016;375(13):1231-41. [URL]
Surgical prophylaxis for ophthalmic surgery

Consider the principles for appropriate prescribing of surgical antibiotic prophylaxis (see Box 2.10).
The aim of antibiotic prophylaxis in ophthalmic surgery is to reduce acute postoperative endophthalmitis, a sight-
threatening complication of intraocular surgery. All intraocular procedures may result in inoculation of the eye
with organisms and subsequent infection. Prevention of endophthalmitis involves a combination of preoperative
screening, antisepsis of the periocular area and ocular surface, intraoperative techniques (including correct wound
construction and sealing), and postoperative patient care.
Active conjunctivitis, dacryocystitis or blepharitis must be treated and resolved before surgery.
After cataract surgery, intracameral administration (injection into the anterior chamber of the eye) of antibiotics at
the end of surgery is considered the most effective method for reducing the risk of endophthalmitis. Use:
cefazolin 1 mg/0.1 mL intracamerally, as a single dose at the end of surgery [Note 37].
Seek expert advice for patients with cefazolin hypersensitivity. In patients hypersensitive to other cephalosporins,
or to penicillins, cefazolin is often tolerated because it shares no common side-chains with other beta lactams (see
Management of patients reporting hypersensitivity to penicillins).
The use of preoperative topical antibiotics does not provide additional benefit to the above interventions.
Postoperative topical antibiotics, though widely prescribed, lack evidence; the rate of endophthalmitis was not
increased in large cohort studies using intracameral antibiotics alone (without postoperative topical antibiotics).
If postoperative topical antibiotics are considered necessary, chloramphenicol is recommended; use:
chloramphenicol 0.5% eye drops, 1 drop into the operated eye, four times a day for up to 7
days.
If chloramphenicol eye drops are used postoperatively, a maximum of 7 days’ treatment is sufficient.
There is a lack of evidence to support use of topical quinolones. Tobramycin does not have activity against Gram-
positive organisms.
Note 37: In these guidelines, intracameral cefazolin is recommended for prevention of endophthalmitis after
cataract surgery because a parenteral formulation of cefuroxime (which was used in the key randomised
controlled trial) is not marketed in Australia.
Surgical prophylaxis for oral maxillofacial surgery

2.34 for the recommendations for surgical prophylaxis for oral maxillofacial surgery.
For perioperative management of complex and potentially contaminated open facial fractures, see Open fractures.
Although there is a risk of bacterial infection following procedures of the skin or subcutaneous tissue (including
procedures that breach the oral mucosa), surgical antibiotic prophylaxis is not routinely indicated for clean or
clean–contaminated procedures (see Box 2.11) of the skin or subcutaneous tissue. However, for patients with
specific cardiac conditions (see Box 2.12) who are undergoing a procedure that involves manipulation of the
gingival or periapical tissue or perforation of the oral mucosa, prophylaxis against streptococcal endocarditis is
required—see Endocarditis prophylaxis for dental procedures.
Oral maxillofacial procedures and their requirement for surgical antibiotic prophylaxis (Table
2.34)

clean or clean–contaminated procedures (see Box
2.11) not listed below
NO
procedures involving insertion of dental implants
procedures involving insertion of prosthetic material,
with the exception of dental implants
open reduction and internal fixation of mandibular

fractures or midfacial (eg Le Fort or zygomatic)
fractures YES [NB1]
intraoral bone grafting procedures
orthognathic surgery (major jaw realignment surgery)
cleft lip and palate repairs

orthognathic surgery, there is insufficient evidence to show that a single dose of prophylaxis is as effective as 24 hours of prophylaxis. Postoperative
doses can be considered but prophylaxis (intravenous or oral) should not continue beyond 24 hours.
For prophylaxis for procedures involving incision through the oral mucosa only (eg cleft lip and palate repairs),
use:
benzylpenicillin 1.2 g (child: 30 mg/kg up to 1.2 g) intravenously, within the 60 minutes

additional doses once the procedure is completed [Note 38].
For prophylaxis for procedures involving incision through the skin and oral mucosa (eg temporomandibular joint
replacement), use:

PLUS
not give additional doses once the procedure is completed [Note 38].
metronidazole (as above). See also Surgical antibiotic prophylaxis for patients with a penicillin or cephalosporin
allergy.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, as a single drug, use:
prevent postoperative infection following orthognathic surgery, there is insufficient evidence to show that a
single dose of prophylaxis is as effective as 24 hours of prophylaxis. Postoperative doses can be considered but
prophylaxis (intravenous or oral) should not continue beyond 24 hours.
Surgical prophylaxis for orthopaedic surgery

Specific considerations for joint arthroplasty
Staphylococcus aureus colonisation increases the risk of postoperative arthroplasty device infection (prosthetic
joint infection). Screen patients before arthroplasty procedures for S. aureus carriage (both methicillin-susceptible
and methicillin-resistant strains). If the results of screening are positive, perform decolonisation.
Treating asymptomatic bacteriuria before arthroplasty procedures does not reduce the risk of postoperative
prosthetic joint infection. Therefore, do not screen for or treat asymptomatic bacteriuria before prosthetic joint
replacement surgery.
Perioperative use of urinary catheters is common in arthroplasty procedures. Do not administer an antibiotic (eg
gentamicin) at the time of catheter insertion or removal, or continue antibiotic prophylaxis until catheter removal.
These practices are not supported by evidence and may cause adverse effects.
The use of antimicrobial-impregnated cement for fixation of the prosthetic device is a common practice. High-
quality data to support the efficacy and cost-effectiveness of this practice are limited.
Surgical antibiotic prophylaxis

2.35 for the recommendations for surgical prophylaxis for orthopaedic surgery.
For antibiotic prophylaxis for limb amputation, see Surgical prophylaxis for vascular surgery. For antibiotic
prophylaxis for spinal surgery, see Surgical prophylaxis for spinal surgery. For antibiotic prophylaxis for open
fractures, see Open fractures.
For revision surgery on an infected prosthetic joint, or when arthroplasty device infection (prosthetic joint
infection) is suspected, it is common to delay surgical antibiotic prophylaxis until after samples are collected.
However, a difference in culture yield has not been demonstrated with prophylaxis given before, compared to after,
collection of samples.
Orthopaedic procedures and their requirement for surgical antibiotic prophylaxis (Table 2.35)
Procedure Is surgical antibiotic prophylaxis indicated?

routine arthroscopy procedures not involving insertion NO
of prosthetic material or avascular tissue
prosthetic large joint replacement [NB1]
procedures involving insertion of prosthetic or allograft

YES
material
internal fixation of fractures of large bones

NB1: Although a single preoperative dose of surgical antibiotic prophylaxis is expected to be sufficient to prevent postoperative infection following total
knee arthroplasty, there is insufficient evidence to show that a single dose of prophylaxis is as effective as 24 hours of prophylaxis. Studies are ongoing.
Postoperative doses can be considered but prophylaxis (intravenous or oral) should not continue beyond 24 hours.
If prophylaxis is indicated for orthopaedic surgery, use:

colonised or infected with MRSA (eg patients undergoing a joint arthroplasty procedure that is a reoperation
[return to theatre or early revision]; see also Box 2.31), add to cefazolin:
prevent postoperative infection following total knee arthroplasty, there is insufficient evidence to show that a
single dose of prophylaxis is as effective as 24 hours of prophylaxis. Postoperative doses can be considered but
prophylaxis (intravenous or oral) should not continue beyond 24 hours.
Surgical prophylaxis for skin and soft tissue surgery

2.36 for the recommendations for surgical prophylaxis for skin and soft tissue surgery.
For prophylaxis for patients treated with medicinal leech therapy, see Prophylaxis for medicinal leech therapy. For
prophylaxis for traumatic wounds requiring surgical management, see Prophylaxis for traumatic wounds requiring
surgical management. Pre-emptive antibiotic therapy is sometimes required for wounds caused by bites and
clenched fists (see Bite wound infections, including clenched-fist injury infections).
Although there is a risk of bacterial infection following procedures of the skin or subcutaneous tissue, surgical
antibiotic prophylaxis (including oral or topical application) is not routinely indicated for clean or clean–
contaminated procedures (see Box 2.11) of the skin or subcutaneous tissue (including procedures that breach the
oral mucosa).
Prophylaxis against staphylococcal and streptococcal endocarditis may be reasonable for patients with specific
cardiac conditions (see Box 2.12) who are undergoing a skin and soft tissue procedure through infected skin, skin
structures or musculoskeletal tissues, even if surgical antibiotic prophylaxis is not required—see Endocarditis
prophylaxis for dermatological or musculoskeletal procedures.
There is no role for antibiotic prophylaxis to prevent prosthetic joint infection for patients undergoing procedures
of the skin or subcutaneous tissue (including procedures that breach the oral mucosa).
Herpes simplex virus (HSV) infection (either primary, or more commonly, reactivation) may follow ablative laser
resurfacing procedures, leading to delayed healing, bacterial superinfection and scarring. Antiviral prophylaxis is
often recommended, particularly for patients who have had previous orofacial HSV infection.
Skin and soft tissue procedures and their requirement for surgical antibiotic prophylaxis (Table
2.36)
Procedures Is surgical antimicrobial prophylaxis indicated?

blepharoplasty
rhytidectomy
NO
other clean or clean–contaminated procedures (see Box
2.11), including those that breach the oral mucosa
CONSIDER perioperative antiviral prophylaxis,
ablative laser facial resurfacing procedures particularly for patients who have had previous orofacial
HSV infection (see discussion above)
breast surgery
oral maxillofacial surgery see the relevant sections
head and neck surgery
For HSV prophylaxis for patients undergoing ablative laser facial resurfacing procedures, use:
1 aciclovir 400 mg orally, 12-hourly for 10 days. Start prophylaxis the morning of the
procedure
OR
1 famciclovir 250 mg orally, 12-hourly for 10 days. Start prophylaxis the morning of the
procedure
OR
1 valaciclovir 500 mg orally, daily for 10 days. Start prophylaxis the morning of the
procedure.
Surgical prophylaxis for spinal surgery

2.37 for the recommendations for surgical prophylaxis for spinal surgery.
Spinal surgery procedures and their requirement for surgical antibiotic prophylaxis (Table 2.37)
Procedure Is surgical antibiotic prophylaxis required?

spinal surgery YES
For prophylaxis for spinal surgery, use:

completed.
Small cohort studies suggest that topical vancomycin applied to the incision reduces infection rates in
neurosurgical spinal procedures. However, high-quality data on the safety and efficacy of this practice are lacking,
so it is not recommended.
Surgical prophylaxis for thoracic surgery

2.38 for the recommendations for surgical prophylaxis for thoracic surgery.
Thoracic surgery procedures and their requirement for surgical antibiotic prophylaxis (Table
2.38)

intercostal catheter insertion
brachiocephalic procedures (eg carotid endarterectomy, NO

brachial artery repair) not involving insertion of
prosthetic material
thoracic surgery procedures associated with an increased

YES
risk of infection, including video-assisted thoracoscopic
surgery (VATS), aneurysm repair,
thromboendarterectomy and vein bypass
If prophylaxis is indicated for thoracic surgery, use:

completed.
For thoracic surgery, a single preoperative dose of surgical antibiotic prophylaxis is sufficient to prevent
postoperative infection. Postoperative (intravenous or oral) antibiotics do not provide benefit and increase the risk
of subsequent infections with resistant pathogens and Clostridium difficile.
Surgical prophylaxis for urological surgery

Screening for preoperative bacteriuria
The likelihood of postoperative infection following a urological procedure is increased if the patient has
bacteriuria, so preoperative screening for bacteriuria is recommended for many urological procedures. If the results
of screening are positive, see Treating preoperative bacteriuria.
For uncomplicated cystoscopic diagnostic procedures, do not screen for bacteriuria because the risk of
postoperative infection is low. However, if the results of urinalysis suggest urinary tract infection, urine culture
should be performed.
For other elective urological procedures that enter the urinary tract, perform preoperative urine culture. In
catheterised patients, collect samples using a new catheter to avoid contamination of the sample by organisms
colonising the old catheter.
If preoperative screening is not possible before an immediate operation, empirical treatment may be required; see
Treating preoperative bacteriuria.
Treating preoperative bacteriuria
If bacteriuria is confirmed by screening, treat with a short course of antibiotics even if the patient is asymptomatic.
For suggested regimens, see Acute cystitis in adults and Acute cystitis in children; use the results of culture and
susceptibility testing to choose the most appropriate regimen. Alternatively, treat with a single preoperative dose of
gentamicin (as below).
For patients with chronic infection of the urinary tract, results of culture and susceptibility testing should guide
antibiotic choice—seek expert advice. It may not be possible to eradicate infection preoperatively and the goal of
antibiotic therapy is to minimise bacterial load at the time of surgery.
If an immediate operation is required and there is clinical evidence of a urinary tract infection but culture results
are unavailable, treat with a single dose of gentamicin (unless it is contraindicated; see Box 2.42). A preoperative
dose of gentamicin may also be used for patients with confirmed bacteriuria before an elective procedure. Use:
gentamicin (adult and child) 3 mg/kg intravenously over 3 to 5 minutes, as a single

preoperative dose [Note 43].
Gentamicin is concentrated in the urinary tract, so a dose of 3 mg/kg is used to treat acute cystitis or asymptomatic
bacteriuria before urological procedures. However, if systemic symptoms are present (eg severe pyelonephritis) a
higher dose of gentamicin is needed; see Principles of aminoglycoside use for dosage.
In patients treated with gentamicin preoperatively in whom urinary tract infection is confirmed, use the results of
culture and susceptibility testing to choose the most appropriate regimen for ongoing treatment. For suggested
regimens, see Acute cystitis in adults and Acute cystitis in children.

Preoperative treatment of bacteriuria does not negate the need for surgical antibiotic prophylaxis. An exception is
when gentamicin is given preoperatively to treat bacteriuria and is also indicated as prophylaxis (eg for
transurethral resection of the prostate). Additional prophylaxis will be required if adequate gentamicin plasma and
tissue concentrations are not achieved at the time of surgical incision and for the duration of the procedure.
Preoperative treatment of bacteriuria does not negate the need for surgical antibiotic prophylaxis.
Gentamicin is increasingly used for prophylaxis for urological surgery because of increased rates of cefazolin
resistance in Enterobacteriaceae.
For catheterised patients, it may be necessary to seek advice on prophylactic antibiotic choice from a clinical
microbiologist.
2.12) who are undergoing urological surgery for which surgical antibiotic prophylaxis is required. If the surgical
antibiotic prophylaxis regimen does not include an antibiotic active against enterococci (eg amoxicillin, ampicillin,
vancomycin), see Endocarditis prophylaxis for genitourinary and gastrointestinal tract procedures for appropriate
add-on recommendations.
(see Box 2.12) who are undergoing urological surgery for which surgical antibiotic prophylaxis is not required, if
the patient has an established genitourinary infection—see Endocarditis prophylaxis for genitourinary and
gastrointestinal tract procedures.
Table 2.39 outlines the indications for surgical antibiotic prophylaxis for urological procedures. For prophylaxis
for micturating cystourethrogram (MCUG), see Imaging to investigate urinary tract infection in children.
Urological procedures and their requirement for surgical antibiotic prophylaxis (Table 2.39)

urodynamic studies NO
extracorporeal shock-wave lithotripsy NO
prostate fiducial marker insertion YES
ureteroscopy procedures YES
endoscopic intrarenal and ureteric stone procedures (eg
percutaneous nephrolithotomy or pyeloscopy for YES
ureteric or kidney stones)
other endoscopic procedures ONLY IF there are risk factors for postoperative
infection (eg urinary tract obstruction or abnormalities,
uncomplicated cystoscopic diagnostic procedures urinary stones, indwelling or externalised catheters)
transurethral resection of the prostate YES
transrectal prostate biopsy YES
transperineal prostate biopsy YES [NB1]
open or laparoscopic urological procedures in which the
urinary tract is not entered (eg vasectomy, scrotal
NO
surgery, varicocele ligation) and prosthetic material is
not implanted
open or laparoscopic urological procedures involving
implantation of prosthetic material (eg penile prostheses, YES
artificial urinary sphincters, mesh)
open or laparoscopic urological procedures where the
YES
urinary tract is entered
NB1: Transperineal prostate biopsy is associated with lower rates of postoperative infection than transrectal prostate biopsy. However, data are limited
and it remains unclear whether antibiotic prophylaxis is required.
Endoscopic urological procedures

general principles of surgical antibiotic prophylaxis for urological surgery. See Table 2.39 for the indications for
surgical prophylaxis for endoscopic urological procedures.
Patients undergoing endoscopic urological procedures, with the exception of uncomplicated cystoscopic diagnostic
procedures, should be screened for bacteriuria preoperatively (see Screening for preoperative bacteriuria). For
patients treated for bacteriuria preoperatively, modify the choice of surgical antibiotic prophylaxis based on the
results of culture and susceptibility testing.
If prophylaxis is indicated for endoscopic urological procedures, in the absence of culture and susceptibility test
results, use:
cefazolin 2 g (child: 30 mg/kg up to 2 g) intravenously, within the 60 minutes before the

doses once the procedure is completed.
Gentamicin is preferred to cefazolin for prophylaxis for endoscopic urological procedures because it is likely to
have activity against a greater percentage of the bacteria associated with postoperative infection. The risk of
gentamicin toxicity is very low when it is given as a single dose for prophylaxis.
Transurethral resection of the prostate
For recommendations for prophylaxis in radical prostatectomy, see Open or laparoscopic urological procedures.
general principles of surgical antibiotic prophylaxis for urological surgery. Surgical antibiotic prophylaxis is
indicated for transurethral resection of the prostate.
Patients undergoing transurethral resection of the prostate should be screened for bacteriuria preoperatively (see
Screening for preoperative bacteriuria). For patients treated for bacteriuria preoperatively, modify the choice of
surgical antibiotic prophylaxis based on the results of culture and susceptibility testing.
For prophylaxis for transurethral resection of the prostate, in the absence of culture and susceptibility test results,
use:
gentamicin 2 mg/kg intravenously over 3 to 5 minutes, within the 120 minutes before the
procedure [Note 45]; intraoperative redosing is unlikely to be required (see here). Do not
give additional doses once the procedure is completed.
cefazolin 2 g intravenously, within the 60 minutes before the procedure; intraoperative

completed.
Gentamicin is preferred to cefazolin for prophylaxis for transurethral resection of the prostate because it is likely to
have activity against a greater percentage of the bacteria associated with postoperative infection. The risk of
gentamicin toxicity is very low when it is given as a single dose for prophylaxis.
Transrectal prostate biopsy
Antibiotic regimens
general principles of surgical antibiotic prophylaxis for urological surgery. Surgical antibiotic prophylaxis is
indicated for transrectal prostate biopsy.
Patients undergoing transrectal prostate biopsy should be screened for bacteriuria preoperatively (see Screening for
preoperative bacteriuria). For patients treated for bacteriuria preoperatively, modify the choice of surgical
antibiotic prophylaxis based on the results of culture and susceptibility testing.
Postoperative infection following transrectal prostate biopsy is increasingly caused by resistant bacteria. There
may be a role for prebiopsy screening for ciprofloxacin-resistant Enterobacteriaceae—see Ciprofloxacin-resistant
Enterobacteriaceae (below) and seek expert advice.
For prophylaxis for transrectal prostate biopsy, in the absence of culture and susceptibility test results, use:
ciprofloxacin 500 mg orally, 120 minutes before the procedure.
Randomised controlled trials have not shown that multiple-dose prophylaxis is superior to single-dose prophylaxis.
However, repeat doses are required in limited circumstances (see here).
Some centres use a higher dose of ciprofloxacin (750 mg or 1 g), but clinical studies have not compared this
approach to the standard regimen.
Ciprofloxacin-resistant Enterobacteriaceae
In some studies, prebiopsy screening for ciprofloxacin-resistant Enterobacteriaceae (with faecal samples or rectal
swabs), with prophylaxis guided by the results of susceptibility testing, reduced the incidence of infective
complications, as well as the overall cost of care. Consider this approach, particularly for patients at high risk of
carriage of ciprofloxacin-resistant Enterobacteriaceae (eg quinolone therapy within the preceding 3 months, risk
factors for infection with a multidrug-resistant Gram-negative bacterium [see Box 2.30]).
There is currently little consensus on the most effective prophylaxis for patients who are colonised with
ciprofloxacin-resistant Enterobacteriaceae. Ciprofloxacin-resistant strains may also be resistant to gentamicin,
trimethoprim+sulfamethoxazole and ceftriaxone. Fosfomycin may be an option for prophylaxis for transrectal
prostate biopsy in patients colonised with ciprofloxacin-resistant Enterobacteriaceae—seek expert advice.
If screening is not possible, seek expert advice for alternative prophylactic antibiotic regimens for patients at high
risk.
A transperineal biopsy may be an alternative diagnostic approach in high-risk patients.
Nonantibiotic measures
Due to insufficient data, a recommendation cannot currently be made about the practice of adjunctive intrarectal
disinfection (eg with povidone-iodine).
The efficacy of disinfecting the biopsy needle with formalin or alcohol between multiple biopsy passes in an
individual patient is uncertain.
Transperineal prostate biopsy

general principles of surgical antibiotic prophylaxis for urological surgery. Surgical prophylaxis is recommended
for transperineal prostate biopsy despite limited data to support its use.
Patients undergoing transperineal prostate biopsy should be screened for bacteriuria preoperatively (see Screening
for preoperative bacteriuria). For patients treated for bacteriuria preoperatively, modify the choice of surgical
antibiotic prophylaxis based on the results of culture and susceptibility testing.
For prophylaxis for transperineal prostate biopsy, in the absence of culture and susceptibility test results, use:
cefazolin 2 g intravenously, within the 60 minutes before the procedure; intraoperative

completed.
gentamicin 2 mg/kg intravenously over 3 to 5 minutes, within the 120 minutes before the
procedure [Note 46]; intraoperative redosing is unlikely to be required (see here). Do not
give additional doses once the procedure is completed
PLUS EITHER
1 vancomycin 15 mg/kg intravenously, started within the 120 minutes before the procedure
(recommended rate 10 mg/minute) [Note 47]; intraoperative redosing may be required
(see here). Do not give additional doses once the procedure is completed
OR
2 clindamycin 600 mg intravenously, within the 120 minutes before the procedure;
Note 47: It is the consensus view of the Antibiotic Expert Groups that the vancomycin infusion should be
started at least 15 minutes before the procedure to ensure adequate blood and tissue concentrations at the time of
Open or laparoscopic urological procedures

general principles of surgical antibiotic prophylaxis for urological surgery. See Table 2.39 for the indications for
surgical prophylaxis for open or laparoscopic urological procedures.
Patients undergoing open or laparoscopic urological procedures should be screened for bacteriuria preoperatively
(see Screening for preoperative bacteriuria). For patients treated for bacteriuria preoperatively, modify the choice
of surgical antibiotic prophylaxis based on the results of culture and susceptibility testing.
The choice of prophylaxis for open or laparoscopic urological procedures depends on whether the bowel lumen is
entered.
If prophylaxis is indicated for an open or laparoscopic urological procedure in which entry into the bowel lumen
is not expected, use:

PLUS
If gentamicin is contraindicated (see Box 2.42), seek expert advice for choice of prophylaxis.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins who are undergoing
procedures in which entry into the bowel lumen is not expected, use cefazolin plus gentamicin as above. See also
Surgical antibiotic prophylaxis for patients with a penicillin or cephalosporin allergy.
For patients with immediate severe or delayed severe hypersensitivity to penicillins who are undergoing
procedures in which entry into the bowel lumen is not expected, use:
PLUS EITHER
completed
OR
In cases of inadvertent rectal injury, administer an immediate dose of metronidazole. Add to the above regimens:
metronidazole 500 mg (child: 12.5 mg/kg up to 500 mg) intravenously, as a single dose.
For prophylaxis for open or laparoscopic urological procedures in which entry into the bowel lumen is expected
(eg ileal conduit, rectocele repair), use:

PLUS

are suitable.
PLUS
Note 49: It is the consensus view of the Antibiotic Expert Groups that the vancomycin infusion should be
started at least 15 minutes before the procedure to ensure adequate blood and tissue concentrations at the time of
Postoperative considerations
Strict maintenance of closed-catheter drainage and early catheter removal reduces the incidence of urinary tract
infection in patients with a temporary indwelling catheter. Do not extend the duration of antibiotic prophylaxis
because the patient has a urinary catheter in situ—this practice is not supported by evidence and may cause
adverse effects, including subsequent infection with resistant pathogens and Clostridium difficile.
At the time of writing, there are inadequate data to recommend postoperative oral antibiotic prophylaxis to prevent
pyelonephritis after cystectomy with ileal conduit or neobladder.
Surgical prophylaxis for vascular surgery

2.40 for the recommendations for surgical prophylaxis for vascular surgery [Note 50].
For elective implantation of prosthetic material, consider Staphylococcus aureus screening (for both methicillin-
susceptible and methicillin-resistant strains). If the results of screening are positive, perform decolonisation.
If the patient is already receiving antibiotic treatment for an established infection, it is not necessary to give
additional antibiotic prophylaxis provided the treatment regimen has activity against the organism(s) most likely to
cause postoperative infection; if an ischaemic limb is being amputated, this should include anaerobes. However,
adjust the timing of the treatment dose to achieve adequate plasma and tissue concentrations at the time of surgical
incision and for the duration of the procedure.
Vascular surgery procedures and their requirement for surgical antibiotic prophylaxis (Table
2.40)

varicose vein procedures
brachial or carotid artery procedures not involving NO

insertion of prosthetic material
vascular reconstructive surgery involving the abdominal
YES
aorta or lower limbs
YES; however, if the patient is being treated with
limb amputation antibiotic therapy for an infected limb, additional
antibiotic prophylaxis may not be required (see above)
If prophylaxis is indicated for vascular surgery, use:

PLUS for amputation of an ischaemic limb
colonised or infected with MRSA (eg patients undergoing a vascular procedure that is a reoperation [return to
theatre or early revision]; see also Box 2.31), add vancomycin to the above regimen:
completed.
completed
PLUS
minutes before surgical incision [Note 52] [Note 53]; intraoperative redosing is unlikely to
be required (see here). Do not give additional doses once the procedure is completed
PLUS for amputation of an ischaemic limb
A single preoperative dose of surgical antibiotic prophylaxis (with or without intraoperative doses) is sufficient to
prevent postoperative infection. Although a single randomised controlled trial [Note 54] demonstrated a benefit
when surgical prophylaxis for vascular surgery was continued until all lines were removed, the World Health
Organization concluded that postoperative doses were not warranted because of the low quality of the study and
the significant evidence to suggest that postoperative doses are not required for the significant majority of
procedures. Extended prophylaxis is associated with an increased risk of adverse effects, including subsequent
infection with resistant pathogens or Clostridium difficile. Postoperative doses are not recommended.
Note 50: The safety and efficacy of intraoperative irrigation with antimicrobial solutions, or soaking surgical
implants (eg vascular grafts, mesh) with antimicrobial solutions before insertion, has not been established. There
is concern about the development of resistance; in particular, rifampicin should not be used as a single drug.
There is also potential for adverse effects. Consequently, these practices cannot be recommended.
at least 15 minutes before the procedure to ensure adequate blood and tissue concentrations at the time of
Note 52: If there is at least a moderate likelihood that the procedure will continue for longer than 6 hours,
consider using a 5 mg/kg gentamicin dose.
Note 54: Hall JC, Christiansen KJ, Goodman M, Lawrence-Brown M, Prendergast FJ, Rosenberg P, et al.
Duration of antimicrobial prophylaxis in vascular surgery. Am J Surg 1998;175(2):87-90. [URL]
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Surgical prophylaxis for orthopaedic surgery
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Berrios-Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, et al. Centers for Disease Control and
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Lamb MJ, Baillie L, Pajak D, Flynn J, Bansal V, Simor A, et al. Elimination of screening urine cultures prior to elective
joint arthroplasty. Clin Infect Dis 2017;64(6):806–9.
Perez-Prieto D, Portillo ME, Puig-Verdie L, Alier A, Gamba C, Guirro P, et al. Preoperative antibiotic prophylaxis in
prosthetic joint infections: not a concern for intraoperative cultures. Diagn Microbiol Infect Dis 2016;86(4):442–5.
Tetreault MW, Wetters NG, Aggarwal V, Mont M, Parvizi J, Della Valle CJ. The Chitranjan Ranawat Award: Should
prophylactic antibiotics be withheld before revision surgery to obtain appropriate cultures? Clin Orthop Relat Res
2014;472(1):52–6.
Voigt J, Mosier M, Darouiche R. Systematic review and meta-analysis of randomized controlled trials of antibiotics and
antiseptics for preventing infection in people receiving primary total hip and knee prostheses. Antimicrob Agents
Chemother 2015;59(11):6696–6707 .
Voigt J, Mosier M, Darouiche R. Antibiotics and antiseptics for preventing infection in people receiving revision total hip
and knee prostheses: a systematic review of randomized controlled trials. BMC Infect Dis 2016;16(1):749. .
Surgical prophylaxis for skin and soft tissue surgery
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Beeson WH, Rachel JD. Valacyclovir prophylaxis for herpes simplex virus infection or infection recurrence following
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Heal CF, Buettner PG, Drobetz H. Risk factors for surgical site infection after dermatological surgery. Int J Dermatol
2012;51(7):796–803 .
Kulichová D, Geimer T, Mühlstädt M, Ruzicka T, Kunte C. Surgical site infections in skin surgery: a single center
experience. J Dermatol 2013;40(10):779–785 .
Stankiewicz M, Coyer F, Webster J, Osborne S. Incidence and predictors of lower limb split-skin graft failure and
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Wall SH, Ramey SJ, Wall F. Famciclovir as antiviral prophylaxis in laser resurfacing procedures. Plast Reconstr Surg
1999;104(4):1103–8; discussion 9.
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Ghobrial GM, Cadotte DW, Williams K, Jr., Fehlings MG, Harrop JS. Complications from the use of intrawound
vancomycin in lumbar spinal surgery: a systematic review. Neurosurg Focus 2015;39(4):E11.
Lopez M, Molina M. Should we add vancomycin antibiotic powder to prevent post operative infection in spine surgery?
- First update. Medwave 2015;15:e6202.
Surgical prophylaxis for thoracic surgery
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perspective. Lancet Infect Dis 2016;16(12):e288–e303 .
Oxman DA, Issa NC, Marty FM, Patel A, Panizales CZ, Johnson NN, et al. Postoperative antibacterial prophylaxis for
the prevention of infectious complications associated with tube thoracostomy in patients undergoing elective general
thoracic surgery: a double-blind, placebo-controlled, randomized trial. JAMA Surg 2013;148(5):440–446 .
Surgical prophylaxis for urological surgery
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Carey MM, Zreik A, Fenn NJ, Chlosta PL, Aboumarzouk OM. Should we use antibiotic prophylaxis for flexible
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Cussans A, Somani BK, Basarab A, Dudderidge TJ. The role of targeted prophylactic antimicrobial therapy before
transrectal ultrasonography-guided prostate biopsy in reducing infection rates: a systematic review. BJU Int
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Heidari Bateni Z, Shahrokh H, Salimi H, Safari H, Tabatabai M, Saedi D. Single-dose versus multiple-dose ciprofloxacin
plus metronidazole prophylaxis in transrectal ultrasound-guided biopsy of the prostate: a randomized controlled trial.
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needle biopsy. Urol J 2016;13(1):2533–2540 .
Qiao LD, Chen S, Wang XF, Yang WM, Niu YJ, Kong CZ, et al. A multi-center, controlled, randomized, open-label
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Rhodes NJ, Gardiner BJ, Neely MN, Grayson ML, Ellis AG, Lawrentschuk N, et al. Optimal timing of oral fosfomycin
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Samarinas M, Dimitropoulos K, Zachos I, Gravas S, Karatzas A, Tzortzis V. A single dose of meropenem is superior to
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Wolf JS, Jr., Bennett CJ, Dmochowski RR, Hollenbeck BK, Pearle MS, Schaeffer AJ, et al. Best practice policy
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Surgical prophylaxis for vascular surgery
intraoperative and postoperative measures for surgical site infection prevention: an evidence-based global
perspective. Lancet Infect Dis 2016;16(12):e288–e303 .
Hall JC, Christiansen KJ, Goodman M, Lawrence-Brown M, Prendergast FJ, Rosenberg P, Mills B, Hall JL. Duration of
antimicrobial prophylaxis in vascular surgery. Am J Surg 1998;175(2):87–90.10.1016/S0002-9610(97)00270-
5.9515521 .
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blinded trial comparing 2 anti-MRSA agents with supplemental coverage of cefazolin before lower extremity
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Prevention of infective endocarditis
Rationale for endocarditis prophylaxis
Infective endocarditis is a relatively uncommon illness with high morbidity and mortality. The incidence in
Australia is approximately five cases per 100 000 person–years, and the in-hospital mortality is 15 to 20%.
For many years, antibiotic prophylaxis was routinely given before dental and other procedures to patients with
cardiac conditions that have a high lifetime risk of infective endocarditis. However, endocarditis after these
procedures is rare, so prophylaxis prevents very few cases.
Endocarditis-related bacteraemia is more likely to result from daily oral hygiene activities than from specific
procedures, and is strongly associated with poor oral hygiene and gingival disease. Therefore, the maintenance of
good oral health and hygiene is more important than the use of antibiotic prophylaxis. Oral hygiene is important
for the general population but particularly for patients with a cardiac condition listed in Box 2.12; see General
measures to prevent infective endocarditis.
Endocarditis can occur after hospitalisation, especially in older, sicker patients with diabetes or chronic kidney
disease. This does not appear to be a sequel to a particular procedure but rather to problems such as intravascular
catheter infections. This emphasises the need for infection prevention and control strategies in hospitals.
No randomised controlled trial has been performed to determine the role of antibiotic prophylaxis, and there are no
human studies showing that it can prevent infective endocarditis. Consequently, guidelines rely on expert
consensus. Since 2002, many international guidelines [Note 1] have significantly reduced the number of
indications for endocarditis prophylaxis. The National Institute for Health and Care Excellence (NICE) in the
United Kingdom (UK) went even further in 2008, recommending that antibiotic prophylaxis was not required for
any person before dental or other procedures.
Studies examining the impact of the changes in guidelines have yielded conflicting results. Some studies indicate
the incidence of infective endocarditis has not increased with restricted or no prophylaxis, but other studies suggest
that infective endocarditis cases have increased after the adoption of new guidelines. In response to these data,
NICE modified their recommendations in 2016 to state that endocarditis prophylaxis is not ‘routinely’ required.
This update allows for clinical judgment to decide if endocarditis prophylaxis is required.
In the absence of high-quality evidence, the Antibiotic Expert Groups continue to recommend antibiotic
prophylaxis against infective endocarditis for a restricted group of patients—see Indications for endocarditis
prophylaxis below.
Note 1: International guidelines on the prevention of infective endocarditis are listed in Further reading.
Indications for endocarditis prophylaxis

Antibiotic prophylaxis against infective endocarditis is recommended only for patients who meet both of the
following criteria:
have a cardiac condition associated with an increased risk of developing infective endocarditis and the
highest risk of adverse outcomes from endocarditis (see Box 2.12)
are undergoing a procedure associated with a high risk of a bacteraemia that is associated with endocarditis
(see Box 2.13).
A printable version of Box 2.12 and Box 2.13 is available here.
Endocarditis prophylaxis is not recommended for situations other than those covered in this topic.
Cardiac conditions for which endocarditis prophylaxis is recommended for patients
undergoing a procedure listed in Box 2.13 (Box 2.12)
Endocarditis prophylaxis is recommended only for patients with the following cardiac conditions (that are
associated with an increased risk of developing infective endocarditis and the highest risk of adverse
outcomes from endocarditis) who are undergoing a procedure listed in Box 2.13 [NB1] [NB2]:
prosthetic cardiac valve, including transcatheter-implanted prosthesis or homograft

prosthetic material used for cardiac valve repair, such as annuloplasty rings and chords
previous infective endocarditis
congenital heart disease but only if it involves:
unrepaired cyanotic defects, including palliative shunts and conduits
repaired defects with residual defects at or adjacent to the site of a prosthetic patch or device (which
inhibit endothelialisation)
rheumatic heart disease in high-risk patients [NB3].
NB1: Endocarditis prophylaxis is not recommended for patients with forms of valvular or structural heart disease not listed in this box, including
patients with mitral valve prolapse, septal defects or cardiac implantable electronic devices.
NB2: Patients with a heart transplant who have developed cardiac valvulopathy may also be at high risk of adverse outcomes from endocarditis;
consult the patient’s cardiologist for specific recommendations.
NB3: See text below for discussion of patients with rheumatic heart disease.
Procedures for which endocarditis prophylaxis is recommended for patients with a cardiac
condition listed in Box 2.12 (Box 2.13) [NB1]
Endocarditis prophylaxis is recommended only for patients with a cardiac condition listed in Box 2.12 who
are undergoing one of the following procedures associated with a high risk of a bacteraemia that is
associated with infective endocarditis:
Dental procedures—only those involving manipulation of the gingival or periapical tissue or perforation
of the oral mucosa (eg extraction, implant placement, biopsy, removal of soft tissue or bone, subgingival
scaling and root planing, replanting avulsed teeth).
Dermatological or musculoskeletal procedures—only those involving infected skin, skin structures or
musculoskeletal tissues.
Respiratory tract or ear, nose and throat procedures—only for tonsillectomy or adenoidectomy, or
invasive respiratory tract or ear, nose and throat procedures to treat an established infection (eg drainage of
abscess).
Genitourinary and gastrointestinal tract procedures—only if surgical antibiotic prophylaxis is required
or for patients with an established infection.
NB1: Endocarditis prophylaxis is not recommended for procedures other than those covered in this topic. However, surgical prophylaxis may be
indicated even if endocarditis prophylaxis is not—see Surgical antibiotic prophylaxis for specific procedures.
It is thought that Aboriginal and Torres Strait Islander people with rheumatic heart disease are at higher risk of
developing infective endocarditis and adverse outcomes from the disease. However, it has been argued that the
higher risk, and poorer outcomes, are associated with socioeconomic disadvantage rather than ethnicity. New
Zealand guidelines recommend prophylaxis for all patients with rheumatic heart disease, specifically including
Maori and Pacific Islander people. It is the consensus view of the Antibiotic Expert Groups that antibiotic
prophylaxis should be administered to all Aboriginal and Torres Strait Islander people with rheumatic heart disease
who are undergoing certain procedures (see Box 2.13). Other patients with rheumatic heart disease who are at
significant socioeconomic disadvantage should also be considered for antibiotic prophylaxis.
General measures to prevent infective endocarditis

Data to support antibiotic prophylaxis are limited, and many cases of infective endocarditis are not preceded by a
procedure. Therefore, general preventive strategies and early recognition and treatment of infective endocarditis
are important.
All people, but particularly those with cardiac abnormalities, should practise good oral hygiene and have regular
dental check-ups, with preventive dental and periodontal treatment to ensure optimal oral health.
For people with a cardiac condition listed in Box 2.12 or any form of native valve disease, the following
preventive strategies are recommended:
twice-yearly dental examination and scaling
timely treatment of all bacterial infections, particularly those caused by Staphylococcus aureus or
streptococci
avoidance of intravascular catheters and invasive procedures, unless necessary
strict adherence to protocols for managing central and peripheral intravenous devices (eg ‘care bundles’)
active discouragement of tattooing, piercing (particularly tongue piercing) and intravenous drug use.
Investigate an unexplained fever in patients with a cardiac condition listed in Box 2.12, because it could be a sign
of infective endocarditis—see Assessment of infective endocarditis. Blood samples should be taken for culture
before the administration of antibiotics.
Endocarditis prophylaxis for dental procedures

Approach to endocarditis prophylaxis for dental procedures
Bacteraemia associated with dental procedures usually involves viridans group streptococci, which are known to
cause infective endocarditis. Traditionally, the presence of ‘significant bleeding’ associated with a dental procedure
was assumed to be an indication of bacteraemia and hence a need for prophylaxis; however, studies show that
bleeding is a poor indicator of bacteraemia from dental procedures.
Self-performed oral hygiene (eg toothbrushing, flossing, use of oral irrigators) can produce a similar incidence of
bacteraemia to that caused by most dental procedures (excluding extractions). As these activities are performed
more frequently than dental procedures, they have the potential to produce regular episodes of bacteraemia.
Bacteraemia from self-performed oral hygiene is strongly associated with poor oral hygiene and gingival disease;
therefore, the maintenance of good oral health and hygiene is likely to be more important than the use of antibiotic
prophylaxis—see General measures to prevent infective endocarditis. Dental procedures are generally of longer
duration than self-performed oral hygiene, so expose patients to a longer duration of bacteraemia. Antibiotic
prophylaxis is therefore warranted for some dental procedures for high-risk patients.
Endocarditis prophylaxis is recommended only for patients with a cardiac condition listed in Box 2.12 who are
undergoing procedures involving manipulation of the gingival or periapical tissue or perforation of the oral mucosa
(eg extraction, implant placement, biopsy, removal of soft tissue or bone, subgingival scaling and root planing,
replanting avulsed teeth).
Other dental procedures do not require endocarditis prophylaxis. Surgical antibiotic prophylaxis may be indicated
even if endocarditis prophylaxis is not—see Surgical prophylaxis for oral maxillofacial surgery.
Endocarditis prophylaxis regimens for dental procedures
Antibiotic prophylaxis regimens
If, after careful evaluation of both the cardiac condition (see Box 2.12) and the dental procedure (see Box 2.13),
antibiotic prophylaxis is considered necessary, give a single dose of antibiotic before the procedure. There is no
proven value to giving a dose after the procedure.
If a patient is having more than one procedure requiring antibiotic prophylaxis, the dentist should plan the
treatment so that all procedures can be completed in a single sitting, or at most two sittings, to avoid the need for
multiple antibiotic doses.
For endocarditis prophylaxis, use:
amoxicillin 2 g (child: 50 mg/kg up to 2 g) orally, 60 minutes before the procedure.
If oral administration is not possible, use:
1 amoxicillin 2 g (child: 50 mg/kg up to 2 g) intramuscularly, 30 minutes before the

procedure
OR
1 amoxicillin 2 g (child: 50 mg/kg up to 2 g) intravenously, within the 60 minutes before the

procedure
OR
1 ampicillin 2 g (child: 50 mg/kg up to 2 g) intramuscularly, 30 minutes before the

procedure
OR
1 ampicillin 2 g (child: 50 mg/kg up to 2 g) intravenously, within the 60 minutes before the

procedure.
Use:
cefalexin 2 g (child: 50 mg/kg up to 2 g) orally, 60 minutes before the procedure.
1 cefazolin 2 g (child: 30 mg/kg up to 2 g) intramuscularly, 30 minutes before the procedure
OR
1 cefazolin 2 g (child: 30 mg/kg up to 2 g) intravenously, within the 60 minutes before the

procedure.
For patients with immediate (severe or nonsevere) or delayed severe hypersensitivity to penicillins, use:
clindamycin 600 mg (child: 20 mg/kg up to 600 mg) orally, 60 to 120 minutes before the
procedure [Note 3].
There is some evidence that moxifloxacin may be used as an alternative to clindamycin for patients with
immediate (severe or nonsevere) or delayed severe hypersensitivity to penicillins, but this has not been validated.
Note 3: An oral liquid formulation of clindamycin is not commercially available; for formulation options for
Considerations for patients recently or currently taking beta lactams
In patients taking long-term benzathine benzylpenicillin for prevention of recurrent rheumatic fever, evidence
suggests that the amoxicillin susceptibility of viridans streptococci in the oral flora is not significantly affected by
the benzathine benzylpenicillin prophylaxis. The consensus view of the Antibiotic Expert Groups is that
amoxicillin is appropriate for endocarditis prophylaxis in this setting.
In contrast, in patients currently taking or who have recently taken a course of beta-lactam therapy (except for the
situation described above), evidence suggests that the amoxicillin susceptibility of viridans streptococci may be
affected. Therefore, a non–beta-lactam antibiotic, such as clindamycin, may be considered for prophylaxis in this
setting.
Endocarditis prophylaxis for dermatological or musculoskeletal

procedures
For patients with a cardiac condition listed in Box 2.12 who are undergoing a surgical procedure involving infected
skin, skin structures or musculoskeletal tissues, it is reasonable to include an antibiotic active against staphylococci
and beta-haemolytic streptococci in the empirical antibiotic treatment regimen (eg an antistaphylococcal penicillin
or a cephalosporin). Adjust the timing of therapy so that an oral dose is administered 60 minutes before the
procedure, an intramuscular dose 30 minutes before the procedure, or an intravenous dose within the 60 minutes
Other dermatological or musculoskeletal procedures do not require endocarditis prophylaxis. However, surgical
antibiotic prophylaxis may be indicated even if endocarditis prophylaxis is not—see Surgical
antibiotic prophylaxis for specific procedures.
Endocarditis prophylaxis for respiratory tract or ear, nose and throat

procedures
Bacteraemia associated with respiratory tract or ear, nose and throat procedures predominantly involves viridans
group streptococci, which are known to cause infective endocarditis. Endocarditis prophylaxis is only
recommended for patients with a cardiac condition listed in Box 2.12 who are undergoing:
a tonsillectomy or adenoidectomy [Note 4]—use the regimen in Endocarditis prophylaxis regimens for
dental procedures, or
an invasive respiratory tract or ear, nose and throat procedure to treat an established infection (eg drainage of
abscess). Empirical antibiotic treatment should include a drug active against viridans group streptococci. If
the infection is suspected or known to be caused by Staphylococcus aureus, also ensure the treatment is
active against S. aureus. Adjust the timing of therapy so that an oral dose is administered 60 minutes before
the procedure, an intramuscular dose 30 minutes before the procedure, or an intravenous dose within the 60
minutes before the procedure.
Other respiratory tract or ear, nose and throat procedures do not require endocarditis prophylaxis. However,
surgical antibiotic prophylaxis may be indicated even if endocarditis prophylaxis is not—see Surgical antibiotic
prophylaxis for specific procedures.
Note 4: Endocarditis prophylaxis is not recommended for tonsillectomy or adenoidectomy in the European
Society of Cardiology endocarditis guideline, but literature suggests that there is a high risk of bacteraemia
following both elective and nonelective tonsillectomy.
Endocarditis prophylaxis for genitourinary and gastrointestinal tract

procedures
Bacteraemia associated with genitourinary and gastrointestinal tract procedures predominantly involves
enterococci, which are known to cause infective endocarditis. However, antibiotic prophylaxis solely to prevent
endocarditis is not routinely recommended for patients undergoing genitourinary or gastrointestinal tract
procedures.
It is reasonable to include a drug with activity against enterococci (eg ampicillin, amoxicillin) [Note 5] in the
antibiotic regimen for patients with a cardiac condition listed in Box 2.12, who are undergoing a genitourinary or
gastrointestinal tract procedure if:
surgical antibiotic prophylaxis is required (see Surgical antibiotic prophylaxis for specific procedures), or
an established genitourinary or gastrointestinal infection is present.
If the regimen for the treatment of an established infection contains an antibiotic with activity against enterococci,
adjust timing of the antienterococcal antibiotic so that an oral dose is administered 60 minutes before the
procedure, an intramuscular dose 30 minutes before the procedure, or an intravenous dose within the 60 minutes
before the procedure (or for vancomycin, see below).
If the treatment or surgical prophylaxis regimen does not include an antibiotic active against enterococci [Note 5],
add:
1 amoxicillin 2 g (child: 50 mg/kg up to 2 g) intramuscularly, 30 minutes before the

procedure
OR
1 amoxicillin 2 g (child: 50 mg/kg up to 2 g) intravenously, within the 60 minutes before the

procedure
OR
1 ampicillin 2 g (child: 50 mg/kg up to 2 g) intramuscularly, 30 minutes before the

procedure
OR
1 ampicillin 2 g (child: 50 mg/kg up to 2 g) intravenously, within the 60 minutes before the
procedure.
1 vancomycin (adult and child) 15 mg/kg intravenously, started within the 15 to 120
minutes before the procedure (recommended rate 10 mg/minute)
OR
2 teicoplanin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, within the 60 minutes
For patients colonised or infected with vancomycin-resistant enterococci, seek expert advice about an appropriate
antibiotic regimen.
Note 5: Cephalosporins are generally ineffective against enterococci.
Further reading
International guidelines on the prevention of infective endocarditis
American Heart Association. Prevention of infective endocarditis guidelines (2007) [URL]
American College of Cardiology/American Heart Association. Focused Update of the 2014 AHA/ACC Guideline
for the Management of Patients With Valvular Heart Disease (2017) [URL]
British Society for Antimicrobial Chemotherapy. Guidelines for the prevention of endocarditis (2006) [URL]
European Society of Cardiology. Guidelines for the management of infective endocarditis (2015) [URL]
National Heart Foundation of New Zealand. Guideline for prevention of infective endocarditis associated with
dental and other medical interventions (2008) [URL]
National Institute for Health and Care Excellence (NICE). Prophylaxis against infective endocarditis (2008
[updated July 2016]) [URL]
Key references
Rationale for endocarditis prophylaxis
Bates KE, Hall M, Shah SS, Hill KD, Pasquali SK. Trends in infective endocarditis hospitalisations at United States
children's hospitals from 2003 to 2014: impact of the 2007 American Heart Association antibiotic prophylaxis
guidelines. Cardiol Young 2017;27(4):686–90.
Cahill TJ, Harrison JL, Jewell P, Onakpoya I, Chambers JB, Dayer M, et al. Antibiotic prophylaxis for infective
endocarditis: a systematic review and meta-analysis. Heart 2017;103(12):937–44.
Chambers JB, Thornhill M, Shanson D, Prendergast B. Antibiotic prophylaxis of endocarditis: a NICE mess. Lancet
Infect Dis 2016;16(3):275–6.
Dayer MJ, Jones S, Prendergast B, Baddour LM, Lockhart PB, Thornhill MH. Incidence of infective endocarditis in
England, 2000-13: a secular trend, interrupted time-series analysis. Lancet 2015;385(9974):1219–28.
DeSimone DC, Tleyjeh IM, Correa de Sa DD, Anavekar NS, Lahr BD, Sohail MR, et al. Incidence of infective
endocarditis due to viridans group streptococci before and after the 2007 American Heart Association's prevention
guidelines: an extended evaluation of the Olmsted County, Minnesota, population and Nationwide Inpatient Sample.
Mayo Clin Proc 2015;90(7):874–81.
Duval X, Millot S, Chirouze C, Selton-Suty C, Moby V, Tattevin P, et al. Oral streptococcal endocarditis, oral hygiene
habits, and recent dental procedures: A case-control study. Clin Infect Dis 2017;64(12):1678–85.
Glenny AM, Oliver R, Roberts GJ, Hooper L, Worthington HV. Antibiotics for the prophylaxis of bacterial endocarditis in
dentistry. Cochrane Database Syst Rev 2013;(10):CD003813.
Keller K, von Bardeleben RS, Ostad MA, Hobohm L, Munzel T, Konstantinides S, et al. Temporal trends in the
prevalence of infective endocarditis in Germany between 2005 and 2014. Am J Cardiol 2017;119(2):317–22.
Khan O, Shafi AM, Timmis A. International guideline changes and the incidence of infective endocarditis: a systematic
review. Open Heart 2016;3(2):e000498.
Lockhart PB, Brennan MT, Thornhill M, Michalowicz BS, Noll J, Bahrani-Mougeot FK, et al. Poor oral hygiene as a risk
factor for infective endocarditis-related bacteremia. J Am Dent Assoc 2009;140(10):1238–44.
Mackie AS, Liu W, Savu A, Marelli AJ, Kaul P. Infective endocarditis hospitalizations before and after the 2007
American Heart Association prophylaxis guidelines. Can J Cardiol 2016;32(8):942–8.
National Institute for Health and Care Excellence (NICE). Prophylaxis against infective endocarditis: antimicrobial
prophylaxis against infective endocarditis in adults and children undergoing interventional procedures [CG64]. London:
NICE; 2008 [updated July 2016]. https://www.nice.org.uk/guidance/CG64
Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, 3rd, Fleisher LA, et al. 2017 AHA/ACC Focused Update
of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: A report of the American
College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol
2017;70(2):252–89.
Pant S, Patel NJ, Deshmukh A, Golwala H, Patel N, Badheka A, et al. Trends in infective endocarditis incidence,
microbiology, and valve replacement in the United States from 2000 to 2011. J Am Coll Cardiol 2015;65(19):2070–6.
Sakai Bizmark R, Chang RR, Tsugawa Y, Zangwill KM, Kawachi I. Impact of AHA's 2007 guideline change on
incidence of infective endocarditis in infants and children. Am Heart J 2017;189:110–9.
Tomas I, Diz P, Tobias A, Scully C, Donos N. Periodontal health status and bacteraemia from daily oral activities:
systematic review/meta-analysis. J Clin Periodontol 2012;39(3):213–28.
Toyoda N, Chikwe J, Itagaki S, Gelijns AC, Adams DH, Egorova NN. Trends in infective endocarditis in California and
New York State, 1998-2013. JAMA 2017;317(16):1652–60.
van den Brink FS, Swaans MJ, Hoogendijk MG, Alipour A, Kelder JC, Jaarsma W, et al. Increased incidence of
infective endocarditis after the 2009 European Society of Cardiology guideline update: a nationwide study in the
Netherlands. Eur Heart J Qual Care Clin Outcomes 2017;3(2):141–7.
Research Interdisciplinary Working Group. Circulation 2007;116(15):1736–54.
Indications for endocarditis prophylaxis
Chen SJ, Liu CJ, Chao TF, Wang KL, Wang FD, Chen TJ, et al. Dental scaling and risk reduction in infective
endocarditis: a nationwide population-based case-control study. Can J Cardiol 2013;29(4):429–33.
Franklin M, Wailoo A, Dayer MJ, Jones S, Prendergast B, Baddour LM, et al. The cost-effectiveness of antibiotic
prophylaxis for patients at risk of infective endocarditis. Circulation 2016;134(20):1568–78.
Janszky I, Gemes K, Ahnve S, Asgeirsson H, Moller J. Invasive procedures associated with the development of
infective endocarditis. J Am Coll Cardiol 2018;71(24):2744–52.
Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, 3rd, Fleisher LA, et al. 2017 AHA/ACC Focused Update
of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: A report of the American
College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol
2017;70(2):252–89.
Ostergaard L, Valeur N, Ihlemann N, Bundgaard H, Gislason G, Torp-Pedersen C, et al. Incidence of infective

endocarditis among patients considered at high risk. Eur Heart J 2018;39(7):623–9.
Thornhill MH, Dayer MJ, Cahill TJ. Infective endocarditis after invasive medical and surgical procedures. J Am Coll
Cardiol 2018;71(24):2753–5.
Thornhill MH, Dayer MJ, Prendergast B, Baddour LM, Jones S, Lockhart PB. Incidence and nature of adverse
reactions to antibiotics used as endocarditis prophylaxis. J Antimicrob Chemother 2015;70(8):2382–8.
Thornhill MH, Jones S, Prendergast B, Baddour LM, Chambers JB, Lockhart PB, et al. Quantifying infective
endocarditis risk in patients with predisposing cardiac conditions. Eur Heart J 2018;39(7):586–95.
General measures to prevent endocarditis
Chen SJ, Liu CJ, Chao TF, Wang KL, Wang FD, Chen TJ, et al. Dental scaling and risk reduction in infective
endocarditis: a nationwide population-based case-control study. Can J Cardiol 2013;29(4):429–33.
Dieckmann R, Boone I, O. Brockmann S, A. Hammerl J, Kolb-Mäurer A, Goebeler M, et al. The risk of bacterial
infection after tattooing: A systematic review of the literature. Deutsches Ärzteblatt International 2016;113(40):665–71.
Duval X, Leport C. Prophylaxis of infective endocarditis: current tendencies, continuing controversies. Lancet Infect
Dis 2008;8(4):225–32.
Juhas E, English JC, 3rd. Tattoo-associated complications. J Pediatr Adolesc Gynecol 2013;26(2):125–9.
Kluger N. Bacterial endocarditis and body art: suggestions for an active prevention. Int J Cardiol 2009;136(1):112–3.
Stirn A. Body piercing: medical consequences and psychological motivations. Lancet 2003;361(9364):1205–15.
Yu CH, Minnema BJ, Gold WL. Bacterial infections complicating tongue piercing. Can J Infect Dis Med Microbiol
2010;21(1):e70–e74.
Endocarditis prophylaxis for dental procedures
DeSimone DC, Tleyjeh IM, Correa de Sa DD, Anavekar NS, Lahr BD, Sohail MR, et al. Incidence of infective
endocarditis due to viridans group streptococci before and after the 2007 American Heart Association's prevention
guidelines: an extended evaluation of the Olmsted County, Minnesota, population and Nationwide Inpatient Sample.
Mayo Clin Proc 2015;90(7):874–81.
Lockhart PB, Brennan MT, Thornhill M, Michalowicz BS, Noll J, Bahrani-Mougeot FK, et al. Poor oral hygiene as a risk
factor for infective endocarditis-related bacteremia. J Am Dent Assoc 2009;140(10):1238–44.
Porter MC, Henderson BA, Healy PE, Coombs GW, Ingram PR, McLellan D, et al. Can interchangeability of
lincosamides be assumed in clinical practice? Comparative MICs of clindamycin and lincomycin for Streptococcus
pyogenes, Streptococcus agalactiae and Staphylococcus aureus. J Antimicrob Chemother 2014;69(3):856–7.
Tubiana S, Blotiere PO, Hoen B, Lesclous P, Millot S, Rudant J, et al. Dental procedures, antibiotic prophylaxis, and
endocarditis among people with prosthetic heart valves: nationwide population based cohort and a case crossover
study. BMJ 2017;358:j3776.
Endocarditis prophylaxis for dermatological or musculoskeletal procedures
Endocarditis prophylaxis for respiratory tract or ear, nose and throat procedures
Klug TE, Henriksen JJ, Rusan M, Fuursted K, Ovesen T. Bacteremia during quinsy and elective tonsillectomy: an
evaluation of antibiotic prophylaxis recommendations for patients undergoing tonsillectomy. J Cardiovasc Pharmacol
Ther 2012;17(3):298–302.
Endocarditis prophylaxis for genitourinary and gastrointestinal tract procedures
ASGE Standards of Practice Committee, Khashab MA, Chithadi KV, Acosta RD, Bruining DH, Chandrasekhara V, et
al. Antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc 2015;81(1):81–9.
Mohee AR, Gascoyne-Binzi D, West R, Bhattarai S, Eardley I, Sandoe JA. Bacteraemia during transurethral resection
of the prostate: What are the risk factors and is it more common than we think? PLoS One 2016;11(7):e0157864.
Mohee AR, West R, Baig W, Eardley I, Sandoe JA. A case-control study: are urological procedures risk factors for the
development of infective endocarditis? BJU Int 2014;114(1):118–24.
Clearance antibiotics for invasive meningococcal or
Hib disease
Indications for clearance antibiotics for invasive meningococcal or Hib
disease
Clearance antibiotics are recommended for some patients (‘index cases’) and close contacts after an episode of:
Neisseria meningitidis (meningococcal) meningitis or other invasive meningococcal disease (eg sepsis)
Haemophilus influenzae type b (Hib) meningitis or other invasive Hib disease (eg epiglottitis).
The purpose of clearance antibiotics (‘meningitis prophylaxis’ or ‘chemoprophylaxis’) is to eradicate

asymptomatic nasopharyngeal carriage, so that susceptible contacts do not develop invasive infection. A close
contact may acquire the organism from the index case, or may be an asymptomatic carrier of the organism that
caused the infection in the index case. Clearance antibiotics for contacts of the index case should be initiated in
collaboration with the local public health authority [Note 1].
Disease can occur in contacts (or rarely, recur in the index case) despite clearance antibiotics. It is essential to
provide education to contacts about frequent, careful observation and the need for medical attention at the first
signs of an unexplained illness.
Patients with invasive meningococcal or Haemophilus influenzae type b disease only require clearance antibiotics
if they were not treated with ceftriaxone, cefotaxime or a quinolone (eg ciprofloxacin, moxifloxacin), because
these drugs clear nasopharyngeal carriage.
Australian public health guidelines for the management of invasive meningococcal disease [Note 2] and invasive
Hib infection [Note 3] include definitions of an index case and close contact, and discussion of the role of
vaccination. For detailed advice on vaccination, see the Australian Immunisation Handbook [URL].
Note 2: Communicable Diseases Network Australia (CDNA). Invasive Meningococcal Disease - CDNA national guidelines for public health units.
Canberra: Department of Health; 2014 [updated 2017]. [URL]
Note 3: Communicable Diseases Network Australia (CDNA). Haemophilus influenzae type b invasive infection: CDNA national guidelines for public
health units. Canberra: Department of Health; 2014. [URL]
Clearance antibiotics for invasive meningococcal disease

After an episode of Neisseria meningitidis (meningococcal) meningitis or other invasive meningococcal disease
(eg sepsis), clearance antibiotics are recommended for some patients (‘index cases’) and close contacts.
Suitable regimens for clearance of N. meningitidis are:
1 ciprofloxacin 500 mg (child younger than 5 years: 30 mg/kg up to 125 mg; child 5 to 12
years: 250 mg) orally, as a single dose [Note 4] [Note 5]
OR
1 ceftriaxone 250 mg (child 1 month or older: 125 mg) intramuscularly, as a single dose
[Note 6]
OR
1 rifampicin 600 mg (neonate: 5 mg/kg; child: 10 mg/kg up to 600 mg) orally, 12-hourly for
2 days.
Ceftriaxone is preferred in pregnant women. Rifampicin is preferred in neonates. Rifampicin is contraindicated in

pregnancy and severe liver disease.
choice.
Note 6: Intramuscular injection of ceftriaxone is painful; consider reconstituting with lidocaine 1%.
Clearance antibiotics for invasive Hib disease

After an episode of Haemophilus influenzae type b (Hib) meningitis or other invasive Hib disease (eg epiglottitis),
clearance antibiotics are recommended for some patients (‘index cases’) and close contacts.
A suitable regimen for clearance of Hib is:
rifampicin 600 mg (neonate: 10 mg/kg; child: 20 mg/kg up to 600 mg) orally, daily for 4
days.
Rifampicin is contraindicated in pregnancy and severe liver disease.
Although data are limited, ceftriaxone can be used if rifampicin is not suitable:
ceftriaxone 1 g (child 1 month or older: 50 mg/kg up to 1 g) intramuscularly or

intravenously, daily for 2 days [Note 7].
Note 7: Intramuscular injection of ceftriaxone is painful; consider reconstituting with lidocaine 1%. Split large intramuscular doses into two
injections.
Key references
Clark J, Lakshman R, Galloway A, Cant A. Does cefotaxime eradicate nasopharyngeal carriage of N meningiditis.
Arch Dis Child 2002;87(5):449.
Communicable Diseases Network Australia (CDNA). Haemophilus influenzae type b Invasive Infection: CDNA national
guidelines for public health units [version 1.0]. Canberra: Department of Health; 2013.
http://www.health.gov.au/internet/main/publishing.nsf/Content/cdna-song-hib.htm
Communicable Diseases Network Australia (CDNA). Invasive Meningococcal Disease: CDNA national guidelines for
public health units [version 1.2]. Canberra: Department of Health; 2017.
http://www.health.gov.au/internet/main/publishing.nsf/Content/cdna-song-IMD.htm
Simmons G, Jones N, Calder L. Equivalence of ceftriaxone and rifampicin in eliminating nasopharyngeal carriage of
serogroup B Neisseria meningitidis. J Antimicrob Chemother 2000;45(6):909–11.
Schwartz B, Al-Tobaiqi A, Al-Ruwais A, Fontaine RE, A'Ashi J, Hightower AW, et al. Comparative efficacy of
ceftriaxone and rifampicin in eradicating pharyngeal carriage of group A Neisseria meningitidis. Lancet
1988;1(8597):1239–42.
Prevention of infection in patients with asplenia or
hyposplenism
Approach to preventing infection in patients with asplenia or
hyposplenism
Patients with asplenia or hyposplenism (impaired splenic function) are at higher risk of fulminant sepsis than the
general population. The most common pathogen associated with sepsis in these patients is Streptococcus
pneumoniae. Other bacteria (including those acquired from animal bites) and parasites (eg malaria) may also cause
sepsis.
Measures to prevent infection in patients with asplenia or hyposplenism are education, immunisation and antibiotic
prophylaxis.
Education includes advice about the risk of sepsis, infection risks associated with travel and animal bites, and the
provision of a fever action plan—see also Self-management of fever in patients with asplenia or hyposplenism.
Spleen Australia [URL] provides patient education material, as well as information about the management of
patients with asplenia or hyposplenism.
Pneumococcal, meningococcal, Haemophilus influenzae type b (Hib) and influenza vaccinations are recommended
for patients with asplenia or hyposplenism. For patients undergoing elective splenectomy, if possible, start
vaccination at least 1 to 2 weeks before surgery. For patients who have undergone an emergency splenectomy, start
vaccination at least 7 days after surgery. For vaccination recommendations, see ‘Persons with functional or
anatomical asplenia’ in the Australian Immunisation Handbook [URL] and Spleen Australia [URL].
Indications for antibiotic prophylaxis for patients with asplenia or

hyposplenism
Antibiotic prophylaxis to reduce the risk of invasive pneumococcal infection is an important consideration in the
management of patients with asplenia and hyposplenism. Although there is evidence to support prophylaxis for
children with sickle cell disease, the role of prophylaxis for other patients with asplenia or hyposplenism is
unclear.
Before starting prophylaxis, explain the harms and benefits of antibiotic prophylaxis so the patient can make an
informed decision about using prophylaxis. For general information about adverse effects associated with
antimicrobial use, see Types of adverse effects of antimicrobials.
Seek expert advice on the management of antibiotic prophylaxis for patients with asplenia or hyposplenism.
Antibiotic prophylaxis is usually indicated for:
children 5 years or younger with asplenia or hyposplenism

patients who have had a splenectomy—prophylaxis is started as soon as oral therapy is tolerated
postoperatively and continued for at least 3 years.
Also consider prophylaxis for patients with asplenia or hyposplenism who are at higher risk of invasive
pneumococcal infection. Factors associated with a higher risk of invasive pneumococcal infection include:
incomplete vaccination against pneumococcal disease

primary immunodeficiency disorder
HIV infection
haematological malignancy
immunosuppressive therapy
previous invasive pneumococcal disease.
Antibiotic prophylaxis regimens for patients with asplenia or

hyposplenism
Antibiotic choice for prophylaxis
For prevention of pneumococcal infection in patients with asplenia or hyposplenism, use:
1 amoxicillin 250 mg (child: 20 mg/kg up to 250 mg) orally, daily; see Duration of
prophylaxis
OR
1 phenoxymethylpenicillin 250 mg (child younger than 1 year: 62.5 mg; 1 to 5 years: 125
mg; 5 years or older: 250 mg) orally, 12-hourly; see Duration of prophylaxis.
Penicillins are the drugs of choice for antibiotic prophylaxis against pneumococcal infection; the use of other
antibiotics is based on an extrapolation of available evidence. Penicillin resistance in Streptococcus pneumoniae is
low and rates of resistance to alternative antibiotics are much higher.

antimicrobial hypersensitivity. Desensitisation is an option for patients with immediate hypersensitivity to
penicillins if adherence to prophylaxis is likely (eg patients with a condition requiring essential medications, such
as haematological malignancies). If 1 day of prophylaxis is missed, the patient’s hypersensitivity will return and
desensitisation must be performed again. Seek expert advice if desensitisation is being considered.
For patients with delayed nonsevere hypersensitivity to penicillins, seek expert advice—a penicillin provocation
test may be appropriate.
For patients who cannot be desensitised or undergo a provocation test, or patients with delayed severe
hypersensitivity to penicillins, seek expert advice to guide antibiotic choice.
Duration of prophylaxis
The optimal duration of prophylaxis for patients with asplenia or hyposplenism remains controversial but should
be based on risk factors for invasive pneumococcal infection, as well as drug tolerability and likelihood of
adherence.
Give antibiotic prophylaxis:
up until the age of 5 years in children with asplenia, or hyposplenism due to sickle cell disease or other
congenital haemoglobinopathy
for at least 3 years after splenectomy.
Consider lifelong prophylaxis for patients who:
have survived overwhelming postsplenectomy infection, particularly invasive pneumococcal infection

are significantly immunocompromised (eg those with coexisting hypogammaglobulinaemia or advanced
liver disease, solid organ transplant recipients)
have had a splenectomy for haematological malignancy, particularly those with graft-versus-host disease
(GVHD) or receiving immunosuppressive therapy.
Self-management of fever in patients with asplenia or hyposplenism

Give patients with asplenia or hyposplenism clear instructions about what to do if they develop symptoms or signs
of infection. Instruct patients to seek urgent medical attention if they develop an unexplained fever and ensure they
have an emergency supply of antibiotics in case medical review is not immediately available.
Instruct patients with asplenia or hyposplenism to seek urgent medical attention if they develop an unexplained fever.
A suggested emergency regimen for adults with asplenia or hyposplenism who develop fever and are awaiting
medical review is:
amoxicillin 2 g orally as a single dose. Then, if medical review is delayed, 1 g 8-hourly

until medical review.
A suggested emergency regimen for children with asplenia or hyposplenism who develop fever and are awaiting
medical review is:
amoxicillin+clavulanate (child 2 months or older) 22.5+3.2 mg/kg up to 875+125 mg
orally, 12-hourly until medical review [Note 1].
For adults and children with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, a
suggested emergency regimen is:
cefuroxime 500 mg (child 3 months or older: 15 mg/kg up to 500 mg) orally, 12-hourly
until medical review [Note 2].
For adults and children with immediate severe or delayed severe hypersensitivity to penicillins, seek expert
advice.
If sepsis or septic shock is confirmed on medical review (see Early recognition of sepsis or septic shock in
adults or Early recognition of sepsis or septic shock in neonates, infants and children for definitions), see Early
intervention for sepsis or septic shock and Empirical regimens for sepsis or septic shock.
Key references
Chong J, Jones P, Spelman D, Leder K, Cheng AC. Overwhelming post-splenectomy sepsis in patients with asplenia
and hyposplenia: a retrospective cohort study. Epidemiol Infect 2017;145(2):397–400.
Davies JM, Lewis MP, Wimperis J, Rafi I, Ladhani S, Bolton-Maggs PH, et al. Review of guidelines for the prevention
and treatment of infection in patients with an absent or dysfunctional spleen: prepared on behalf of the British
Committee for Standards in Haematology by a working party of the Haemato-Oncology task force. Br J Haematol
2011;155(3):308–17.
Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet 2011;378(9785):86–97.
Kanhutu K, Jones P, Cheng AC, Grannell L, Best E, Spelman D. Spleen Australia guidelines for the prevention of
sepsis in patients with asplenia and hyposplenism in Australia and New Zealand. Intern Med J 2017;47(8):848–55.
Rankine-Mullings AE, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in children with
sickle cell disease. Cochrane Database Syst Rev 2017;(10):CD003427.
Rubin LG, Schaffner W. Clinical practice. Care of the asplenic patient. N Engl J Med 2014;371(4):349–56.
Theilacker C, Ludewig K, Serr A, Schimpf J, Held J, Bogelein M, et al. Overwhelming postsplenectomy infection: A
prospective multicenter cohort study. Clin Infect Dis 2016;62(7):871–8.
Postexposure prophylaxis against bloodborne viruses
Approach to postexposure prophylaxis against bloodborne viruses
Bloodborne viruses include hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus
(HIV) and human T-cell lymphotropic virus type I (HTLV-I). Transmission of a bloodborne virus can result from:
percutaneous injury (eg needlestick injury, injury with a sharp object)

contact of mucous membranes or nonintact skin (eg chapped or abraded) with blood, tissue, or other
potentially infectious body fluids (eg sexual exposure)
transmission from mother to child during pregnancy, labour or breastfeeding.
This topic covers the general principles of postexposure prophylaxis (PEP) in adults. Detailed local protocols
(based on state, national or international guidelines) for occupational and nonoccupational exposures should be
available from individual health services.
For postexposure prophylaxis in children, see ANZPID Guidelines for Post-Exposure Prophylaxis (PEP) for Blood
Borne Viruses in Children [URL].
For postexposure prophylaxis against HIV in neonates, see Neonatal antiretroviral prophylaxis. For postexposure
prophylaxis against hepatitis B virus in neonates, see the Australasian Society for Infectious Diseases (ASID)
guideline Management of Perinatal Infections [URL].
Perform the following after all adult exposures to bloodborne viruses:
Obtain details of the exposure, including the time and nature of the exposure, and details of the exposed
person and the source.
Perform a risk assessment of the exposure, taking into account the type of exposure, the type and amount of
fluid involved, the infectious status of the source (if known), and the susceptibility of the exposed person.
Test the source (if possible) for hepatitis B surface antigen (HBsAg), hepatitis C antibody and HIV
antibody/antigen. If the source is hepatitis C antibody positive, perform hepatitis C polymerase chain
reaction (PCR) testing.
Test the exposed person for baseline hepatitis B surface antibody, and retain the blood sample in case further
testing (eg hepatitis C antibody, HIV antibody/antigen) is required.
In cases of sexual exposure, test the exposed person for other sexually transmitted pathogens—see
Investigations for STIs and, for women of reproductive age presenting within 5 days of sexual intercourse,
offer emergency contraception—see Emergency (postcoital) contraception.
In cases of sexual assault, see also Post–sexual assault antimicrobial prophylaxis.
Provide counselling and follow-up for all exposed people. This should include information about the need
for any special precautions to prevent transmission at work, in the household and in the community during
the follow-up period.
Management of suspected or confirmed exposure to hepatitis B virus

The general principles of postexposure prophylaxis (PEP) against hepatitis B virus are summarised in Table 2.41.
Management of adults with suspected or confirmed exposure to hepatitis B virus (Table 2.41)
Exposed person is immune [NB1] Exposed person is not immune [NB1]

No further follow-up testing required.
Source is HBsAg negative No further follow-up testing required.
and unlikely to be in Start a course of hepatitis B vaccination as
window period No preventive measures required. soon as possible, preferably within 24 hours
of exposure [NB2].
Test the exposed person for HBsAg at
baseline, 3 months and 6 months after the
exposure.
Source is HBsAg positive No further follow-up testing required. Start a course of hepatitis B vaccination as
or status unknown soon as possible, preferably within 24 hours
No preventive measures required. of exposure [NB2].
Administer hepatitis B immunoglobulin

within 72 hours of exposure [NB2].
HBsAg = hepatitis B surface antigen
NB1: A person is immune if they have evidence of seroconversion after hepatitis B vaccination, or natural immunity from past infection.
NB2: For immunisation recommendations, see the Australian Immunisation Handbook [URL].
Management of suspected or confirmed exposure to hepatitis C virus

General principles:
If the source is hepatitis C (HCV) antibody negative and unlikely to be in the window period, no further
follow-up testing of the source or exposed person is required.
If the source is hepatitis C antibody positive but the polymerase chain reaction (PCR) test is negative for
hepatitis C, the need for follow-up testing of the exposed person is determined on a case-by-case basis.
In all other circumstances, perform follow-up testing of the exposed person, including hepatitis C antibodies
at baseline and 3 months after exposure. Additional testing, including PCR for hepatitis C, may be required
depending on the clinical circumstance.
At the time of writing, effective passive or active immunoprophylaxis is not available and postexposure
antiviral prophylaxis is not recommended. Consider early antiviral therapy if seroconversion occurs (see
Acute hepatitis C).
Management of suspected or confirmed exposure to HIV

General principles:
If the source is HIV antibody/antigen negative and unlikely to be in the window period, no further follow-up
testing of the source or exposed person is required.
In all other circumstances, the exposed person should have HIV antibody/antigen testing at baseline and 4 to
6 weeks, and, if HIV postexposure prophylaxis [PEP] is prescribed, 3 months after exposure.
It is essential to seek expert advice from a physician experienced in the management of HIV or to consult
local guidelines before initiating postexposure prophylaxis against HIV infection.
The risk of HIV transmission from a single exposure is determined by the type of exposure and the HIV
status of the source (or the likelihood that the source is HIV positive, if their status is unknown).
Recommendations for postexposure prophylaxis against HIV depend on the exposed person’s risk of
acquiring HIV infection; see Table 2.42. If indicated, start postexposure prophylaxis as soon as possible and
within 72 hours after exposure. If it has been longer than 72 hours since exposure, seek expert advice—
postexposure prophylaxis should only be offered in exceptional circumstances.
Inform people receiving postexposure prophylaxis of the potential adverse effects of treatment and the
possibility of drug interactions.
Consider HIV pre-exposure prophylaxis (PrEP), depending on the exposed person’s risk of subsequent HIV
infection.
Postexposure prophylaxis (PEP) for adults with suspected or confirmed exposure to HIV (Table
2.42) [NB1] [NB2]
Type of exposure HIV status of source

HIV positive and not HIV positive but Unknown HIV status
taking antiretroviral viral load
treatment, or taking undetectable
treatment but viral load
detectable or unknown
not recommended unless the
not recommended source is MSM or from a high-
Anal intercourse use three-drug regimen
[NB3] prevalence country [NB4]; if so,
use two-drug regimen
not recommended source is MSM or from a high-
Vaginal intercourse use three-drug regimen
[NB3] prevalence country [NB4]; if so,
Oral intercourse not recommended [NB5] not recommended not recommended
Nonoccupational mucous
use three-drug regimen (but
membrane or nonintact
depends on type of bodily not recommended not recommended
skin exposure to source
fluid [NB6])
bodily fluid
Occupational mucous if the source is at high risk of
membrane or nonintact not recommended being HIV positive, consider
use three-drug regimen
skin exposure to source [NB7] two-drug regimen while awaiting
bodily fluid test results
if the source is at high risk of
Occupational needlestick consider two-drug being HIV positive, consider
injury or sharps exposure regimen [NB7] two-drug regimen while awaiting
test results
Needlestick injury from
discarded needle in not applicable not applicable not recommended
community
Shared needles and other not recommended source is MSM or from a high-
injecting equipment [NB3] prevalence country [NB4]; if so,
MSM = men who have sex with men
NB1: The recommendations in this table do not apply to people taking HIV pre-exposure prophylaxis (PrEP). If the exposed person was taking PrEP at
the time of exposure, see 'Individuals who are on PrEP' in the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) Post-
Exposure Prophylaxis After Non-Occupational and Occupational Exposure to HIV: Australian National Guidelines (Second edition) [URL]
NB2: If PEP is recommended, see text below for drug regimens.
NB3: PEP is not recommended if the source provides a reliable history, adheres to antiretroviral therapy, is reviewed regularly and has no other sexually
transmitted infections.
NB4: A high-prevalence country has more than 1% HIV prevalence in the general population; see the UNAIDS Key Population Atlas website for the
seroprevalence in individual countries.
NB5: The estimated risk of HIV transmission from oral intercourse is so low as to be unmeasurable.
NB6: PEP is not recommended for nonoccupational exposure to any of the following bodily fluids (unless contaminated with blood): urine, nasal
secretions, saliva, sweat or tears.
NB7: Assess the role of PEP for an individual on a case-by-case basis. The Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine
(ASHM) Post-Exposure Prophylaxis After Non-Occupational and Occupational Exposure to HIV: Australian National Guidelines (Second edition) state
‘it is reasonable to always offer PEP to a healthcare worker who has significant exposure to a source who is HIV positive, even if the source has an
undetectable viral load’.
If a two-drug regimen is indicated, suitable regimens include:
1 lamivudine 300 mg orally, daily for 4 weeks
PLUS
tenofovir disoproxil fumarate 300 mg orally, daily for 4 weeks
OR
1 tenofovir disoproxil fumarate+emtricitabine 300+200 mg orally, daily for 4 weeks [Note

1]
OR
2 lamivudine+zidovudine 150+300 mg orally, 12-hourly for 4 weeks [Note 2].
If a three-drug regimen is indicated, add to any of the above regimens:
1 dolutegravir 50 mg orally, daily for 4 weeks
OR
1 raltegravir 400 mg orally, 12-hourly for 4 weeks
OR
1 rilpivirine 25 mg orally, daily for 4 weeks.
Dolutegravir was associated with an increased risk of neural tube defects in an interim analysis of a single study.
Further data are required to establish teratogenic risk in early pregnancy.
For further information about initiating antiretroviral therapy, see Table 2.12, and Antiretroviral drug interactions.
If there is exposure to drug-resistant HIV or adverse effects of the above regimens limit their use, seek expert
advice.
For further information about assessing the risk of HIV transmission and regimens for PEP against HIV, see the
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) Post-Exposure Prophylaxis
After Non-Occupational and Occupational Exposure to HIV: Australian National Guidelines (Second
edition) [URL].
Note 1: Tenofovir disoproxil fumarate+emtricitabine is available as a fixed-dose combination product (eg Truvada).
Note 2: Lamivudine+zidovudine is available as a fixed-dose combination product (eg Combivir).
Management of suspected or confirmed exposure to human T-cell

lymphotropic virus type I
Data on the efficacy of postexposure prophylaxis (PEP) against human T-cell lymphotropic virus type I (HTLV-I)
are inconclusive. Seek expert advice for patients with possible exposure to human T-cell lymphotropic virus type I.
For higher-risk exposures (eg percutaneous injury with a hollow blood-containing needle), consider:
lamivudine+zidovudine 150+300 mg orally, 12-hourly for 4 weeks [Note 3].
Note 3: Lamivudine+zidovudine is available as a fixed-dose combination product (eg Combivir).
Further reading
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine. Post-Exposure Prophylaxis after Non-
Occupational and Occupational Exposure to HIV: Australian National Guidelines (Second edition). ASHM; 2016
[URL]
Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. Updated guidelines
for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to
HIV. Centers for Disease Control and Prevention (CDC); 2016. [URL]
Cresswell F, Waters L, Briggs E, Fox J, Harbottle J, Hawkins D, et al. UK guideline for the use of HIV Post-
Exposure Prophylaxis Following Sexual Exposure, 2015. Int J STD AIDS 2016;27(9):713–38. [URL]
Schillie S, Murphy TV, Sawyer M, Ly K, Hughes E, Jiles R, et al. CDC guidance for evaluating health-care
personnel for hepatitis B virus protection and for administering postexposure management. MMWR Recomm Rep
2013;62(RR-10):1–19. [URL]
Updated US Public Health Service Guidelines for the management of occupational exposures to HIV and
recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol 2013;34(9):875–92. [URL]
Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR Morb Mortal Wkly
Rep 2013;62(18):362–5. [URL]
Charles PG, Angus PW, Sasadeusz JJ, Grayson ML. Management of healthcare workers after occupational
exposure to hepatitis C virus. Med J Aust 2003;179(3):153–7. [URL]
Key references
Approach to postexposure prophylaxis against bloodborne viruses
ASHA; updated 2017. www.sti.guidelines.org.au
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM). Post-exposure prophylaxis after
non-occupational and occupational exposure to HIV: Australian National Guidelines. 2nd ed. Sydney: ASHM; 2016.
https://www.ashm.org.au/HIV/PEP/
Australian Technical Advisory Group on Immunisation. Australian Immunisation Handbook. Canberra: Australian
Government Department of Health; 2018. https://immunisationhandbook.health.gov.au/
National HBV Testing Policy Expert Reference Committee. National HBV Testing Policy v1.2. Canberra:
Commonwealth of Australia; 2015 [Accessed Aug 2018]. http://testingportal.ashm.org.au/hbv
Management of suspected or confirmed exposure to hepatitis B virus
ASHA; updated 2017. www.sti.guidelines.org.au/
https://www.ashm.org.au/HIV/PEP/
Australian Technical Advisory Group on Immunisation. Australian Immunisation Handbook. Canberra: Australian
Government Department of Health; 2018. https://immunisationhandbook.health.gov.au/
National HBV Testing Policy Expert Reference Committee. National HBV Testing Policy v1.2. Canberra:
Commonwealth of Australia; 2015 [Accessed Aug 2018]. http://testingportal.ashm.org.au/hbv
Schillie S, Murphy TV, Sawyer M, Ly K, Hughes E, Jiles R, et al. CDC guidance for evaluating health-care personnel
for hepatitis B virus protection and for administering postexposure management. MMWR Recomm Rep 2013;62(RR-
10):1–19.
Management of suspected or confirmed exposure to hepatitis C virus
https://www.ashm.org.au/HIV/PEP
Centers for Disease Control and Prevention. Testing for HCV infection: an update of guidance for clinicians and
laboratorians. MMWR Morb Mortal Wkly Rep 2013;62(18):362–5.
Charles PG, Angus PW, Sasadeusz JJ, Grayson ML. Management of healthcare workers after occupational exposure
to hepatitis C virus. Med J Aust 2003;179(3):153–7.
National HCV Testing Policy Expert Reference Committee. National Hepatitis C Testing Policy v 1.2. Canberra:
Commonwealth of Australia; 2017 [Accessed Aug 2018]. http://testingportal.ashm.org.au/hcv
Management of suspected or confirmed exposure to HIV
ASHA; updated 2017. www.sti.guidelines.org.au/
https://www.ashm.org.au/HIV/PEP
Centers for Disease Control and Prevention (CDC). Interim statement regarding potential fetal harm from exposure to
dolutegravir – implications for HIV post-exposure prophylaxis (PEP). Atlanta, GA: CDC; 2018 [Accessed Aug 2018].
https://www.cdc.gov/hiv/basics/pep.html
Centers for Disease Control and Prevention (CDC), US Department of Health and Human Services. Updated
guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational
exposure to HIV—United States, 2016. Atlanta, GA: CDC; 2016. https://www.cdc.gov/hiv/guidelines/preventing.html
Cresswell F, Waters L, Briggs E, Fox J, Harbottle J, Hawkins D, et al. UK guideline for the use of HIV post-exposure
prophylaxis following sexual exposure, 2015. Int J STD AIDS 2016;27(9):713–38.
Kuhar DT, Henderson DK, Struble KA, Heneine W, Thomas V, Cheever LW, et al. Updated US Public Health Service
guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for
postexposure prophylaxis. Infect Control Hosp Epidemiol 2013;34(9):875–92.
Management of suspected or confirmed exposure to human T-cell lymphotropic virus type I
Hewagama S, Krishnaswamy S, King L, Davis J, Baird R. Human T-cell lymphotropic virus type 1 exposures following
blood-borne virus incidents in central Australia, 2002-2012. Clin Infect Dis 2014;59(1):85–7.
Prevention of infection in patients with cirrhosis and
upper gastrointestinal bleeding
Prevention of infection in patients with cirrhosis and upper
gastrointestinal bleeding
Antibiotic prophylaxis is recommended for all patients who have cirrhosis with acute upper gastrointestinal
bleeding (variceal or nonvariceal) because it reduces the risk of infection, recurrent haemorrhage and mortality.
The benefit of antibiotic prophylaxis in patients with cirrhosis categorised as Child–Turcotte–Pugh (Child–Pugh)
class A is likely to be small because the rate of infection and mortality in this group of patients is low. However, in
these guidelines, antibiotic prophylaxis is recommended for all patients with cirrhosis and upper gastrointestinal
bleeding because further research is required before antibiotic prophylaxis can be targeted by Child–Turcotte–
Pugh class.
Antibiotic prophylaxis should be started at presentation to hospital and before endoscopy. The optimal antibiotic
prophylaxis regimen has not been determined. Intravenous prophylaxis may be appropriate when the patient is
actively bleeding, with a switch to oral antibiotic prophylaxis once oral intake has resumed. Use:
OR
1 ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 12-hourly [Note 1]

[Note 2].
Once the patient is haemodynamically stable and able to tolerate oral medication, switch to oral prophylaxis; use:
norfloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally, 12-hourly [Note 3] [Note 4].
The optimal duration of prophylaxis is uncertain. Although most randomised controlled trials were for 7 days and
many guidelines recommend prophylaxis for a maximum of 7 days, there is evidence to support a duration of 3
days.
To reduce the emergence of antibiotic resistance, use the shortest possible duration of prophylaxis (intravenous +
oral)—3 days is recommended as a minimum standard. The maximum duration is 7 days. Consider stopping
antibiotic prophylaxis once bleeding has resolved and vasoactive drugs (eg octreotide) have been stopped. At this
stage, switching to oral prophylaxis is not required if prophylaxis has already been given for the minimum duration
(ie 3 days).
Patients with cirrhosis may also require antibiotic prophylaxis to prevent spontaneous bacterial peritonitis—see
Prevention of spontaneous bacterial peritonitis in patients with cirrhosis.
Note 1: Avoid ciprofloxacin in patients taking quinolones (ie norfloxacin or ciprofloxacin) for prophylaxis of spontaneous bacterial peritonitis.
choice.
Note 3: Norfloxacin is not licensed for use in children on the basis of animal studies that showed an adverse effect on cartilage development with
quinolone use; however, there are few data from human trials to support this finding. Norfloxacin can be used in children when it is the drug of choice.
Note 4: An oral liquid formulation of norfloxacin is not commercially available; for formulation options for children or people with swallowing
Key references
Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila FI, Soares-Weiser K, Uribe M. Antibiotic prophylaxis for cirrhotic
patients with upper gastrointestinal bleeding. Cochrane Database Syst Rev 2010;(9):CD002907.
Dyson JK, Rajasekhar P, Wetten A, Ashraf HH, Ng S, Paremal S, et al. Implementation of a ‘care bundle’ improves the
management of patients admitted to hospital with decompensated cirrhosis. Aliment Pharmacol Ther
2016;44(10):1030–8.
European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients
with decompensated cirrhosis. J Hepatol 2018;69(2):406–60.
Fortune B, Garcia-Tsao G. Current management strategies for acute esophageal variceal hemorrhage. Curr Hepatol
Rep 2014;13(1):35–42.
Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification,
diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
Hepatology 2017;65(1):310–35.
Jia Y, Dwivedi A, Elhanafi S, Ortiz A, Othman M, Zuckerman M. Low risk of bacteremia after endoscopic variceal
therapy for esophageal varices: a systematic review and meta-analysis. Endosc Int Open 2015;3(5):E409–17.
Kuo MT, Yang SC, Lu LS, Hsu CN, Kuo YH, Kuo CH, et al. Predicting risk factors for rebleeding, infections, mortality
following peptic ulcer bleeding in patients with cirrhosis and the impact of antibiotics prophylaxis at different clinical
stages of the disease. BMC Gastroenterol 2015;15:61.
Lee TH, Huang CT, Lin CC, Chung CS, Lin CK, Tsai KC. Similar rebleeding rate in 3-day and 7-day intravenous
ceftriaxone prophylaxis for patients with acute variceal bleeding. J Formos Med Assoc 2016;115(7):547–52.
Moon AM, Dominitz JA, Ioannou GN, Lowy E, Beste LA. Use of antibiotics among patients with cirrhosis and upper
gastrointestinal bleeding is associated with reduced mortality. Clin Gastroenterol Hepatol 2016;14(11):1629–37 e1.
Pauwels A, Mostefa-Kara N, Debenes B, Degoutte E, Levy VG. Systemic antibiotic prophylaxis after gastrointestinal
hemorrhage in cirrhotic patients with a high risk of infection. Hepatology 1996;24(4):802–6.
Runyon BA. Management of adult patients with ascites due to cirrhosis: Update 2012 [practice guideline]. Alexandria,
Virginia: American Association for the Study of Liver Diseases; 2012. https://www.aasld.org/publications/practice-
guidelines-0
Tandon P, Abraldes JG, Keough A, Bastiampillai R, Jayakumar S, Carbonneau M, et al. Risk of bacterial infection in
patients with cirrhosis and acute variceal hemorrhage, based on Child-Pugh class, and effects of antibiotics. Clin
Gastroenterol Hepatol 2015;13(6):1189–96 e2.
Tripathi D, Stanley AJ, Hayes PC, Patch D, Millson C, Mehrzad H, et al. U.K. guidelines on the management of
variceal haemorrhage in cirrhotic patients. Gut 2015;64(11):1680–704.
Turnidge JD, Gottlieb T, Mitchell DH, Coombs GW, Pearson JC, Bell JM, et al. Australian Group on Antimicrobial
Resistance Community-onset Gram-negative surveillance program annual report, 2010. Commun Dis Intell Q Rep
2013;37(3):E219–23.
Turnidge JD, Gottlieb T, Mitchell DH, Coombs GW, Pearson JC, Bell JM, et al. Hospital-onset Gram-negative
surveillance program annual report, 2011. Commun Dis Intell Q Rep 2014;38(1):E49–53.
Primary prophylaxis in immunocompromised adults
without HIV infection
Infections are opportunistic if they occur more frequently or are more severe in patients with immune compromise.
This topic covers primary prophylaxis of opportunistic infections in adults with healthcare-associated immune
compromise (eg organ transplant, immunosuppressive therapy). Prevention and treatment of opportunistic
infections in adults with HIV infection is covered in Opportunistic and co-infections in adults with HIV infection.
Immune compromise caused by other immunodeficiency disorders (eg primary immunodeficiency disorders), and
immunocompromised children are beyond the scope of these guidelines.
While immune compromise caused by a chronic medical condition (eg diabetes, chronic kidney disease) is
associated with an increased risk of infection, the role of primary prophylaxis in these conditions is beyond the
scope of this topic. Chronic medical conditions further increase the risk of opportunistic infections in patients with
healthcare-associated immune compromise (eg organ transplant).
For treatment and secondary prophylaxis of infections in immunocompromised patients, refer to the relevant
clinical topic.
For immunisation recommendations in immunocompromised patients, see the Australian Immunisation

Handbook [URL].
Interventions to prevent opportunistic infections in

immunocompromised patients
Interventions to prevent opportunistic infections in immune compromise are:
primary antimicrobial prophylaxis—aims to prevent a new infection (eg Pneumocystis jirovecii

pneumonia [PJP]) in patients identified as high risk
immunisation—aims to prevent a vaccine-preventable infection (eg influenza, hepatitis B). For details, see
the Australian Immunisation Handbook [URL]
treatment of latent infection—aims to prevent reactivation of infection (eg tuberculosis)
pre-emptive (or early) treatment—aims to prevent occurrence of active disease by screening
asymptomatic patients for an infection and starting antimicrobial treatment before the patient displays
features of disease (eg cytomegalovirus)
secondary prophylaxis (or maintenance therapy)—aims to prevent recurrence after initial treatment of an
infection (eg PJP).
Primary antimicrobial prophylaxis of opportunistic infections is covered in this topic, with some discussion of
treatment of latent infection and pre-emptive treatment. For secondary prophylaxis, refer to the relevant clinical
topic (eg Pneumocystis jirovecii pneumonia).
See the guidelines listed in Further reading for details about nonpharmacological preventive measures such as
screening before starting immunosuppressive therapy, infection control measures, and advice about diet and other
lifestyle factors.
Assessing the need for antimicrobial prophylaxis in

immunocompromised adults without HIV infection
Overview
This section covers assessing the need for and duration of antimicrobial prophylaxis in the following groups of
immunocompromised adults:
patients taking corticosteroid therapy

patients taking immunomodulatory drugs for nonmalignant conditions
patients with haematological malignancies
patients treated with chemotherapy for solid organ malignancies
solid organ transplant patients
haematopoietic stem cell transplant patients.
At the time of writing, data to support the need for antimicrobial prophylaxis recommendations for patients treated
with immune checkpoint inhibitors (eg ipilimumab, nivolumab, pembrolizumab) and tyrosine kinase inhibitors (eg
imatinib, dasatinib, nilotinib) is lacking. Perform a risk assessment for the individual patient and seek expert
advice.
Patients taking corticosteroid therapy

The need for antimicrobial prophylaxis in patients taking corticosteroid therapy depends on:
corticosteroid dose and potency

duration of therapy and cumulative dose
whether the patient is taking other immunosuppressive drugs
whether the patient has a clinical condition associated with immune compromise (eg malignancy,
autoimmune disease, T-cell defects or significant lymphopenia).
Patients taking at least 20 mg of prednisolone daily for more than 2 weeks are at increased risk of infection. For
antimicrobial prophylaxis recommendations in patients taking at least 20 mg of prednisolone daily for 2 to 4
weeks, see Table 2.43. For antimicrobial prophylaxis recommendations in patients taking at least 20 mg of
prednisolone daily for more than 4 weeks, see Table 2.44. For patients taking other corticosteroids, see Table
2.45 for doses approximately equivalent to prednisolone 20 mg. Short-course pulse corticosteroids (eg
methylprednisolone 1 g intravenously daily for up to 5 days) may increase the risk of infection, but the role of
antimicrobial prophylaxis is unclear—seek expert advice.
Antimicrobial prophylaxis reduces the risk of infection; however, infection can occur despite prophylaxis.
Adherence to antimicrobial prophylaxis increases efficacy. Nonpharmacological preventive measures (including
infection control, diet and lifestyle strategies) also reduce the risk of infection—see the guidelines listed in Further
reading.
For patients taking systemic corticosteroids for a rheumatological condition, see also Table 12.3.
Antimicrobial prophylaxis for patients taking at least 20 mg of prednisolone daily (or equivalent)
for 2 to 4 weeks (Table 2.43) [NB1] [NB2]
Strongyloides stercoralis
Perform baseline Strongyloides serology in patients with a past or present epidemiological risk of acquiring S.
stercoralis [NB3].
S. stercoralis prophylaxis (or pre-emptive treatment) is recommended for:
patients with positive Strongyloides serology

patients with negative serology who live in or visit an area in which S. stercoralis infection is endemic.
For antimicrobial regimens and duration of therapy, see here.

Burkholderia pseudomallei
Perform baseline B. pseudomallei serology in patients who live or have lived in an endemic region such as
tropical regions of Australia [NB4].
B. pseudomallei prophylaxis is recommended for:
patients with positive B. pseudomallei serology

patients with a history of melioidosis (B. pseudomallei infection) but no clinical evidence of current
disease.
Consider giving primary prophylaxis during the wet season [NB5] to patients with negative B. pseudomallei
serology who live in or visit an endemic area.

Other
Hepatitis B virus and tuberculosis reactivation can occur—some patients require antimicrobial treatment. See
Hepatitis B virus prophylaxis and Prevention of tuberculosis.
The risk of Listeria monocytogenes meningitis is increased. Consult local protocols and consider dietary and food
safety measures to prevent L. monocytogenes infection [NB6].
If the patient has recurrent oral mucocutaneous or genital herpes simplex virus (HSV) infection, consider
suppressive therapy. See Recurrent episodes of oral mucocutaneous herpes and Suppressive therapy for genital
herpes.
NB1: It is not possible to establish the precise corticosteroid dosage and duration of therapy that increases the risk of infection. The consensus view of
the Antibiotic Expert Groups is that antimicrobial prophylaxis is indicated for patients taking a daily prednisolone dose of at least 20 mg (or equivalent).
NB2: For doses of other corticosteroids approximately equivalent to prednisolone 20 mg, see Table 2.45.
NB3: Patients at risk of acquiring S. stercoralis include those who were born, live in or visit endemic areas. This includes patients from tropical or
central Australia or remote Aboriginal and Torres Strait Islander communities, as well as older patients from southern European countries, and refugees
and migrants from developing countries.
NB4: Tropical regions of Australia refer to regions north of 20°S latitude. This includes areas of Queensland north of Mackay, the Northern Territory
north of Tennant Creek, and Western Australia north of Port Hedland.
NB5: In tropical regions of Australia, the wet season is usually from October to April. Melioidosis is more common in this season.
NB6: For dietary and food safety measures to prevent L. monocytogenes infection, see the Food Standards Australia New Zealand website.
Antimicrobial prophylaxis for patients taking at least 20 mg of prednisolone daily (or equivalent)
for more than 4 weeks (Table 2.44) [NB1] [NB2]

PJP prophylaxis is indicated for patients with at least one of the following risk factors:
a condition associated with immune compromise (eg malignancy, T-cell defects, significant lymphopenia)
an active autoimmune disease such as dermatological or rheumatological conditions (eg rheumatoid
arthritis, scleroderma, systemic lupus erythematosus), giant cell arteritis or sarcoidosis
use of other immunosuppressive drugs.
For antimicrobial regimens, see here.
Duration of PJP prophylaxis:
The optimal duration of PJP prophylaxis is uncertain. Assess the patient’s level of immune compromise and risk
of infection before stopping PJP prophylaxis. Review the benefit of ongoing prophylaxis regularly.
After stopping corticosteroids, continue PJP prophylaxis for at least 6 weeks. However, a longer duration of
prophylaxis may be needed if the patient is taking other immunosuppressive drugs—seek expert advice.
If the corticosteroid dose has been tapered to below 20 mg daily of prednisolone (or equivalent) but is unlikely to
be stopped, the need for ongoing PJP prophylaxis is uncertain—seek expert advice.
stercoralis [NB3].



disease.

Other
herpes.
NB1: It is not possible to establish the precise corticosteroid dosage and duration of therapy that increases the risk of infection. The consensus view of
the Antibiotic Expert Groups is that antimicrobial prophylaxis is indicated for patients taking a daily prednisolone dose of at least 20 mg (or equivalent).
NB2: For doses of other corticosteroids approximately equivalent to prednisolone 20 mg, see Table 2.45.
Corticosteroid doses approximately equivalent to prednisolone 20 mg daily (Table 2.45)
Corticosteroid Route Equivalent daily dose

cortisone acetate oral 100 mg
dexamethasone oral, intravenous, intramuscular 4 mg
hydrocortisone oral, intravenous, intramuscular 80 mg
methylprednisolone sodium succinate intravenous, intramuscular 20 mg
prednisone oral 20 mg
Patients taking immunomodulatory drugs for nonmalignant conditions
Overview
This section covers assessing the need for and duration of antimicrobial prophylaxis in patients taking the
following immunomodulatory drugs for a nonmalignant condition:
cyclophosphamide
tumour necrosis factor inhibitors
rituximab
alemtuzumab
natalizumab
eculizumab.
To assess the need for antimicrobial prophylaxis in patients taking immunomodulatory drugs for malignancy, see:
Patients with haematological malignancies

Patients treated with chemotherapy for solid organ malignancies.
Novel immune-modulatory monoclonal antibodies and small-molecule inhibitors (eg natalizumab, eculizumab)
cause specific immune deficits—understanding the mechanism of immunomodulation is important to predict and
prevent subsequent infection. Experience with novel immune-modulatory monoclonal antibodies and small-
molecule inhibitors is rapidly evolving. Seek expert advice for the latest information on infection risks with these
drugs.
Patients taking cyclophosphamide for a nonmalignant condition
Patients taking cyclophosphamide (orally or intravenously) for a nonmalignant condition are at increased risk of
infection. For antimicrobial prophylaxis recommendations, see Table 2.46.
reading.
Antimicrobial prophylaxis for patients taking cyclophosphamide for a nonmalignant condition

(Table 2.46)

PJP prophylaxis is indicated for all patients.
Continue PJP prophylaxis for the duration of treatment with cyclophosphamide. After stopping
cyclophosphamide, continue PJP prophylaxis for 6 weeks. For patients with significant lymphopenia, continue
prophylaxis until the lymphocyte count has recovered for 3 to 6 months. A longer duration of prophylaxis may be
needed if the patient is taking other immunosuppressive drugs—seek expert advice.
Other
The risk of Listeria monocytogenes meningitis is increased. Consult local protocols and consider
nonpharmacological dietary and food safety measures to prevent L. monocytogenes infection [NB1].
Patients with past or present risk of melioidosis (Burkholderia pseudomallei infection) or Strongyloides
stercoralis infection may require antimicrobial prophylaxis. See Burkholderia pseudomallei prophylaxis
and Strongyloides stercoralis prophylaxis.
herpes.
Patients taking tumour necrosis factor inhibitors for a nonmalignant condition
Patients taking a tumour necrosis factor inhibitor (eg adalimumab, certolizumab, etanercept, golimumab,
infliximab) for a nonmalignant condition are at increased risk of infection. For antimicrobial prophylaxis
recommendations, see Table 2.47.
reading.
Antimicrobial prophylaxis for patients taking tumour necrosis factor inhibitors for a
nonmalignant condition (Table 2.47)

PJP prophylaxis is indicated for patients with risk factors for PJP; these include:
patients treated with other immunosuppressive drugs

patients with T-cell defects or significant lymphopenia.
Continue PJP prophylaxis for the duration of treatment with the tumour necrosis factor inhibitor. After stopping
the tumour necrosis factor inhibitor, continue PJP prophylaxis for 6 weeks. For patients with significant
lymphopenia, continue prophylaxis until the lymphocyte count has recovered for 3 to 6 months.
Other
Risk of tuberculosis reactivation is high, so treatment of latent tuberculosis infection is almost always indicated.
See Prevention of tuberculosis.
Hepatitis B virus reactivation can occur—some patients require antiviral treatment. See Hepatitis B virus
prophylaxis.
stercoralis infection may require antimicrobial prophylaxis. See Burkholderia pseudomallei prophylaxis and
Strongyloides stercoralis prophylaxis.
herpes.
Patients taking rituximab for a nonmalignant condition
Patients taking rituximab for a nonmalignant condition are at increased risk of infection. For antimicrobial
prophylaxis recommendations, see Table 2.48.
reading.
Antimicrobial prophylaxis for patients taking rituximab for a nonmalignant condition (Table 2.48)

PJP prophylaxis is indicated for patients with risk factors for PJP; these include:
patients treated with other immunosuppressive drugs

patients with T-cell defects or significant lymphopenia.
Patients treated with rituximab monotherapy (ie without other immunosuppressive drugs) are at low risk of PJP;
there is limited evidence to support giving PJP prophylaxis to these patients.
Continue PJP prophylaxis for the duration of treatment with rituximab, and for at least 12 months after stopping
rituximab or until the lymphocyte count has recovered for 3 to 6 months, whichever is later.
Other
Hepatitis B virus reactivation can occur, including in patients who are hepatitis B surface antigen (HBsAg)
negative but who have antibodies to hepatitis B core antigen (anti-HBc). See Hepatitis B virus prophylaxis.
Tuberculosis reactivation can occur—some patients require antimicrobial treatment. See Prevention of
tuberculosis.
herpes.
Patients taking alemtuzumab for multiple sclerosis
Patients taking alemtuzumab for relapsing-remitting multiple sclerosis are at increased risk of infection. For
antimicrobial prophylaxis recommendations, see Table 2.49.
reading.
Antimicrobial prophylaxis for patients taking alemtuzumab for multiple sclerosis (Table 2.49)

The risk of PJP is increased. Some centres recommend routine antimicrobial prophylaxis—seek expert advice or
consult local protocols.

Continue PJP prophylaxis for the duration of treatment with alemtuzumab, and for at least 2 months after stopping
alemtuzumab or until the lymphocyte count has recovered for 3 to 6 months, whichever is later.
Herpes simplex virus (HSV) and varicella-zoster virus (VZV)
Antiviral prophylaxis for HSV and VZV is indicated for all patients.
For antiviral regimens, see here.
Duration of antiviral prophylaxis:
Continue antiviral prophylaxis for the duration of treatment with alemtuzumab, and for 1 month after stopping
alemtuzumab. If the patient has significant lymphopenia when stopping alemtuzumab, continue antiviral
prophylaxis for a further 3 to 6 months.
Other
Tuberculosis reactivation can occur—some patients require antimicrobial treatment. See Prevention of
tuberculosis.
The risk of hepatitis B virus reactivation is significant when alemtuzumab is used to treat haematological
malignancy, but data to guide risk assessment when alemtuzumab is used for multiple sclerosis are lacking—seek
expert advice and see Hepatitis B virus prophylaxis.
The risk of cytomegalovirus infection may be increased—consult local protocols or seek expert advice.
Patients taking natalizumab for multiple sclerosis
Natalizumab inhibits vascular endothelial adhesion of lymphocytes and monocytes. Patients taking natalizumab
for relapsing-remitting multiple sclerosis are at increased risk of progressive multifocal leukoencephalopathy
(PML) caused by reactivation of the John Cunningham virus (JCV); see Progressive multifocal
leukoencephalopathy (John Cunningham virus).
Other opportunistic infections (eg herpes simplex virus infection, reactivation of tuberculosis) are rarely associated
with natalizumab therapy; however, evidence to recommend antimicrobial prophylaxis is lacking.
Patients taking eculizumab for a nonmalignant condition
Eculizumab blocks the formation of the membrane attack complex. Patients treated with eculizumab for a
nonmalignant condition (eg paroxysmal nocturnal haemoglobinuria, atypical haemolytic uraemic syndrome) are at
an increased risk of invasive meningococcal disease, even if immunised; see Neisseria meningitidis prophylaxis in
adults treated with eculizumab.
Adherence to antimicrobial prophylaxis increases efficacy.
Rarely, cases of other opportunistic infections, including Streptococcus pneumoniae, Haemophilus influenzae type
B and invasive mould infections have occurred in patients taking eculizumab. However, evidence to recommend
additional antimicrobial prophylaxis for these pathogens is lacking.
Patients with haematological malignancies

In patients receiving chemotherapy for haematological malignancy, the risk of infection depends on:
the type of malignancy (eg lymphoma, leukaemia, myeloma)

the treatment regimen (particularly regimens containing fludarabine and monoclonal or biological therapies
[eg rituximab, small-molecule inhibitors such as tyrosine kinase inhibitors])
the severity and duration of neutropenia
patient factors such as age and comorbidities.
For recommendations for antimicrobial prophylaxis according to cancer treatment protocols, see the eviQ Cancer
Treatments Online website (choose ‘Haematology and BMT’, then the type of cancer and chemotherapy regimen,
then ‘Clinical information’).
reading.
Patients treated with chemotherapy for solid organ malignancies
In patients receiving chemotherapy for solid organ malignancies, the risk of infection depends on:
the treatment regimen (particularly regimens containing fludarabine and monoclonal or biological therapies
[eg rituximab, small-molecule inhibitors such as tyrosine kinase inhibitors])
the severity and duration of neutropenia
patient factors such as age and comorbidities.
For recommendations for antimicrobial prophylaxis according to cancer treatment protocols, see the eviQ Cancer
Treatments Online website (choose ‘Medical oncology’, then the type of cancer and chemotherapy regimen, then
‘Clinical information’).
reading.
Solid organ transplant patients
Overview
This section covers assessing the need for and duration of antimicrobial prophylaxis for:
kidney transplant patients

liver transplant patients
heart transplant patients
lung and heart–lung transplant patients.
The risk of infection in solid organ transplant recipients depends on:
the type of transplant

the relatedness of the match
the type and dosage of immunosuppressive therapy (induction and maintenance)
whether the patient has had episodes of acute or chronic rejection
the time since the transplant
the age and comorbidities of the recipient.
Antimicrobial prophylaxis after organ transplant is a highly specialised area. The following text is a general guide
to the usual indications for antimicrobial prophylaxis. Seek expert advice from the transplant centre or an
infectious diseases physician before changing or stopping prophylaxis.
Kidney transplant
Following a kidney transplant, patients are at increased risk of infection. For antimicrobial prophylaxis
recommendations, see Table 2.50. Additional perioperative antibiotic prophylaxis may also be required; this is
beyond the scope of these guidelines.
reading.
Antimicrobial prophylaxis for kidney transplant patients (Table 2.50) [NB1]

PJP prophylaxis is indicated in all patients.
Start prophylaxis after the transplant when the patient is stable and tolerating oral medications. For antimicrobial
regimens, see here.
Continue PJP prophylaxis for at least 6 to 12 months after transplant or following treatment of rejection episodes,
or indefinitely if the patient has significant ongoing immunosuppression. Some centres routinely continue
prophylaxis indefinitely—consult local protocols.
Cytomegalovirus (CMV)
Indications for CMV prophylaxis are beyond the scope of these guidelines—refer to local protocols. The choice
between universal prophylaxis and pre-emptive treatment depends on several factors, including the availability of
CMV monitoring, and the risk of CMV reactivation.
For universal prophylaxis, start on day 10 after transplant. For antiviral regimens, see Universal prophylaxis.
For pre-emptive treatment, start when indicated based on viral load or the rate of change in viral load. For
antiviral regimens, see Pre-emptive treatment.
Duration of CMV prophylaxis:
Assess the patient’s level of immune compromise and risk of infection before stopping CMV prophylaxis.
For universal prophylaxis, continue for 3 to 6 months after transplant, or for 1 to 3 months following treatment of
rejection episodes (eg with antilymphocyte therapy).
For pre-emptive treatment, continue until one or two CMV DNA nucleic acid amplification (eg polymerase chain
reaction [PCR]) test results are negative—consult local protocols.
Herpes simplex virus (HSV)
Some transplant centres give HSV prophylaxis to patients who are HSV IgG positive—consult local protocols.
HSV prophylaxis is not required if the patient is receiving valganciclovir or ganciclovir for CMV prophylaxis.
Start prophylaxis after the transplant when the patient is stable and tolerating oral medications. For antiviral
regimens, see here.
Duration of HSV prophylaxis:
Continue HSV prophylaxis for 1 month. Restart prophylaxis during treatment of rejection episodes and continue
for 1 month.
Suppressive therapy:
If the patient has recurrent oral mucocutaneous or genital HSV infection, suppressive therapy is recommended.
See Recurrent episodes of oral mucocutaneous herpes and Suppressive therapy for genital herpes.
stercoralis [NB2].



disease.

Other
NB1: Antimicrobial prophylaxis after organ transplant is a highly specialised area. This table is a general guide to the usual indications for antimicrobial
prophylaxis. Seek expert advice from the transplant centre or an infectious diseases physician before changing or stopping prophylaxis.
Liver transplant
Following a liver transplant, patients are at increased risk of infection. For antimicrobial prophylaxis
recommendations, see Table 2.51. Additional perioperative antibiotic prophylaxis may also be required; this is
reading.
Antimicrobial prophylaxis for liver transplant patients (Table 2.51) [NB1]

regimens, see here.
Continue PJP prophylaxis for at least 6 months after transplant or following treatment of rejection episodes, or
indefinitely if the patient has significant ongoing immunosuppression.
For universal prophylaxis, start on day 10 after transplant. For antiviral regimens, see Universal prophylaxis.
antiviral regimens, see Pre-emptive treatment.
For universal prophylaxis, continue for 3 to 6 months after transplant, or for 1 to 3 months following treatment of
rejection episodes (eg with antilymphocyte therapy).
regimens, see here.
Continue HSV prophylaxis for 1 month. Restart prophylaxis during treatment of rejection episodes and continue
for 1 month.
Yeast and mould infections
Antifungal prophylaxis is indicated for patients at the highest risk for invasive yeast or mould infection—refer to
local protocols or seek expert advice. Some centres give yeast prophylaxis because infection with Candida
species is more common. However, invasive aspergillosis has higher morbidity and mortality. Examples of
patients at the highest risk of fungal infection include patients undergoing a repeat transplant, patients with
fulminant liver failure, and patients with kidney failure requiring renal replacement therapy.
Start prophylaxis early in the postoperative period and refer to local protocols for drug choice and duration of
therapy.
stercoralis [NB2].



disease.

Other
Hepatitis B virus and tuberculosis reactivation can occur—some patients require antimicrobial treatment. For
details, see Hepatitis B virus prophylaxis and Prevention of tuberculosis.
Heart transplant
Following a heart transplant, patients are at increased risk of infection. For antimicrobial prophylaxis
recommendations, see Table 2.52. Additional surgical antibiotic prophylaxis is also required; see Surgical
prophylaxis for cardiac surgery.
For infection prophylaxis in heart–lung transplant patients, see Lung and heart–lung transplant.
reading.
Antimicrobial prophylaxis for heart transplant patients (Table 2.52) [NB1]

regimens, see here. PJP prophylaxis with trimethoprim+sulfamethoxazole also provides prophylaxis against
Toxoplasma gondii.
or indefinitely if the patient has significant ongoing immunosuppression. Most centres routinely continue
Toxoplasma gondii
T. gondii prophylaxis is indicated if the recipient is T. gondii IgG negative but the donor is positive. T. gondii
prophylaxis is not required if the patient is receiving trimethoprim+sulfamethoxazole for PJP prophylaxis. If the
patient is hypersensitive to trimethoprim+sulfamethoxazole and requires prophylaxis for both PJP and T. gondii,
see here for regimens.
Start prophylaxis after the transplant when the patient is stable and tolerating oral medications.
Duration of T. gondii prophylaxis:
Limited data are available to guide duration of T. gondii prophylaxis—seek expert advice. If the patient is taking
trimethoprim+sulfamethoxazole for both PJP and T. gondii prophylaxis, use the duration of PJP prophylaxis as a
guide.
Indications for CMV prophylaxis are beyond the scope of these guidelines—refer to local protocols. Pre-emptive
treatment is not well studied in heart transplant recipients; universal prophylaxis is the preferred approach.
Start universal prophylaxis on day 1 after transplant. For antiviral regimens, see Universal prophylaxis.
Continue CMV universal prophylaxis for at least 6 months after transplant, or for 1 to 3 months following
treatment of rejection episodes (eg with antilymphocyte therapy). Some centres continue CMV prophylaxis
indefinitely if there is a serological mismatch between the organ donor and recipient.
Start HSV prophylaxis after the transplant when the patient is stable and tolerating oral medications. For antiviral
regimens, see here.
Continue HSV prophylaxis for 1 to 3 months. Restart prophylaxis during treatment of rejection episodes and
continue for 1 to 3 months.
stercoralis [NB2].



disease.

Other
Lung and heart–lung transplant
Following a lung or heart–lung transplant, patients are at increased risk of infection. For antimicrobial prophylaxis
recommendations, see Table 2.53. Additional perioperative antibiotic prophylaxis may be required; this is beyond
the scope of these guidelines.
reading.
Antimicrobial prophylaxis for lung or heart–lung transplant patients (Table 2.53) [NB1]

Toxoplasma gondii.
or indefinitely if the patient has significant ongoing immunosuppression. Most centres routinely continue
Toxoplasma gondii
T. gondii prophylaxis is indicated for heart–lung transplant recipients who are T. gondii IgG negative, but the
donor is positive. T. gondii prophylaxis is not required if the patient is receiving trimethoprim+sulfamethoxazole
for PJP prophylaxis. If the patient is hypersensitive to trimethoprim+sulfamethoxazole and requires prophylaxis
for both PJP and T. gondii, see here for regimens.
guide.
Indications for CMV prophylaxis are beyond the scope of these guidelines—refer to local protocols. Pre-emptive
treatment is not well studied in lung and heart–lung transplant recipients; universal prophylaxis is the preferred
approach.
Start universal prophylaxis on day 1 after transplant. For antiviral regimens, see Universal prophylaxis.
Continue CMV universal prophylaxis for at least 6 months after transplant, or for 1 to 3 months following
treatment of rejection episodes (eg with antilymphocyte therapy). Some centres continue CMV prophylaxis
indefinitely if there is a serological mismatch between the organ donor and recipient.
regimens, see here.
Continue HSV prophylaxis for 1 to 3 months. Restart prophylaxis during treatment of rejection episodes and
continue for 1 to 3 months.
See Recurrent episodes oral mucocutaneous herpes and Suppressive therapy for genital herpes.
Mould infection
Some centres recommend routine antifungal prophylaxis against mould infection, while others recommend
prophylaxis only for high-risk patients—refer to local protocols.
Prophylaxis is typically started on day 1 after transplant or early in the postoperative period. Antifungal regimens
vary between centres; see here for example regimens.
Duration of antifungal prophylaxis:
Antifungal prophylaxis is often continued for 3 months; consult local protocols.

stercoralis [NB2].



disease.
Other
Haematopoietic stem cell transplant patients
Overview
This section covers assessing the need for and duration of antimicrobial prophylaxis for:
allogeneic haematopoietic stem cell transplant (HSCT) patients

autologous HSCT patients.
HSCT is used primarily for the treatment of haematological malignancy. The risk of infection after HSCT depends
on:
pretransplant factors such as chemotherapy and complications (eg neutropenia)

the type of transplant and graft
the time since the transplant
whether the patient has graft-versus-host disease (GVHD)
the relatedness of the human leukocyte antigen (HLA) match
the intensity of the conditioning regimen
post-transplant immunosuppressive therapy
the time to neutrophil engraftment.
HSCT recipients who are not receiving immunosuppressive therapy and do not have GVHD can reach immune
competence approximately 24 months after the transplant.
Antimicrobial prophylaxis after HSCT is a highly specialised area. The following text is a general guide to the
usual indications for antimicrobial prophylaxis. Seek expert advice from the transplant centre or an infectious
diseases physician before changing or stopping prophylaxis.
Allogeneic haematopoietic stem cell transplant
Following an allogeneic HSCT, patients are at increased risk of infection. For antimicrobial prophylaxis
recommendations, see Table 2.54. Additional antibiotic prophylaxis may be required before the transplant; this is
reading.
Immunity to vaccine-preventable diseases is partially or completely lost after an allogeneic HSCT and patients
require revaccination. For information on the revaccination schedule after HSCT, consult local protocols and see
the Australian Immunisation Handbook [URL].
Antimicrobial prophylaxis for allogeneic haematopoietic stem cell transplant patients (Table
2.54) [NB1]

Toxoplasma gondii.

Continue PJP prophylaxis for 12 months after transplant or after stopping immunosuppressive therapy, whichever
is later.
Toxoplasma gondii
T. gondii prophylaxis is indicated for patients who are T. gondii IgG positive. T. gondii prophylaxis is not required
if the patient is receiving trimethoprim+sulfamethoxazole for PJP prophylaxis. If the patient is hypersensitive to
trimethoprim+sulfamethoxazole and requires prophylaxis for both PJP and T. gondii, see here for regimens.
guide.
For universal prophylaxis, start from engraftment. For antiviral regimens, see Universal prophylaxis.
antiviral regimens, see Pre-emptive treatmenty.
For universal prophylaxis, continue until day 100 after transplant, or until day 180 if the patient has an episode of
CMV disease before day 100, significant graft-versus-host disease (GVHD), or is taking corticosteroids or other
ongoing immunosuppression at day 100.
HSV prophylaxis is indicated for patients who are HSV IgG positive. HSV prophylaxis is not required if the
patient is receiving valganciclovir or ganciclovir for CMV prophylaxis.
Start HSV prophylaxis on the day before stem cell infusion. For antiviral regimens, see here.
Continue HSV prophylaxis until engraftment, or longer if there is significant ongoing immunosuppression. If the
patient is varicella-zoster virus (VZV) IgG positive, ongoing prophylaxis is required (see below).
Varicella-zoster virus (VZV)
VZV prophylaxis is indicated for patients who are VZV IgG positive. VZV prophylaxis is not required if the
patient is receiving valganciclovir or ganciclovir for CMV prophylaxis.
Start VZV prophylaxis at engraftment. For antiviral regimens, see here.
Duration of VZV prophylaxis:
Continue VZV prophylaxis until 1 year after transplant, or longer if there is significant ongoing
immunosuppression.
Mould infection
Antifungal prophylaxis against mould infection is recommended for high-risk patients such as patients with pre-
engraftment neutropenia expected to last for more than 14 days, patients with previous infection or colonisation
with Aspergillus species or other moulds, and patients with GVHD or other complications postengraftment
requiring treatment with corticosteroids. Refer to local protocols.
Start antifungal prophylaxis on the day of stem cell infusion (if indicated pre-engraftment) or at onset of GVHD.
For antifungal regimens, see here.
Refer to local protocols for duration of antifungal prophylaxis. Most centres continue prophylaxis for at least 75
days, or until the daily prednisolone dose is less than 15 mg, whichever is later. A longer duration of prophylaxis
may be needed for patients with GVHD—seek expert advice and consult local protocols.
Yeast infection
Antifungal prophylaxis against yeast infection is indicated for patients with neutropenia expected to last less than
14 days; however, yeast prophylaxis is not required if the patient is receiving mould prophylaxis.
Start prophylaxis on the day of stem cell infusion (if indicated pre-engraftment). For antifungal regimens, see
here.
Refer to local protocols for duration of antifungal prophylaxis. Most centres continue prophylaxis for at least 75
days or until corticosteroids are stopped, whichever is later.
Streptococcus pneumoniae
Antibiotic prophylaxis against S. pneumoniae is indicated for patients with GVHD, patients with
hypogammaglobulinaemia and patients who develop bronchiolitis obliterans.
For antibiotic regimens, see here.
Duration of antibiotic prophylaxis:
Refer to local protocols for duration of S. pneumoniae prophylaxis. Recommendations vary; at a minimum,
continue prophylaxis for the duration of immunosuppressive treatment. Some units continue for longer (eg 2
years).
stercoralis [NB2].



disease.

Other
Hepatitis B virus and tuberculosis reactivation can occur, including in patients who are hepatitis B surface
antigen (HBsAg) negative but who have antibodies to hepatitis B core antigen (anti-HBc). See Hepatitis B virus
prophylaxis and Prevention of tuberculosis.
Primary antiviral influenza prophylaxis may be indicated for hospitalised patients during institutional outbreaks.
See Influenza virus prophylaxis.
NB1: Antimicrobial prophylaxis after haematopoietic stem cell transplant is a highly specialised area. This table is a general guide to the usual
indications for antimicrobial prophylaxis. Seek expert advice from the transplant centre or an infectious diseases physician before changing or stopping
prophylaxis.
Autologous haematopoietic stem cell transplant
Following an autologous HSCT, patients are at increased risk of infection. For antimicrobial prophylaxis
recommendations, see Table 2.55. Additional antibiotic prophylaxis may be required before the transplant; this is
reading.
Immunity to vaccine-preventable diseases is partially or completely lost after an autologous HSCT and patients
require revaccination. For information on the revaccination schedule after HSCT, consult local protocols and see
the Australian Immunisation Handbook [URL].
Antimicrobial prophylaxis for autologous haematopoietic stem cell transplant patients (Table
2.55) [NB1]

PJP prophylaxis is indicated for patients with haematological malignancy.
regimens, see here.
Continue PJP prophylaxis for 3 to 6 months after transplant or after stopping immunosuppressive therapy,
whichever is later.
CMV prophylaxis or screening is not routinely indicated—refer to local protocols. CMV testing should only be
performed if there is clinical suspicion of CMV disease.
HSV prophylaxis is indicated for patients with neutropenia who are HSV IgG positive.
Start prophylaxis on the day before stem cell infusion. For antiviral regimens, see here.
Continue HSV prophylaxis until engraftment or day 30, whichever is shorter. If the patient is varicella-zoster
virus (VZV) IgG positive, ongoing prophylaxis is required (see below).
Varicella-zoster virus (VZV)
VZV prophylaxis is indicated for patients who are VZV IgG positive.
Start VZV prophylaxis at engraftment. For antiviral regimens, see here.
Duration of VZV prophylaxis:
Continue VZV prophylaxis for 12 months after transplant, or longer if there is significant ongoing
immunosuppression.
Mould infection
Antifungal prophylaxis against mould infection is not routinely indicated. Use prophylaxis for patients with a
history of invasive aspergillosis (or other mould infection), or patients who have been treated with extensive
chemotherapy (particularly fludarabine) for refractory malignancy. Seek expert advice or consult local protocols.
Yeast infection
Antifungal prophylaxis against yeast infection is indicated for patients who have been treated with extensive
chemotherapy (particularly fludarabine) for refractory malignancy, those treated with a conditioning
chemotherapy regimen associated with a greater risk of mucositis, or if prolonged neutropenia is anticipated.
Start antifungal prophylaxis on the day of stem cell infusion. For antifungal regimens, see here.
Continue antifungal prophylaxis until the neutrophil count recovers (more than 0.5 × 109/L).
stercoralis [NB2].



disease.

Other
Primary antiviral influenza prophylaxis may be indicated for hospitalised patients during institutional outbreaks
—see Influenza virus prophylaxis.
NB1: Antimicrobial prophylaxis after haematopoietic stem cell transplant is a highly specialised area. This table is a general guide to the usual
indications for antimicrobial prophylaxis. Seek expert advice from the transplant centre or an infectious diseases physician before changing or stopping
prophylaxis.
Pneumocystis jirovecii pneumonia prophylaxis in immunocompromised

adults without HIV infection
Introduction
This section includes regimens for primary prophylaxis of Pneumocystis jirovecii pneumonia (PJP) in
immunocompromised adults without HIV infection. To assess if primary PJP prophylaxis is indicated, see
Assessing the need for antimicrobial prophylaxis in immunocompromised adults without HIV infection.
For primary prophylaxis of PJP in adults with HIV infection, see Pneumocystis jirovecii pneumonia in adults with
HIV infection.
For detailed recommendations for PJP prophylaxis in patients with haematological and other malignancies, see the
Australian and New Zealand antifungal guidelines [Note 1].
For treatment and secondary prophylaxis of PJP, see Pneumocystis jirovecii pneumonia (PJP).
Note 1: Cooley L, Dendle C, Wolf J, Teh BW, Chen SC, Boutlis C, et al. Consensus guidelines for diagnosis,
prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid
malignancies, 2014. Intern Med J 2014;44(12b):1350-63. [URL]
Preferred PJP prophylaxis

Trimethoprim+sulfamethoxazole is the most effective prophylaxis against PJP and is recommended unless
contraindicated (eg in patients hypersensitive to trimethoprim+sulfamethoxazole, patients taking high-dose
methotrexate).
Trimethoprim+sulfamethoxazole is the most effective prophylaxis against PJP.
The trimethoprim+sulfamethoxazole regimens below also provide protection against Toxoplasma gondii infection.
For prophylaxis against both PJP and T. gondii in patients unable to take trimethoprim+sulfamethoxazole, see
Toxoplasma gondii prophylaxis in immunocompromised adults without HIV infection.
PJP prophylaxis with trimethoprim+sulfamethoxazole also provides prophylaxis against Toxoplasma gondii.
A Cochrane review [Note 2] found the regimens below to be effective for prevention of PJP. The choice of
regimen depends on patient preference, adherence and tolerability. Use:
1 trimethoprim+sulfamethoxazole 80+400 mg orally, daily; for duration of prophylaxis, see

Assessing the need for antimicrobial prophylaxis in immunocompromised adults without
HIV infection
OR
1 trimethoprim+sulfamethoxazole 160+800 mg orally, daily; for duration of prophylaxis,

see Assessing the need for antimicrobial prophylaxis in immunocompromised adults
OR
1 trimethoprim+sulfamethoxazole 160+800 mg orally, 3 times weekly; for duration of

prophylaxis, see Assessing the need for antimicrobial prophylaxis in
immunocompromised adults without HIV infection [Note 3].

expert advice if desensitisation is being considered. If desensitisation is not an option, see Alternative PJP
prophylaxis.
Note 2: Stern A, Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in
non-HIV immunocompromised patients. Cochrane Database Syst Rev 2014;(10):CD005590. [URL]
Alternative PJP prophylaxis

For PJP prophylaxis in patients with nonsevere hypersensitivity to trimethoprim+sulfamethoxazole, or those
unable to take trimethoprim+sulfamethoxazole, use:
1 dapsone 100 mg orally, daily; for duration of prophylaxis, see Assessing the need for
antimicrobial prophylaxis in immunocompromised adults without HIV infection [Note 4]
[Note 5] [Note 6]
OR
2 pentamidine 300 mg via nebuliser, every 4 weeks; for duration of prophylaxis, see
Assessing the need for antimicrobial prophylaxis in immunocompromised adults without
HIV infection [Note 7] [Note 8]
OR
3 atovaquone 1500 mg orally with fatty food or full-fat milk, daily; for duration of
use pentamidine or atovaquone (see dosages above). Do not give dapsone because there is a possibility of cross-
hypersensitivity).
Toxoplasma gondii prophylaxis in immunocompromised adults without

HIV infection
Introduction
This section includes regimens for antimicrobial prophylaxis against Toxoplasma gondii in immunocompromised
adults without HIV infection. To assess if T. gondii prophylaxis is indicated, see Assessing the need for
antimicrobial prophylaxis in immunocompromised adults without HIV infection.
Cases of T. gondii infection may occur despite prophylaxis. Refer to local protocols or the guidelines listed in
Further reading for advice about patient screening and nonpharmacological preventive measures.
Preferred T. gondii prophylaxis

Trimethoprim+sulfamethoxazole is the most effective prophylaxis against Toxoplasma gondii. Prophylaxis against
Pneumocystis jirovecii pneumonia (PJP) with trimethoprim+sulfamethoxazole protects against T. gondii infection.
For trimethoprim+sulfamethoxazole regimens, see here.
Before prescribing toxoplasmosis prophylaxis, check if the patient is taking prophylaxis against Pneumocystis jirovecii
pneumonia.

expert advice if desensitisation is being considered. If desensitisation is not an option, see Alternative T. gondii
prophylaxis.
Alternative T. gondii prophylaxis
For prophylaxis against both T. gondii and PJP in patients with nonsevere hypersensitivity to
trimethoprim+sulfamethoxazole, or those unable to take trimethoprim+sulfamethoxazole, consider dapsone daily
or weekly (in combination with weekly pyrimethamine and calcium folinate). Consider patient preference,
adherence and tolerability when choosing between the daily and weekly regimens.
If a daily dapsone-based regimen is preferred, use:
dapsone 50 mg orally, daily; for duration of prophylaxis, see Assessing the need for
antimicrobial prophylaxis in immunocompromised adults without HIV infection [Note 9]
[Note 10]
PLUS
pyrimethamine 50 mg orally, once weekly; for duration of prophylaxis, see Assessing the
need for antimicrobial prophylaxis in immunocompromised adults without HIV infection
PLUS
calcium folinate 30 mg orally, once weekly (preferably not on the same day
pyrimethamine is taken); for duration of prophylaxis, see Assessing the need for
If a weekly dapsone-based regimen is preferred, use:
dapsone 200 mg orally, once weekly; for duration of prophylaxis, see Assessing the need
for antimicrobial prophylaxis in immunocompromised adults without HIV infection [Note
9] [Note 10]
PLUS
pyrimethamine 75 mg orally, once weekly (on the same day dapsone is taken); for
duration of prophylaxis, see Assessing the need for antimicrobial prophylaxis in
PLUS
calcium folinate 30 mg orally, once weekly (preferably not on the day dapsone and
pyrimethamine are taken); for duration of prophylaxis, see Assessing the need for
These dapsone-based regimens are derived from studies in patients with HIV infection. Some centres recommend
atovaquone (alone, or in combination with pyrimethamine and calcium folinate), but data on effectiveness are
limited to small retrospective studies.
choosing a safe and effective regimen is complex—seek expert advice. Do not give dapsone because there is a
hypersensitivity).
Cytomegalovirus prophylaxis in immunocompromised adults without
HIV infection
Introduction
This section includes regimens for antiviral prophylaxis (universal prophylaxis) and pre-emptive treatment of
cytomegalovirus (CMV) infection in immunocompromised adults without HIV infection.
To assess if CMV universal prophylaxis or pre-emptive treatment is indicated, see Assessing the need for
The two approaches for patient management are:
universal prophylaxis
pre-emptive treatment.
The approach depends on several factors, including the availability of CMV monitoring and the risk of CMV
reactivation. Some units use a hybrid approach, with universal prophylaxis during the first 30 days after allogeneic
haematopoietic stem cell transplant (HSCT) and a switch to pre-emptive therapy thereafter.
If valganciclovir or ganciclovir are given for CMV prophylaxis, aciclovir or valaciclovir are not needed for herpes
simplex virus (HSV) or varicella-zoster virus (VZV) prophylaxis.
CMV prophylaxis with valganciclovir or ganciclovir provides prophylaxis against herpes simplex virus and varicella-zoster
virus.
International guidelines [Note 11] are available for further information about CMV management (including
prophylaxis) in solid organ transplant patients.
For treatment and secondary prophylaxis of CMV infection, see Cytomegalovirus (CMV) infection.
Note 11: Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, et al. The Third
International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation.
Transplantation 2018. [URL]
Universal prophylaxis
For universal CMV prophylaxis, use:
valganciclovir 900 mg orally, daily; for duration of prophylaxis, see Assessing the need
for antimicrobial prophylaxis in immunocompromised adults without HIV infection.
For allogeneic HSCT recipients with active graft-versus-host disease (GVHD) of the gut, patients with severe
diarrhoea, or those unable to tolerate oral therapy, use:
ganciclovir 5 mg/kg intravenously, daily. Switch to oral valganciclovir (see dosage above)
when possible; for duration of prophylaxis, see Assessing the need for antimicrobial
prophylaxis in immunocompromised adults without HIV infection.
Some transplant centres use a reduced dosage of ganciclovir (eg given 3 or 5 times weekly).
Pre-emptive treatment
Pre-emptive treatment involves monitoring the patient’s CMV viral load to detect viral replication before the
patient develops symptoms, then starting early antiviral treatment to prevent progression to symptomatic CMV
disease. See Cytomegalovirus (CMV) infection for treatment of symptomatic CMV disease.
Monitor the patient’s CMV DNA by nucleic acid amplification tests (NAAT) (eg polymerase chain reaction [PCR])
on peripheral whole blood or serum once- or twice-weekly from the time of engraftment. The threshold for starting
pre-emptive treatment has not been established due to variability in diagnostic assays—consult local protocols or
the transplant centre for interpretation of results.
The need for pre-emptive treatment is determined by the viral load or the rate of change in the viral load—consult
local protocols. Take into account the risk of infection, the degree of immunosuppression and the type of
transplant. Some centres start pre-emptive treatment if two consecutive CMV DNA NAAT (eg PCR) results are
positive, regardless of the viral load.
For pre-emptive treatment of CMV, use:
valganciclovir 900 mg orally, 12-hourly; see below for duration of therapy.
For allogeneic HSCT recipients with active GVHD of the gut, patients with severe diarrhoea, or those unable to
tolerate oral therapy, use:
ganciclovir 5 mg/kg intravenously, 12-hourly. Switch to oral valganciclovir (see dosage

above) when possible; see below for duration of therapy.
Duration of therapy: measure CMV DNA weekly in whole blood. Stop treatment when one or two CMV DNA
results are negative—consult local protocols. If the patient developed symptomatic CMV disease, secondary
prophylaxis (maintenance therapy) may be required. If the patient did not develop symptomatic CMV disease,
maintenance therapy is not usually required—seek expert advice or consult local protocols.
Continue CMV DNA monitoring for 100 days after the transplant, or for 180 days if there is significant ongoing
GVHD or immunosuppression at day 100.
Yeast and mould antifungal prophylaxis in immunocompromised adults

Introduction
This section includes regimens for antifungal prophylaxis against yeast and mould infection in
immunocompromised adults without HIV infection. To assess if antifungal prophylaxis against yeast and mould
infection is indicated, see Assessing the need for antimicrobial prophylaxis in immunocompromised adults without
HIV infection.
For detailed recommendations for prophylaxis against yeast and mould infections in haematology patients, see the
Australian and New Zealand antifungal guidelines [Note 12].
Note 12: Fleming S, Yannakou CK, Haeusler GM, Clark J, Grigg A, Heath CH, et al. Consensus guidelines for
antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2014. Intern
Med J 2014;44(12b):1283-97. [URL]
Mould infection
Aspergillus, Lomentospora and Scedosporium species are the most likely mould pathogens in
immunocompromised adults. Antifungal prophylaxis for mould infection also protects against infection with yeast
(eg Candida species). To assess if antifungal prophylaxis for mould infection is required, see Assessing the need
Seek expert advice on antifungal prophylaxis after liver transplant, lung or heart–lung transplant or for patients
with acute lymphocytic leukaemia (ALL) treated with vinca alkaloids (eg vincristine). An alternative to azole
therapy (eg amphotericin B liposomal or lipid complex, an echinocandin) may be required in these patients—refer
to local protocols.
Seek expert advice on antifungal prophylaxis for liver, lung or heart–lung transplant patients, or those treated with vinca
alkaloids.
For antifungal prophylaxis against mould infection in other patients, use:
1 posaconazole modified-release tablets 300 mg orally, 12-hourly for two doses, then 300
mg daily; for duration of prophylaxis, see Assessing the need for antimicrobial
prophylaxis in immunocompromised adults without HIV infection [Note 13]
OR
2 voriconazole tablets (adult 40 kg or more) 400 mg orally, 12-hourly for two doses, then
200 mg orally, 12-hourly; for duration of prophylaxis, see Assessing the need for
antimicrobial prophylaxis in immunocompromised adults without HIV infection. Monitor
plasma concentration (see Monitoring antimicrobial blood concentrations).
For patients who cannot swallow a tablet formulation, use an oral liquid formulation:
1 posaconazole liquid 200 mg orally with fatty food or an acidic beverage, 8-hourly; for
immunocompromised adults without HIV infection. Monitor plasma concentration (see
Monitoring antimicrobial blood concentrations) [Note 13]
OR
2 voriconazole liquid (adult 40 kg or more) 400 mg orally, 12-hourly for two doses, then
200 mg orally, 12-hourly; for duration of prophylaxis, see Assessing the need for
antimicrobial prophylaxis in immunocompromised adults without HIV infection. Monitor
plasma concentration (see Monitoring antimicrobial blood concentrations).
If oral therapy is not possible, use:
1 posaconazole 300 mg intravenously, daily; give a loading dose of 300 mg intravenously

12-hourly for two doses if not switching from oral posaconazole. For duration of
OR
1 voriconazole 4 mg/kg intravenously, 12-hourly; give a loading dose of 6 mg/kg

intravenously 12-hourly for two doses if not switching from oral voriconazole. For
Switch to oral therapy when the patient is able to tolerate and absorb oral therapy.
If intravenous therapy is required but an azole cannot be used, seek expert advice. Options include amphotericin B
liposomal or lipid complex, or an echinocandin, but evidence is limited.
Note 13: Oral preparations of posaconazole are not bioequivalent; appropriate dosing and administration
depends on the preparation.
Yeast infection
Candida species are the most likely yeast pathogens in immunocompromised adults without HIV infection. To
assess if antifungal prophylaxis against yeast infection is indicated, see Assessing the need for antimicrobial
prophylaxis in immunocompromised adults without HIV infection. Prophylaxis against yeast infection is not
necessary if the patient is taking prophylaxis against mould infection.
Prophylaxis against yeast infection is not necessary if the patient is taking prophylaxis against mould infection.
For antifungal prophylaxis against infection with yeast (eg Candida species), use:
fluconazole 200 mg orally, daily; for duration of prophylaxis, see Assessing the need for
Some centres use a higher dosage of fluconazole (eg 400 mg daily) for allogeneic haematopoietic stem cell
transplant (HSCT) patients—refer to local protocols.
Herpes simplex virus and varicella-zoster virus prophylaxis in

This section includes regimens for antiviral prophylaxis against herpes simplex virus (HSV) and varicella-zoster
virus (VZV) infection in immunocompromised adults without HIV infection. To assess if HSV and VZV antiviral
prophylaxis is indicated, see Assessing the need for antimicrobial prophylaxis in immunocompromised adults
without HIV infection. HSV and VZV prophylaxis is not required in patients already receiving valganciclovir or
ganciclovir for cytomegalovirus prophylaxis.
HSV and VZV prophylaxis is not required in patients receiving valganciclovir or ganciclovir for cytomegalovirus prophylaxis.
For HSV and VZV antiviral prophylaxis, use:
valaciclovir 500 mg orally, 12-hourly; for duration of prophylaxis, see Assessing the need
If the patient is unable to tolerate or absorb oral therapy, use:
aciclovir 5 mg/kg intravenously, 8-hourly. Switch to oral valaciclovir (see dosage above)
when possible. For duration of prophylaxis, see Assessing the need for antimicrobial
prophylaxis in immunocompromised adults without HIV infection.
For varicella-zoster virus immunisation recommendations, see the Australian Immunisation Handbook [URL].
Hepatitis B virus prophylaxis in immunocompromised adults without

HIV infection
Immunocompromised patients are at risk of developing a severe reactivation of hepatitis B virus. Test patients for
hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B core antigen (anti-HBc) before starting
immunosuppressive therapy.
Prophylaxis is indicated for immunocompromised patients who are HBsAg positive, and for some patients who are
HBsAg negative but anti-HBc positive (eg those who undergo conditioning for allogeneic haematopoietic stem
cell transplant (HSCT), those receiving rituximab); see the Australian consensus guidelines [Note 14] for more
detail.
If prophylaxis to prevent reactivation of hepatitis B is indicated, use entecavir or a tenofovir disoproxil salt (ie
fumarate, maleate or phosphate)—for dosages, see Table 6.12.
For hepatitis B virus immunisation recommendations, see the Australian Immunisation Handbook [URL].
Note 14: Doyle J, Raggatt M, Slavin M, McLachlan SA, Strasser SI, Sasadeusz JJ, et al. Hepatitis B
management during immunosuppression for haematological and solid organ malignancies: an Australian
consensus statement. Med J Aust 2019;210(10):462-8. [URL]
Mycobacterium tuberculosis prophylaxis in immunocompromised adults

Consider screening immunocompromised patients for Mycobacterium tuberculosis infection. If latent tuberculosis
is identified, treatment (antimicrobial prophylaxis) is indicated to reduce the incidence of progression to active
disease. Treatment of latent tuberculosis in patients receiving immunosuppressive therapy requires expert advice.
See also Additional considerations for latent tuberculosis in patients receiving immunosuppressive therapy. For
treatment regimens, see Treatment of latent tuberculosis.
Influenza virus prophylaxis in immunocompromised adults without

HIV infection
Immunocompromised patients are at high risk of poor outcomes following influenza infection.
For postexposure influenza prophylaxis for immunocompromised patients, see Postexposure prophylaxis for
influenza.
Primary antiviral prophylaxis may be indicated for immunocompromised patients during institutional outbreaks
—consult the local infection control team. Evidence of influenza transmission in a high-risk unit (eg
haematopoietic stem cell transplant [HSCT] unit) may be an indication for primary prophylaxis in all patients in
the unit. If primary prophylaxis is indicated, use:
oseltamivir 75 mg orally, daily.
Duration of therapy: the duration of primary antiviral prophylaxis for institutional outbreaks is not established—
seek expert advice from the local infection control team. Some units give prophylaxis for 10 days after the last
confirmed case of influenza in the unit, but others give prophylaxis until the end of the influenza season.
For influenza immunisation recommendations, see the Australian Immunisation Handbook [URL].
Streptococcus pneumoniae prophylaxis in immunocompromised adults
This section includes regimens for antibiotic prophylaxis against Streptococcus pneumoniae in
immunocompromised adults without HIV infection. To assess if S. pneumoniae prophylaxis is indicated, see
Assessing the need for antimicrobial prophylaxis in immunocompromised adults without HIV infection.
For S pneumoniae prophylaxis in patients with asplenia or hyposplenism, see Prevention of infection in asplenic
and hyposplenic patients.
For S. pneumoniae prophylaxis in immunocompromised adults without HIV infection, use:
amoxicillin 250 mg orally, daily; for duration of prophylaxis, see Assessing the need for
Penicillins are the drugs of choice for antibiotic prophylaxis of S. pneumoniae. Penicillin resistance in S.
pneumoniae is low and rates of resistance to alternative antibiotics are much higher.
If hypersensitivity to penicillins is reported, assess whether the patient has immune-mediated hypersensitivity—
see Types of antimicrobial hypersensitivity. Consider desensitisation for patients with immediate penicillin
hypersensitivity if adherence to prophylaxis is likely (eg patients with a condition requiring essential medications,
such as haematological malignancies). If 1 day of prophylaxis is missed, the patient’s hypersensitivity will return
and desensitisation must be performed again. Seek expert advice if desensitisation is being considered. For patients
with delayed nonsevere hypersensitivity to penicillins, seek expert advice—a penicillin provocation test may be
appropriate.
For patients who cannot be desensitised or undergo a provocation test, or patients with delayed severe
hypersensitivity to penicillins, seek expert advice to guide antibiotic choice.
For S. pneumoniae immunisation recommendations, see the Australian Immunisation Handbook [URL].
Strongyloides stercoralis prophylaxis in immunocompromised adults

This section includes regimens for antimicrobial prophylaxis and pre-emptive treatment of Strongyloides
stercoralis in immunocompromised adults without HIV infection.
For treatment of symptomatic S. stercoralis infection, see Strongyloidiasis.
stercoralis—ie those who were born, live in or visit endemic areas. This includes patients from tropical or central
Australia or remote Aboriginal and Torres Strait Islander communities, as well as older patients from southern
European countries, and refugees and migrants from developing countries.
For pre-emptive treatment in asymptomatic immunocompromised adults with positive Strongyloides serology,
use:
ivermectin 200 micrograms/kg orally with fatty food, daily for 2 days; repeat after 14 days
(ie on days 15 and 16) to complete a four-dose course.
Immunocompromised patients who live in or visit a Strongyloides-endemic area (eg remote Aboriginal and Torres
Strait Islander communities) should receive ongoing prophylaxis; use:
ivermectin 200 micrograms/kg orally with fatty food, once every 3 months while the
patient remains immunocompromised and continues to live in or visit an endemic area.
S. stercoralis prophylaxis is recommended for patients with significant immunosuppression and negative
Strongyloides serology who live in or visit a Strongyloides-endemic area (eg remote Aboriginal and Torres Strait
Islander communities). In this circumstance, significant immunosuppression is defined as use of prednisolone 20
mg daily or more (or equivalent; see Table 2.45) for more than 2 weeks, or any other potent immunosuppressive
drug (eg used for chemotherapy or following organ transplant). Use:
ivermectin 200 micrograms/kg orally with fatty food, as a single dose.
Immunocompromised patients who live in or visit a Strongyloides-endemic area (eg remote Aboriginal and Torres
Strait Islander communities) should receive ongoing prophylaxis; use:
ivermectin 200 micrograms/kg orally with fatty food, once every 3 months while the
patient remains immunocompromised and continues to live in or visit an endemic area.
Burkholderia pseudomallei prophylaxis in immunocompromised adults

This section includes regimens for antibiotic prophylaxis against Burkholderia pseudomallei in
Perform baseline B. pseudomallei serology in patients with significant immunosuppression who have lived in an
area where melioidosis is endemic, such as tropical regions of Australia [Note 15]. In this circumstance, significant
immunosuppression is defined as use of prednisolone 20 mg daily or more (or equivalent; see Table 2.45) for more
than 2 weeks, or any other potent immunosuppressive drug (eg used for chemotherapy or following organ
transplant immunosuppression therapy). If serology is positive or the patient has previously been treated for
melioidosis, investigate thoroughly for subclinical disease and treat if present (see Melioidosis).
For patients with positive B. pseudomallei serology, or a history of melioidosis but no clinical evidence of
current disease, monitor closely and use:
trimethoprim+sulfamethoxazole 160+800 mg orally, daily. Prophylaxis is often continued

indefinitely; seek expert advice before stopping therapy.
If the patient has negative B. pseudomallei serology but lives in or visits an endemic area, consider giving
primary prophylaxis during the wet season only [Note 16]. Use:
trimethoprim+sulfamethoxazole 160+800 mg orally, daily during the wet season.
Note 15: Tropical regions of Australia refer to regions north of 20°S latitude. This includes areas of Queensland
Note 16: In tropical regions of Australia, the wet season is usually from October to April. Melioidosis is more
common in this season.
Neisseria meningitidis prophylaxis in adults treated with eculizumab

This section includes regimens for antibiotic prophylaxis against Neisseria meningitidis in adults treated with
eculizumab for paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome.
Patients treated with eculizumab are at greater risk of invasive meningococcal disease. Immunisation is required
before, or at the time of, starting therapy with eculizumab. For meningococcal disease immunisation
recommendations, see the Australian Immunisation Handbook [URL].
All patients treated with eculizumab require antibiotic prophylaxis against N. meningitidis.
Antibiotic prophylaxis against N. meningitidis is recommended in all patients treated with eculizumab, including
those that have been immunised, because cases of invasive meningococcal disease have occurred in immunised
patients. Start prophylaxis at the same time as eculizumab therapy. Use:
1 amoxicillin 250 mg orally, daily. Continue prophylaxis for the duration of treatment with
eculizumab and for 60 days after stopping eculizumab
OR
1 phenoxymethylpenicillin 250 mg orally, 12-hourly. Continue prophylaxis for the duration

of treatment with eculizumab and for 60 days after stopping eculizumab.
For patients hypersensitive to penicillins, seek expert advice.
Progressive multifocal leukoencephalopathy (John Cunningham virus)

Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of the John Cunningham virus
(JCV). PML is a serious adverse effect of natalizumab treatment for relapsing-remitting multiple sclerosis. It can
also occur in advanced HIV infection and as a rare adverse effect of immunosuppressive therapy and cancer
chemotherapy.
In patients taking natalizumab, the estimated incidence of PML is 2.1 cases per 1000 patients treated. Assess the
patient’s risk of PML before starting natalizumab. Consult the product information for pretreatment screening and
risk assessment criteria.
Monitor patients receiving natalizumab for features of PML such as progressive cognitive decline, visual changes,
ataxia and seizures.
Further reading
Guidelines for solid organ transplant patients
American Society of Transplantation (AST). Infectious disease guidelines. [URL]
European Directorate for the Quality of Medicines & HealthCare of the Council of Europe (EDQM). Guide to the
quality and safety of organs for transplantation. 7th ed. France: EDQM; 2018. [URL] (see ‘Chapter 8. Risk of
transmission of infectious diseases’)
Husain S, Sole A, Alexander BD, Aslam S, Avery R, Benden C, et al. The 2015 International Society for Heart and
Lung Transplantation Guidelines for the management of fungal infections in mechanical circulatory support and
cardiothoracic organ transplant recipients: Executive summary. J Heart Lung Transplant 2016;35(3):261–82.
[URL]
White SL, Rawlinson W, Boan P, Sheppeard V, Wong G, Waller K, et al. Infectious Disease Transmission in Solid
Organ Transplantation: Donor Evaluation, Recipient Risk, and Outcomes of Transmission. Transplant Direct
2019;5(1):e416. [URL]
Guidelines for oncology, haematology and haematopoietic stem cell transplant patients
Australian and New Zealand Consensus Guidelines for the Use of Antifungal Agents in the
Haematology/oncology Setting 2014. [URL]
Baden LR, Swaminathan S, Angarone M, Blouin G, Camins BC, Casper C, et al. Prevention and Treatment of
Cancer-Related Infections, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc
Netw 2016;14(7):882–913. [URL]
eviQ, Cancer Institute NSW. eviQ Cancer Treatments Online. [URL]
Maertens J, Marchetti O, Herbrecht R, Cornely OA, Fluckiger U, Frere P, et al. European guidelines for antifungal
management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3—2009 update.
Bone Marrow Transplant 2011;46(5):709–18. [URL]
Slavin MA, Heath CH, Thursky KA, Morrissey CO, Szer J, Ling LM, et al. Antifungal prophylaxis in adult stem
cell transplantation and haematological malignancy. Intern Med J 2008;38(6b):468–76. [URL]
Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, et al. Antimicrobial Prophylaxis for Adult
Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin
Oncol 2018:JCO1800374. [URL]
Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious
complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow
Transplant 2009;15(10):1143–238. [URL]
Yokoe D, Casper C, Dubberke E, Lee G, Munoz P, Palmore T, et al. Infection prevention and control in health-care
facilities in which hematopoietic cell transplant recipients are treated. Bone Marrow Transplant 2009;44(8):495–
507. [URL]
Cervical cancer screening in immunocompromised women:
The American College of Obstetricians and Gynecologists. Practice Bulletin No. 168: Cervical cancer screening
and prevention. Obstet Gynecol 2016;128(4):e111–30. [URL]
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Wilck MB, Zuckerman RA. AST Infectious Diseases Community of Practice. Herpes simplex virus in solid organ
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Mycobacterium tuberculosis prophylaxis in immunocompromised adults without HIV infection
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Influenza virus prophylaxis in immunocompromised adults without HIV infection
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hematopoietic stem cell transplant recipients: a retrospective case-control study. Clin Infect Dis 2007;45(2):187–93.
Streptococcus pneumoniae prophylaxis in immunocompromised adults without HIV infection
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Strongyloides stercoralis prophylaxis in immunocompromised adults without HIV infection
2004;17(1):208–17.
Mejia R, Nutman TB. Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections
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Burkholderia pseudomallei prophylaxis in immunocompromised adults without HIV infection
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Majoni SW, Hughes JT, Heron B, Currie BJ. Trimethoprim+Sulfamethoxazole Reduces Rates of Melioidosis in High-
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Neisseria meningitidis prophylaxis in adults treated with eculizumab
Hall V, Pai Mangalore R, He S, Stevens K, Trubiano JA, Holmes NE, et al. Fulminant meningococcal sepsis due to
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McNamara LA, Topaz N, Wang X, Hariri S, Fox L, MacNeil JR. High risk for invasive meningococcal disease among
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Progressive multifocal leukoencephalopathy (John Cunningham virus)
Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, et al. Risk of natalizumab-

associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366(20):1870–80.
Prevention of invasive group A streptococcal infection
Approach to preventing iGAS infection
Group A streptococcus (Streptococcus pyogenes) causes a wide range of infections, most of which are noninvasive and localised
to skin or mucosal surfaces (eg impetigo, pharyngitis). Group A streptococcal infection is considered invasive if S. pyogenes is
identified from a normally sterile site (eg blood, joint fluid). Presentations of invasive group A streptococcal (iGAS) infection
include skin and soft tissue infection complicated by bacteraemia, bone and joint infection, pneumonia, meningitis, necrotising
fasciitis and toxic shock syndrome.
This topic includes guidance on antibiotic prophylaxis to prevent infection in close contacts of a patient with an invasive group A
streptococcal infection. Although antibiotic prophylaxis is an important consideration, evidence to support its efficacy for
prevention of invasive group A streptococcal infection is limited.
Surveillance data suggest that the risk of invasive group A streptococcal infection for household contacts of patients with such an
infection may be more than 2000 times the risk for the general population. One study [Note 1] estimated that within 30 days
following an index case infection, approximately 1 in 220 household contacts will develop invasive group A streptococcal
infection. Assuming antibiotic prophylaxis is effective, it was estimated the number of household contacts needing prophylaxis to
prevent a single case of invasive group A streptococcal infection is similar to that for meningococcal disease.
International and local guidelines for management of contacts of patients with invasive group A streptococcal infection vary
widely. At the time of writing, there is no Australian national guidance for the public health management of invasive group A
streptococcal infection. Guidelines developed by states, territories and institutions should be used if available—see Further
reading.
Regardless of whether antibiotic prophylaxis is given, it is essential to provide written information about the possible symptoms of
invasive group A streptococcal infection to close contacts of patients. Advise close contacts to seek urgent medical attention if
they develop symptoms suggestive of infection within 30 days of diagnosis of the index case.
Provide written information to close contacts of a patient with an invasive group A streptococcal infection.
Note 1: Mearkle R, Saavedra-Campos M, Lamagni T, Usdin M, Coelho J, Chalker V, et al. Household transmission of invasive
group A Streptococcus infections in England: a population-based study, 2009, 2011 to 2013. Euro Surveill 2017;22(19): pii:
30532. [URL]
Indications for iGAS antibiotic prophylaxis

For a single probable or confirmed case of invasive group A streptococcal (iGAS) infection, discuss the role of antibiotic
prophylaxis for close contacts with an expert (eg an infectious diseases physician, clinical microbiologist or, in jurisdictions where
invasive group A streptococcal infection is a notifiable disease, the local public health authority [Note 2]).
The definition of a close contact varies between guidelines and settings and often includes household contacts, sexual contacts,
and people who have had mucous membrane or nonintact skin exposure to potentially infectious material. See the guidelines listed
in Further reading for detailed information.
Consider giving antibiotic prophylaxis to all household contacts, but particularly the following (who are at higher risk of
infection):
mother–neonate contacts, if either the mother or a neonate develops invasive group A streptococcal infection during the first
28 days after birth
household contacts older than 75 years.
Antibiotic prophylaxis may be considered for other close contacts in some circumstances—seek expert advice.
If antibiotic prophylaxis is given to close contacts, offer prophylaxis to all household members to prevent recolonisation.
An outbreak of invasive group A streptococcal infection is defined as two or more epidemiologically linked cases (eg inpatient
facility, long-term care facility, childcare centre, community cluster) with an identical strain on molecular typing. In such an event,
an outbreak control team should be formed to manage the outbreak. Members of this team should include an infectious diseases
physician or clinical microbiologist and, in jurisdictions where invasive group A streptococcal infection is a notifiable disease, the
local public health authority [Note 2]. The outbreak management plan should include consideration of a screening and antibiotic
prophylaxis strategy.
Note 2: Contact details for Australian state and territory government health departments and public health units are available
here.
Prophylaxis regimens for iGAS infection

If antibiotic prophylaxis is indicated for close contacts of patients with probable or confirmed invasive group A streptococcal
infection, start prophylaxis as soon as possible; secondary cases usually occur shortly after the index case infection. The optimal
antibiotic prophylaxis regimen for invasive group A streptococcal (iGAS) infection has not been determined—suitable regimens
include:
1 benzathine benzylpenicillin intramuscularly, as a single dose [Note 3] [Note 4]

neonate and child 6 kg or less: 0.3 million units (0.6 mL)
OR
1 cefalexin 1 g (neonate and child: 25 mg/kg up to 1 g) orally, 12-hourly for 10 days
Benzathine benzylpenicillin is long acting; do not confuse benzathine benzylpenicillin with benzylpenicillin, which is short acting.
For close contacts with delayed nonsevere hypersensitivity to penicillins, cefalexin can be used in most cases [Note 5].
For close contacts with immediate (nonsevere or severe) or delayed severe hypersensitivity to penicillins, antibiotic choice
depends on the susceptibility of the isolate from the index case (as rates of resistance to non–beta-lactam antibiotics are higher). If
susceptibility results are not available, a reasonable regimen is:
Note 3: It is unclear if eradication of pharyngeal group A streptococcus carriage is required to prevent secondary cases. Limited
evidence suggests the addition of rifampicin to benzathine benzylpenicillin increases the rate of pharyngeal carriage eradication.
However, the role of rifampicin in the prevention of secondary invasive group A streptococcal infection is uncertain, and routine
combination prophylaxis is not recommended.
Note 4: All benzathine benzylpenicillin preparations (benzathine benzylpenicillin 900 mg/2.3 mL [equivalent to 1.2 million
units]; benzathine benzylpenicillin tetrahydrate 1 200 000 units/2.3 mL [equivalent to 1016.6 mg benzathine benzylpenicillin
tetrahydrate]; benzathine benzylpenicillin tetrahydrate 600 000 units/1.17 mL [equivalent to 517 mg benzathine benzylpenicillin
tetrahydrate]) contain the same concentration of benzathine benzylpenicillin.
Note 5: It is safe to use cefalexin in patients who had a delayed nonsevere reaction to a penicillin in the distant past. It is also
safe to use cefalexin in patients who have had a delayed nonsevere reaction recently, unless the reaction involved amoxicillin or
ampicillin, because cross-reactivity between these drugs is possible. For patients who have had a recent delayed nonsevere
reaction to amoxicillin or ampicillin, use the drug recommended for patients with immediate (nonsevere or severe) or delayed
severe hypersensitivity.
Further reading
Cummins A, Millership S, Lamagni T, Foster K. Control measures for invasive group A streptococci (iGAS) outbreaks in care
homes. J Infect 2012;64(2):156–61. [URL]
State and institutional guidelines
New South Wales Government—Invasive Group A Streptococcus control guideline [URL]
Northern Territory Government—Public health management of invasive group A streptococcal infection [URL]
Queensland Government—Invasive Group A streptococcal disease - Queensland Health guidelines for public health units [URL]
The Royal Children’s Hospital Melbourne—Invasive group A streptococcal infections: management of household contacts [URL]
International guidelines
Health Protection Agency Group A Streptococcus Working Group. Interim UK guidelines for management of close community
contacts of invasive group A streptococcal disease. Commun Dis Public Health 2004;7(4):354–61. [URL]
Prevention of Invasive Group A Streptococcal Infections Workshop Participants. Prevention of invasive group A streptococcal
disease among household contacts of case patients and among postpartum and postsurgical patients: recommendations from the
Centers for Disease Control and Prevention. Clin Infect Dis 2002;35(8):950–9. [URL]
Shulman ST, Bisno AL, Clegg HW, Gerber MA, Kaplan EL, Lee G, et al. Clinical practice guideline for the diagnosis and
management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis
2012;55(10):1279–82. [URL]
Steer JA, Lamagni T, Healy B, Morgan M, Dryden M, Rao B, et al. Guidelines for prevention and control of group A streptococcal
infection in acute healthcare and maternity settings in the UK. J Infect 2012;64(1):1–18. [URL]
Key references
Approach to preventing iGAS infection
Boyd R, Patel M, Currie BJ, Holt DC, Harris T, Krause V. High burden of invasive group A streptococcal disease in the Northern
Territory of Australia. Epidemiol Infect 2016;144(5):1018–27.
Carapetis JR, Jacoby P, Carville K, Ang SJ, Curtis N, Andrews R. Effectiveness of clindamycin and intravenous immunoglobulin, and
risk of disease in contacts, in invasive group a streptococcal infections. Clin Infect Dis 2014;59(3):358–65.
Centre for Disease Control Northern Territory of Australia. Public health management of invasive Group A streptococcal infection.
Northern Territory: Department of Health; 2015. http://digitallibrary.health.nt.gov.au/prodjspui/handle/10137/1187
Cummins A, Millership S, Lamagni T, Foster K. Control measures for invasive group A streptococci (iGAS) outbreaks in care homes. J
Infect 2012;64(2):156–61.
Health Protection Agency Group A Streptococcus Working Group. Interim UK guidelines for management of close community contacts
of invasive group A streptococcal disease. Commun Dis Public Health 2004;7(4):354–61.
Health Victoria. Streptococcal disease (Group A beta-haemolytic streptococcus) Victoria: Communicable Disease Prevention and
Control, Department of Health and Human Services; Accessed March 2018. https://www2.health.vic.gov.au/public-health/infectious-
diseases/disease-information-advice/streptococcal-disease
Mearkle R, Saavedra-Campos M, Lamagni T, Usdin M, Coelho J, Chalker V, et al. Household transmission of invasive group A
Streptococcus infections in England: a population-based study, 2009, 2011 to 2013. Euro Surveill 2017;22(19).
Prevention of Invasive Group A Streptococcal Infections Workshop Participants. Prevention of invasive group A streptococcal disease
among household contacts of case patients and among postpartum and postsurgical patients: recommendations from the Centers for
Disease Control and Prevention. Clin Infect Dis 2002;35(8):950–9.
Queensland Health. Invasive Group A streptococcal disease - Queensland Health guidelines for public health units, Version 2.0.
Brisbane: Queensland Health; 2017. https://www.health.qld.gov.au/cdcg/index/igas
Royal Childrens Hospital Melbourne (RCH). Clinical Practice Guidelines: Invasive group A streptococcal infections: management of
household contacts. Melbourne: RCH; Accessed Sept 2017.
https://www.rch.org.au/clinicalguide/guideline_index/Invasive_group_A_streptococcal_infections__management_of_household_contacts/
Shulman ST, Bisno AL, Clegg HW, Gerber MA, Kaplan EL, Lee G, et al. Clinical practice guideline for the diagnosis and management
of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis 2012;55(10):1279–82.
infection in acute healthcare and maternity settings in the UK. J Infect 2012;64(1):1–18.
Indications for iGAS antibiotic prophylaxis
Infect 2012;64(2):156–61.
Mearkle R, Saavedra-Campos M, Lamagni T, Usdin M, Coelho J, Chalker V, et al. Household transmission of invasive group A
Streptococcus infections in England: a population-based study, 2009, 2011 to 2013. Euro Surveill 2017;22(19).
Brisbane: Queensland Health. 2018. https://www.health.qld.gov.au/cdcg/index/igas.
Prophylaxis regimens for iGAS infection
Australian Commission on Safety and Quality in Health Care (ACSQHC). AURA 2017: second Australian report on antimicrobial use
and resistance in human health. Sydney: ACSQHC; 2017. https://www.safetyandquality.gov.au/antimicrobial-use-and-resistance-in-
Chaudhary S, Bilinsky SA, Hennessy JL, Soler SM, Wallace SE, Schacht CM, et al. Penicillin V and rifampin for the treatment of group
A streptococcal pharyngitis: a randomized trial of 10 days penicillin vs 10 days penicillin with rifampin during the final 4 days of therapy.
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DeMuri GP, Wald ER. The group A streptococcal carrier state reviewed: Still an enigma. J Pediatric Infect Dis Soc 2014;3(4):336–42.
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Tanz RR, Shulman ST, Barthel MJ, Willert C, Yogev R. Penicillin plus rifampin eradicates pharyngeal carriage of group A streptococci.
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Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature, interpreted and
distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Prophylaxis for medicinal leech therapy
Prophylaxis for medicinal leech therapy
Medicinal leech therapy (hirudotherapy) is most commonly used following plastic or reconstructive surgery.
Wound infection complicates medicinal leech therapy in approximately 14% of cases, with the severity
ranging from mild to severe with associated sepsis. Aeromonas species live symbiotically in the digestive tract
of leeches and are the most commonly identified pathogens from wound infections complicating medicinal
leech therapy.
Antibiotic prophylaxis reduces the risk of infection from medicinal leech therapy; however, there is limited
clinical evidence to determine the optimal antibiotic regimen. Antimicrobial resistance has been identified in
Aeromonas species isolated from medicinal leeches, the tank water used to house medicinal leeches, and
patients who developed infection after medicinal leech therapy. Therefore, regular testing of tank water to
identify pathogens (by culture and susceptibility testing) as well as consideration of local epidemiology assists
in determining the most appropriate antibiotic for prophylaxis.
A reasonable regimen for antibiotic prophylaxis for medicinal leech therapy is:
trimethoprim+sulfamethoxazole 160+800 mg (child 1 month or over: 4+20 mg/kg up

to 160+800 mg) orally, immediately before starting medicinal leech therapy, then 12-
hourly for the duration of leech therapy and for 24 hours after stopping leech therapy.
For patients with hypersensitivity to trimethoprim+sulfamethoxazole, or if local susceptibility data

indicates high rates of trimethoprim+sulfamethoxazole resistance in Aeromonas, use:
ciprofloxacin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, immediately before
starting medicinal leech therapy, then 12-hourly for the duration of leech therapy and
for 24 hours after stopping leech therapy [Note 1] [Note 2].
Do not use quinolones for first-line prophylaxis because their use is associated with the development of
resistance.
For management of established infection associated with medicinal leech therapy, see here.
Note 1: Ciprofloxacin is not licensed for use in children on the basis of animal studies that showed an adverse effect on cartilage development
with quinolone use; however, there are few data from human trials to support this finding. Ciprofloxacin can be used in children when it is the
drug of choice.
Note 2: An oral liquid formulation of ciprofloxacin is not commercially available; for formulation options for children or people with
swallowing difficulties, see the Don’t Rush to Crush Handbook, published by the Society of Hospital Pharmacists of Australia [URL].
Key references
Elyassi AR, Terres J, Rowshan HH. Medicinal leech therapy on head and neck patients: a review of literature and
proposed protocol. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116(3):e167–72.
Giltner CL, Bobenchik AM, Uslan DZ, Deville JG, Humphries RM. Ciprofloxacin-resistant Aeromonas hydrophila
cellulitis following leech therapy. J Clin Microbiol 2013;51(4):1324–6.
Herlin C, Bertheuil N, Bekara F, Boissiere F, Sinna R, Chaput B. Leech therapy in flap salvage: Systematic review
and practical recommendations. Ann Chir Plast Esthet 2017;62(2):e1–e13.
Kruer RM, Barton CA, Roberti G, Gilbert B, McMillian WD. Antimicrobial prophylaxis during Hirudo medicinalis
therapy: a multicenter study. J Reconstr Microsurg 2015;31(3):205–9.
Patel KM, Svestka M, Sinkin J, Ruff Pt. Ciprofloxacin-resistant Aeromonas hydrophila infection following leech
therapy: a case report and review of the literature. J Plast Reconstr Aesthet Surg 2013;66(1):e20–2.
Sartor C, Bornet C, Guinard D, Fournier PE. Transmission of Aeromonas hydrophila by leeches. Lancet
2013;381(9878):1686.
Verriere B, Sabatier B, Carbonnelle E, Mainardi JL, Prognon P, Whitaker I, et al. Medicinal leech therapy and
Aeromonas spp. infection. Eur J Clin Microbiol Infect Dis 2016;35(6):1001–6.
Wang EW, Warren DK, Ferris VM, Casabar E, Nussenbaum B. Leech-transmitted ciprofloxacin-resistant
Aeromonas hydrophila. Arch Otolaryngol Head Neck Surg 2011;137(2):190–3.
Whitaker IS, Kamya C, Azzopardi EA, Graf J, Kon M, Lineaweaver WC. Preventing infective complications
following leech therapy: is practice keeping pace with current research? Microsurgery 2009;29(8):619–25.
Whitaker IS, Oboumarzouk O, Rozen WM, Naderi N, Balasubramanian SP, Azzopardi EA, et al. The efficacy of
medicinal leeches in plastic and reconstructive surgery: a systematic review of 277 reported clinical cases.
Microsurgery 2012;32(3):240–50.
Wilmer A, Slater K, Yip J, Carr N, Grant J. The role of leech water sampling in choice of prophylactic antibiotics in
medical leech therapy. Microsurgery 2013;33(4):301–4.
Q fever
Q fever
Q fever is a zoonosis caused by Coxiella burnetii, but cases can occur without evidence of exposure to animals. Q
fever can present as cholestatic hepatitis or, occasionally, atypical pneumonia; however, symptoms can be
nonspecific so Q fever should be considered in any undiagnosed febrile illness. Q fever endocarditis, bone and
joint infection, and infection of aneurysms and vascular grafts are rare and can be difficult to diagnose. Diagnosis
of Q fever relies on serology and nucleic acid amplification testing (eg polymerase chain reaction [PCR]) [Note 1].
Acute Q fever usually resolves spontaneously within 2 to 6 weeks. There is no value in treating nonpregnant
patients after spontaneous recovery; however, patients with cardiac valve disease or vascular grafts require careful
investigation and follow-up to exclude the development of endocarditis or graft infection.
For acute infection in adults, use:
For acute infection in children of all ages, use:
doxycycline 2.2 mg/kg up to 100 mg orally, 12-hourly for up to 14 days.
For children 8 years or younger who have mild or uncomplicated disease, treat with doxycycline for 5 days only. If
fever does not resolve within 5 days, complete the 14-day course of doxycycline.
Doxycycline is recommended to treat Q fever in children of all ages because it is the most effective treatment. The
risk of dental adverse effects in young children is minimal, particularly when a single short course of doxycycline
is used.
Doxycycline is contraindicated in pregnancy. Trimethoprim+sulfamethoxazole (TGA pregnancy category C) is

recommended instead for the treatment of Q fever in pregnant women; although it has been associated with
congenital abnormalities when used during pregnancy, the benefit of treatment for Q fever outweighs the potential
harms. Concomitant use of folic acid reduces the risk of congenital abnormalities. In pregnant women, use:
trimethoprim+sulfamethoxazole 160+800 mg orally, 12-hourly
PLUS
folic acid 5 mg orally, daily.
Treatment is recommended until 32 weeks’ gestation, even if the patient has spontaneously recovered, to prevent
fetal and maternal complications. Seek expert advice for the management of pregnant women beyond 32 weeks’
gestation.
For chronic infection, prolonged synergistic therapy (with hydroxychloroquine) may be required. For Q fever
endocarditis (see Culture-negative endocarditis), bone and joint infection and infection of aneurysms and
vascular grafts, seek expert advice. Valve surgery may be required.
Note 1: For information about testing, see the Communicable Diseases Network Australia Q Fever Laboratory Case Definition [URL].
Key references
Boast A, Curtis N, Gwee A. Question 1: Teething issues: can doxycycline be safely used in young children? Arch Dis
Child 2016;101(8):772–4.
Cross R, Ling C, Day NP, McGready R, Paris DH. Revisiting doxycycline in pregnancy and early childhood--time to
rebuild its reputation? Expert Opin Drug Saf 2016;15(3):367–82.
Eldin C, Mailhe M, Lions C, Carrieri P, Safi H, Brouqui P, et al. Treatment and prophylactic strategy for Coxiella burnetii
infection of aneurysms and vascular grafts: A retrospective cohort study. Medicine (Baltimore) 2016;95(12):e2810.
Eldin C, Melenotte C, Mediannikov O, Ghigo E, Million M, Edouard S, et al. From Q Fever to Coxiella burnetii infection:
A paradigm change. Clin Microbiol Rev 2017;30(1):115–90.
Keijmel SP, Delsing CE, Bleijenberg G, van der Meer JWM, Donders RT, Leclercq M, et al. Effectiveness of long-term
doxycycline treatment and cognitive-behavioral therapy on fatigue severity in patients with Q fever fatigue syndrome
(qure study): A randomized controlled trial. Clin Infect Dis 2017;64(8):998–1005.
Million M, Raoult D. Recent advances in the study of Q fever epidemiology, diagnosis and management. J Infect
2015;71 Suppl 1:S2–9.
Million M, Roblot F, Carles D, D'Amato F, Protopopescu C, Carrieri MP, et al. Reevaluation of the risk of fetal death and
malformation after Q Fever. Clin Infect Dis 2014;59(2):256–60.
Morroy G, Keijmel SP, Delsing CE, Bleijenberg G, Langendam M, Timen A, et al. Fatigue following acute Q-fever: A
systematic literature review. PLoS One 2016;11(5):e0155884.
Poyhonen H, Nurmi M, Peltola V, Alaluusua S, Ruuskanen O, Lahdesmaki T. Dental staining after doxycycline use in
children. J Antimicrob Chemother 2017;72(10):2887–90.
Pneumonia diagnosis and follow-up
Pneumonia diagnosis
Clinical features of pneumonia
Pneumonia is an infection of the lung parenchyma. It is one of the leading infective causes of morbidity and
mortality worldwide.
The incidence of pneumonia in patients presenting in primary care with symptoms of a lower respiratory tract
infection varies from 0.4 to 5% in studies. It is important to differentiate pneumonia from acute bronchitis, a self-
limiting infection of the lower respiratory tract. Unlike pneumonia, acute bronchitis is not associated with potentially
life-threatening problems, such as severe hypoxaemia. As acute bronchitis is usually a viral infection, antibiotics are
not indicated.
It is important to differentiate pneumonia from acute bronchitis because antibiotics are not indicated for acute bronchitis.
The signs and symptoms of pneumonia and acute bronchitis overlap. Both pneumonia and bronchitis typically
present with cough. Patients with either pneumonia or acute bronchitis can have purulent or coloured sputum; this is
not predictive of bacterial infection.
In one large cohort study [Note 1], the following signs were identified as independent predictors of pneumonia in
adults with symptoms of a lower respiratory tract infection: temperature greater than 37.8°C, crepitations (crackles)
on auscultation, oxygen saturation less than 95% on room air, and heart rate greater than 100 beats/minute.
Additional clinical features that make a diagnosis of pneumonia more likely include rigors, pleuritic chest pain, and
tachypnoea at rest. On chest examination, dullness to percussion, poor air entry, bronchial breath sounds or
crepitations (crackles) that do not clear with coughing also suggest parenchymal involvement and a diagnosis of
pneumonia.
In contrast, patients with acute bronchitis are unlikely to have rigors, tachycardia, or tachypnoea at rest. While fever
may be present, it usually subsides after the first few days of illness. On chest examination, wheeze can be present,
and a few scattered crepitations (crackles) can occur, but these should clear with coughing. For further information
and management of acute bronchitis, see Acute bronchitis.
Note 1: Moore M, Stuart B, Little P, Smith S, Thompson MJ, Knox K, et al. Predictors of pneumonia in lower respiratory tract infections: 3C prospective
cough complication cohort study. Eur Respir J 2017;50(5). [URL]
Imaging to confirm the diagnosis of pneumonia
Evidence of new pulmonary consolidation on chest X-ray is the accepted standard for diagnosing pneumonia. If
clinical signs and symptoms suggest pneumonia, a chest X-ray is indicated, both to confirm the diagnosis and, for
adults, to provide a comparison for follow-up imaging if this is required (see Expected clinical course of
pneumonia).
It is particularly important to perform a chest X-ray for patients with unexplained hypoxaemia or significant
breathlessness. In patients with comorbid lung disease, immunocompromised patients and the elderly, the signs of
pneumonia are often more subtle; perform a chest X-ray if the diagnosis is unclear.
Performing a chest X-ray to confirm the diagnosis of pneumonia can be difficult in some patient groups managed in
the community (eg children, residents of aged-care facilities), and the benefit–harm profile of imaging should be
assessed for the individual patient.
If the chest X-ray is performed very early in the illness (eg in the first 24 hours), the infiltrate may not be evident. If
pneumonia is suspected clinically but consolidation is not obvious on the chest X-ray, consider repeating the X-ray
in a few days’ time.
Patients who are not improving on empirical antibiotic therapy should have a chest X-ray if it was not done initially
(see also Approach to managing patients with pneumonia who are not improving).
Finding the right pneumonia topic in these guidelines
After confirming the diagnosis of pneumonia, use Figure 2.6 to find the right topic for pneumonia management.
Finding the right pneumonia topic in these guidelines (Figure 2.6)
NB1: If an aged-care facility resident is managed in hospital, treat as for Community-acquired pneumonia in adults.
Approach to pneumonia in patients with COPD and bronchiectasis

Diagnosis of pneumonia in patients with COPD or bronchiectasis
Symptoms of an exacerbation of chronic obstructive pulmonary disease (COPD) or bronchiectasis overlap with
pneumonia. An accurate diagnosis is important as treatment of exacerbations differs from treatment of pneumonia.
Consider a diagnosis of pneumonia if the patient is more unwell than with previous exacerbations. Signs suggestive
of pneumonia include tachypnoea at rest, tachycardia, rigors, and crepitations (crackles) on auscultation that do not
clear with coughing. A chest X-ray is usually required—see Pneumonia diagnosis.
For antibiotic management of exacerbations of COPD, see Antibiotic management of COPD. For antibiotic
management of exacerbations of bronchiectasis, see Antibiotic management of bronchiectasis.
Management of pneumonia in patients with COPD or bronchiectasis

The most common pathogens that cause pneumonia in patients with COPD and bronchiectasis are the same as in
patients without comorbid lung disease (eg Streptococcus pneumoniae). Due to frequent infections and antibiotic
exposure, sputum culture results may identify multidrug-resistant bacteria. However, these bacteria are more likely
to be colonising organisms rather than the cause of pneumonia.
The usual pneumonia pathogens (eg Streptococcus pneumoniae) are the most common cause of pneumonia in patients with COPD
or bronchiectasis.
For patients with COPD or bronchiectasis who have low- to moderate-severity pneumonia, no change to standard
empirical antibiotic therapy is required. However, the empirical regimen may need to be adjusted for patients with
high-severity pneumonia who are colonised with multidrug-resistant Gram-negative pathogens, such as
Pseudomonas aeruginosa. For antibiotic management (including adjustments for high-severity disease where
applicable), see the relevant pneumonia topic:
Community-acquired pneumonia in adults

Community-acquired pneumonia in children
Community-acquired pneumonia in aged-care facilities
Hospital-acquired pneumonia
Ventilator-associated pneumonia
Aspiration pneumonia
Directed therapy for pneumonia.
In patients with COPD or bronchiectasis who have pneumonia, ensure airway clearance strategies are optimised (eg
chest physiotherapy).
Approach to pneumonia in immunocompromised patients

Immunocompromised patients are at greater risk of pneumonia than people who are not immunocompromised.
Immunocompromised patients include patients with neutropenia, immunodeficiency disorders, advanced HIV
infection, or haematological malignancies, and patients receiving immunosuppressive therapy or chemotherapy.
Although a broad range of pathogens can cause pneumonia in immunocompromised patients, the most common
pathogens are the same as in patients without immune compromise (eg Streptococcus pneumoniae).
Even in immunocompromised patients, the usual pneumonia pathogens (eg Streptococcus pneumoniae) are still the most common
cause of pneumonia.
For immunocompromised patients with low- to moderate-severity pneumonia who do not have profound
immunosuppression, no change to standard empirical antibiotic therapy is required. For regimens, see the relevant
pneumonia topic:

For immunocompromised patients with high-severity pneumonia or those with significant immunosuppression
(eg recent solid organ or haematopoietic stem cell transplant), it is important to consider investigations for unusual
pathogens early. Consider early referral to a respiratory physician to discuss the utility of bronchoscopy to obtain
samples for extensive microbiological testing. The patient’s respiratory function and need for intubation
influence the timing of bronchoscopy. Seek expert advice on whether to adjust empirical antibiotic therapy while
awaiting the results of investigations.
Unusual pathogens to consider in patients with high-severity pneumonia or those with significant
immunosuppression include:
Aspergillus species—can cause invasive aspergillosis in patients with significant immunosuppression (eg
neutropenia after intensive chemotherapy). See Aspergillosis for management
Burkholderia pseudomallei—can cause pneumonia in tropical regions of Australia [Note 2], particularly in
patients with risk factors (see Box 2.17). See Melioidosis for management
Gram-negative bacteria, including Pseudomonas aeruginosa—especially in patients with haematological
malignancy or immunoglobulin deficiencies. See Directed therapy for pneumonia for management
Legionella species—see Legionella pneumonia in adults for management
Mycobacterium tuberculosis—especially in patients from high-prevalence areas. See Tuberculosis for
management
Nocardia and Cryptococcus species—usually cause focal lung infections. See Nocardiosis and Pulmonary
cryptococcosis for management
Nontuberculous mycobacteria—see Nontuberculous mycobacterial infections for management
Pneumocystis jirovecii—see Pneumocystis jirovecii pneumonia (PJP) for management
respiratory viruses that can cause pneumonitis—for example, cytomegalovirus (see Cytomegalovirus (CMV)
infection for management) and respiratory syncytial virus (RSV)
Strongyloides stercoralis in patients with past or present epidemiological risk (see here for risk factors)—see
Strongyloidiasis for management.
If an immunocompromised patient is not improving as expected on empirical antibiotic therapy, consider other
complications or differential diagnoses, as well as the unusual pathogens listed above. For further details, see
Approach to managing patients with pneumonia who are not improving. Seek expert advice on whether to adjust
empirical antibiotic therapy while awaiting the results of investigations.
Note 2: Tropical regions of Australia refer to regions north of 20°S latitude. This includes areas of Queensland north of Mackay, the Northern Territory
Expected clinical course of pneumonia
Once treatment for pneumonia has started, the patient’s symptoms should steadily improve. The rate of recovery is
influenced by the severity of pneumonia and the patient’s general health and comorbidities.
Fever should subside within the first few days of appropriate therapy and appetite will improve. Cough, sputum
production (if present), chest discomfort and breathlessness may take several weeks to resolve. Patients can report
fatigue for months after an episode of pneumonia.
Infiltrates seen on chest X-ray can take weeks to resolve. A repeat chest X-ray is recommended 6 to 8 weeks after the
episode of pneumonia for patients in whom there is a clinical suspicion of lung malignancy (eg elderly, smokers).
Approach to managing patients with pneumonia who are not improving

If signs and symptoms do not improve as expected with appropriate antibiotic therapy, reassess the diagnosis before
escalating antibiotic therapy. Also ensure airway clearance strategies are optimised (eg chest physiotherapy). For
patients managed in the community, review disease severity and whether to admit the patient to hospital.
Complications of pneumonia and differential diagnoses to consider are listed in Box 2.14. Review the results of
previous diagnostic tests (eg nose and throat swabs, sputum samples). Further imaging studies such as a repeat chest
X-ray or chest computed tomography (CT) scan may be considered to investigate for complications or alternative
diagnoses. Consider testing for an unrecognised immune system disorder, such as HIV infection. If extensive
microbiological testing is needed, discuss the need for bronchoscopy with a respiratory physician.
Seek expert advice on whether to adjust empirical antibiotic therapy.

Considerations in patients with pneumonia who are not improving on empirical antibiotic
therapy (Box 2.14)
If a patient is not improving with empirical antibiotic therapy for pneumonia, consider:
complications of pneumonia—lung abscess, parapneumonic effusion and empyema should be considered in

patients with persistent symptoms such as fever and chest discomfort. For management of these
complications, see Lung abscess and Parapneumonic effusion and empyema
noninfective causes—including heart failure, noninfective exacerbations of COPD, acute respiratory distress
syndrome, and interstitial lung diseases (eg cryptogenic organising pneumonia, hypersensitivity
pneumonitis, idiopathic pulmonary fibrosis, sarcoidosis). Breathlessness and hypoxaemia are often the
prominent symptoms
undiagnosed immunodeficiency—consider whether pneumonia is the presenting feature of an undiagnosed
immunodeficiency
unusual respiratory pathogens—consider investigations for unusual pathogens, particularly in
immunocompromised patients. Unusual pathogens include [NB1]:
anaerobes not adequately treated with standard empirical therapy—especially in patients with severe
periodontal disease or putrid sputum. See here for management
atypical pathogens such as Legionella, Mycoplasma and Chlamydophila (Chlamydia) species—see
Directed therapy for pneumonia for management
Burkholderia pseudomallei—can cause pneumonia in tropical regions of Australia [NB2], particularly
in patients with risk factors (see Box 2.17). See Melioidosis for management
cytomegalovirus—can cause pneumonitis. See Cytomegalovirus (CMV) infection for management
Gram-negative bacteria, including Pseudomonas aeruginosa—especially in patients with
haematological malignancy, immunoglobulin deficiencies, comorbid lung disease, hazardous alcohol
consumption or recent antibiotic exposure. See Directed therapy for pneumonia for management
fungal pathogens such as Aspergillus and Cryptococcus species—see Overview of fungal
pneumonia for management
influenza, parainfluenza, human metapneumovirus, coronavirus, respiratory syncytial virus (RSV) and
other respiratory viruses that can cause pneumonia and pneumonitis—if suspected, perform nose and
throat swabs for nucleic acid amplification testing (eg polymerase chain reaction [PCR])
Mycobacterium tuberculosis—especially in patients from high-prevalence areas in whom symptom
onset was not acute. See Tuberculosis for management
Nocardia species—see Nocardiosis for management
nontuberculous mycobacteria—see Nontuberculous mycobacterial infections for management
Pneumocystis jirovecii—see Pneumocystis jirovecii pneumonia (PJP)
Strongyloides stercoralis in patients with past or present epidemiological risk (see here for risk
factors)—see Strongyloidiasis for management.
NB1: The unusual pathogens that are most important in immunocompromised patients are listed in Approach to pneumonia in immunocompromised
patients.
Pneumonia prevention
Discuss preventive strategies with patients at risk of pneumonia, particularly those who have had pneumonia
because they are at risk of recurrence. Preventive strategies include:
immunisation against influenza and Streptococcus pneumoniae—see the Australian Immunisation

Handbook [URL]
smoking cessation—see Smoking cessation for further information
exercise and management of obesity
medication review to identify medications that have been associated with an increased incidence of pneumonia
(eg proton pump inhibitors, benzodiazepines and other sedatives)
reducing the risk of aspiration events in patients with recurrent aspiration—see Management of recurrent
aspiration for strategies.
Key references
Pneumonia diagnosis
Cao AM, Choy JP, Mohanakrishnan LN, Bain RF, van Driel ML. Chest radiographs for acute lower respiratory tract
infections. Cochrane Database Syst Rev 2013;(12):CD009119.
Gordon J, Miller G, Pan Y. Ordering chest X-rays in Australian general practice. Aust Fam Physician 2015;44(8):537–9.
Moore M, Stuart B, Little P, Smith S, Thompson MJ, Knox K, et al. Predictors of pneumonia in lower respiratory tract
infections: 3C prospective cough complication cohort study. Eur Respir J 2017;50(5).
Royal Australian College of General Practitioners. Tests, treatments and procedures clinicians and consumers should
question. Recommendation 7: Choosing Wisely Australia. Sydney: NPS MedicineWise; Last reviewed 22 April 2015.
http://www.choosingwisely.org.au/recommendations/racgp
van Vugt SF, Verheij TJ, de Jong PA, Butler CC, Hood K, Coenen S, et al. Diagnosing pneumonia in patients with acute
cough: clinical judgment compared to chest radiography. Eur Respir J 2013;42(4):1076–82.
World Health Organization (WHO). The top 10 causes of death factsheet [website]. Geneva: WHO.
http://www.who.int/mediacentre/factsheets/fs310/en/
Expected clinical course of pneumonia
National Institute for Health and Care Excellence (NICE). Pneumonia in adults: diagnosis and management [CG191].
London: NICE; 2014. https://www.nice.org.uk/guidance/cg191
Pneumonia prevention
Dang TT, Majumdar SR, Marrie TJ, Eurich DT. Recurrent pneumonia: a review with focus on clinical epidemiology and
modifiable risk factors in elderly patients. Drugs Aging 2015;32(1):13–9.
Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA. Risk of community-acquired pneumonia with
outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. PLoS One 2015;10(6):e0128004.
Tolppanen AM, Koponen M, Tanskanen A, Lavikainen P, Sund R, Tiihonen J, et al. Antipsychotic use and risk of
hospitalization or death due to pneumonia in persons with and those without Alzheimer disease. Chest
2016;150(6):1233–41.
Community-acquired pneumonia (CAP) is pneumonia that develops in a patient in the community, or in a patient
who has been in hospital for less than 48 hours. This topic covers management of adults with CAP, including
residents of aged-care facilities who are being treated in hospital. It details assessment of pneumonia severity,
clinical and microbiological investigations, and empirical regimens for CAP in patients in nontropical and tropical
regions of Australia.
Management of CAP in children, CAP in residents of aged-care facilities who are being treated in the facility,
hospital-acquired pneumonia and ventilator-associated pneumonia is covered elsewhere; to find the right
pneumonia topic in these guidelines, see Figure 2.6.
If a pathogen is known, see Directed therapy for pneumonia.
Most cases of pneumonia—not just aspiration pneumonia—develop due to aspiration of bacteria from the
oropharynx. Antibiotic regimens for CAP in these guidelines can be used for initial treatment of aspiration
pneumonia in patients from the community (see Approach to managing aspiration pneumonia).
For general information about diagnosis of pneumonia, management of pneumonia in special patient groups (eg
patients with chronic obstructive pulmonary disease, bronchiectasis or immune compromise), recovery from
pneumonia, strategies to prevent further episodes of pneumonia and management of patients with pneumonia who
are not improving, see Pneumonia diagnosis and follow-up.
CAP in adults: aetiology

In adults, the most common bacterial cause of community-acquired pneumonia (CAP) is Streptococcus
pneumoniae. Atypical bacterial pathogens (eg Mycoplasma pneumoniae, Chlamydophila (Chlamydia) pneumoniae
and Legionella species) are also important causes of CAP. For a summary of pathogens that cause CAP in adults,
see Table 2.56.
CAP in immunocompromised patients can be caused by uncommon pathogens—see Approach to pneumonia in

immunocompromised patients.
For patients with suspected pneumonia who do not respond to empirical therapy, consider other diagnoses and
uncommon pathogens. For example, consider tuberculosis in patients with prolonged symptoms, particularly in the
elderly, immunocompromised patients, and patients who have previously resided in countries with a high
prevalence of tuberculosis. For further information, see Approach to managing patients with pneumonia who are
not improving.
Aetiology of community-acquired pneumonia (CAP) in adults (Table 2.56) [NB1]
Pathogen Details
Most common bacterial cause of CAP.
Streptococcus pneumoniae Most common cause of high-severity CAP, CAP in the elderly and death from
CAP.
Legionella species are acquired from environmental sources.
Patients may present with nonrespiratory symptoms, including confusion and

diarrhoea. Hyponatraemia may be present.
Risk factors for Legionella disease include chronic lung disease, smoking,
diabetes, end-stage kidney disease, malignancy, and immune compromise,
including chronic corticosteroid use.
Legionella species Of the 424 confirmed cases of Legionella pneumonia in Australia in 2014,
Legionella pneumophila caused 46% (98% of which were serogroup 1) and
Legionella longbeachae caused 39%.
L. pneumophila serogroup 1 is the serogroup most commonly associated with

outbreaks, whereas L. longbeachae causes sporadic infections (eg after
exposure to potting mix).
L. pneumophila causes more severe CAP, whereas L. longbeachae usually

causes less severe CAP.
These atypical pathogens are more commonly associated with CAP in young
Mycoplasma pneumoniae and adults. They rarely cause CAP in residents of aged-care facilities.
Chlamydophila (Chlamydia)
Infection with these pathogens may be indicated by a nonproductive cough for
pneumoniae 5 or more days and characteristically bilateral lower zone infiltrates on chest X-
ray.
A zoonotic atypical pathogen acquired after exposure to infected birds, either
Chlamydophila (Chlamydia) directly or from environmental sources such as dried droppings.
psittaci
Nonrespiratory signs and symptoms may be prominent.
C. burnetii, which causes Q fever, is acquired from inhalation of bacteria after
direct or indirect contact with animals (eg exposure in rural settings, contact
Coxiella burnetii with skins or contaminated dust).
Nonrespiratory signs and symptoms may be prominent.

H. influenzae causes less than 5% of cases of CAP in adults, predominantly in
patients with chronic obstructive pulmonary disease (COPD).
Haemophilus influenzae
For further details on managing pneumonia in patients with COPD, see
Approach to pneumonia in patients with COPD and bronchiectasis.
Enterobacteriaceae are uncommon causes of high-severity CAP.
The identification of enteric Gram-negative bacilli in sputum usually reflects

colonisation or prior antibiotic use, especially in patients with low- to
Enterobacteriaceae (eg Klebsiella
moderate-severity CAP.
pneumoniae)
For further information on pneumonia caused by Enterobacteriaceae, see
Multidrug-resistant Enterobacteriaceae pneumonia or Nonmultidrug-resistant
Enterobacteriaceae pneumonia.
P. aeruginosa is a rare cause of CAP. The pneumonia is usually necrotising or
destructive in nature.
Pseudomonas aeruginosa Patients with chronic suppurative lung disease (eg bronchiectasis) can be
colonised with P. aeruginosa. For further details on managing pneumonia in
patients with bronchiectasis, see Approach to pneumonia in patients with
COPD and bronchiectasis.
B. pseudomallei and A. baumannii are Gram-negative bacteria that can cause
Burkholderia pseudomallei and
CAP in tropical regions of Australia [NB2]. For risk factors for pneumonia
Acinetobacter baumannii
caused by these bacteria, see Box 2.17.
S. aureus is an uncommon cause of CAP. It should be considered in patients
with high-severity CAP or cavitary pneumonia. Staphylococcal CAP can occur
as a primary infection, or secondary to influenza.
Staphylococcus aureus (including Staphylococcal CAP is more commonly caused by methicillin-susceptible S.

methicillin-resistant S. aureus aureus (MSSA). Community-associated methicillin-resistant S. aureus (CA-
[MRSA]) MRSA) strains also cause severe infection.
Cavitation is a feature of CAP caused by both MSSA and CA-MRSA.

Multifocal S. aureus lung infection may indicate underlying endocarditis. For
other features of staphylococcal pneumonia, see Staphylococcal pneumonia.
Respiratory viruses can cause pneumonia as a sole pathogen, or as co-infection
with bacterial pathogens.
Respiratory viruses (eg influenza,
RSV and hMPV are frequent causes of viral upper respiratory tract infection in
respiratory syncytial virus [RSV],
the community. Rarely, they cause high-severity bilateral CAP requiring
human metapneumovirus
intensive care support; this is more common in elderly patients.
[hMPV], parainfluenza viruses,
adenovirus) Consider influenza (eg depending on the season), and review the need for
isolation (for patients in hospital) and empirical antiviral therapy while
awaiting the results of investigations (see Influenza).
NB1: For information on microbiological investigations, see CAP in adults: clinical and microbiological investigations.
CAP in adults: management overview
Figure 2.7 provides an overview of the management of community-acquired pneumonia (CAP) in adults.
Management overview of adults with community-acquired pneumonia (Figure 2.7)
NB1: In this topic, CAP includes suspected aspiration pneumonia, and pneumonia in patients who have been in hospital for less than 48 hours.
NB3: Gram stain of poor quality sputum samples can give misleading results. Ensure a good quality specimen (presence of polymorphs, but few or no
squamous epithelial cells on microscopy), collected before starting antibiotics, is used for adjusting therapy. The pathogen should be predominant in
the Gram stain as well as the culture.
CAP in adults: assessment of pneumonia severity

Red flags and pneumonia severity scoring tools
Careful assessment of pneumonia severity and comorbidities is required for all patients with community-acquired
pneumonia (CAP) to guide appropriate empirical antibiotics and the site of care. For an overview of management
of CAP in adults, see Figure 2.7. For residents of aged-care facilities, see also Community-acquired pneumonia in
aged-care facilities.
Disease severity assessment involves:
identifying patients with low-severity CAP. These patients have a low risk of complications and are usually
suitable for management in the community
identifying patients who have high-severity CAP associated with a risk of acute organ failure. These
patients usually require intensive care support and monitoring.
In most patients, pneumonia cannot be categorised as either low-severity or high-severity. These patients are
classified as having moderate-severity CAP and usually require inpatient management.
Box 2.15 lists red flags that can be used to guide whether to admit the patient to hospital. Box 2.16 lists red flags
that can be used to identify patients who may need intensive care support. The red flags in this topic use modified
clinical parameters identified in studies of pneumonia severity.
Use of the red flags to assess patients does not replace clinical judgment. Each flag provides a static measure in a
dynamic situation. Patients can deteriorate over the initial 24 to 48 hours, so regular observation during this period
is essential. Each patient assessment must incorporate a consideration of the clinical and social context of the
patient. If patient observation is not possible in the community (eg due to social circumstances), admit the patient
to hospital.
Formal pneumonia severity scoring tools are described in Pneumonia severity scoring tools for community-
acquired pneumonia in adults. They can be used to guide whether to admit the patient to hospital (CRB-65,
CURB-65 and Pneumonia Severity Index [PSI]), or identify patients at higher risk of death or requiring intensive
care support (SMART-COP and CORB). The tools are not designed to suggest likely pathogens.
Step 1: Decide whether to admit the patient to hospital

The parameters listed in Box 2.15 (red flags) are considered by the Antibiotic Expert Groups to indicate patients
likely to need inpatient management. For residents of aged-care facilities, see also Community-acquired
pneumonia in aged-care facilities.
Red flags for hospital admission in adults with community-acquired pneumonia (Box 2.15)
[NB1]
Patients with any of the following parameters need close clinical observation, and are therefore likely to need
inpatient management [NB2]:
tachypnoea (respiratory rate 22 breaths/minute or more)

heart rate higher than 100 beats/minute
hypotension (systolic blood pressure lower than 90 mmHg)
acute-onset confusion
oxygen saturation lower than 92% on room air (or lower than baseline in patients with comorbid lung
disease)
multilobar involvement on chest X-ray
blood lactate concentration more than 2 mmol/L [NB3].
NB1: Many of the red flags are derived from formal pneumonia severity scoring tools. Based on expert opinion, some parameters are more
conservative than the parameters in the scoring tools to enable early identification of patients at risk of deterioration.
NB2: When deciding if inpatient management is required, in addition to the red flags, assess the patient’s social circumstances (in particular, the
availability of home support), age, comorbidities, ability to tolerate and absorb oral therapy, need for supportive oxygen therapy, functional status
and goals of care.
NB3: Blood lactate can be measured using arterial or venous blood gas analysis. Venous blood gas analysis is acceptable for rapid lactate
assessment (see Arterial or venous blood gases).
Patients with any of the red flags for hospital admission listed in Box 2.15 need regular observation in case of
deterioration, so usually require admission to hospital. The presence of these red flags does not indicate that
broader-spectrum empirical antibiotic therapy is needed. Assess the patient’s need for intensive care support; see
Step 2: Identify patients who may need intensive care support.
The presence of red flags for hospital admission listed in Box 2.15 does not indicate that broader-spectrum empirical antibiotic
therapy is needed.
Patients without red flags for hospital admission have low-severity CAP that can usually be safely managed in the
community. For antibiotic therapy, see Empirical therapy: low-severity CAP in adults. In addition to the red flags,
assess the patient’s social circumstances (in particular, the availability of home support), age, comorbidities, ability
to tolerate and absorb oral therapy, need for supportive oxygen therapy, functional status and goals of care when
deciding if inpatient management is required. Elderly patients in particular are at higher risk of deterioration.
When a patient without red flags requires admission to hospital for other reasons (eg comorbidities or social
circumstances), treat with oral antibiotic therapy as for low-severity CAP (see Empirical therapy: low-severity
CAP in adults). If the patient cannot tolerate or absorb oral therapy, use intravenous therapy (see Empirical
therapy: moderate-severity CAP in adults).
The pneumonia severity scoring tools CRB-65, CURB-65 and PSI can also be used to decide whether to admit a
patient to hospital—see Pneumonia severity scoring tools for community-acquired pneumonia in adults.
Step 2: Identify patients who may need intensive care support
The parameters listed in Box 2.16 (red flags) are considered by the Antibiotic Expert Groups to indicate patients
who may require intensive care support. Always assess the patient’s goals of care and suitability for intensive care
management to determine whether intensive care support is appropriate.
Red flags for intensive care support in adults with community-acquired pneumonia (Box 2.16)
[NB1]
Patients with any of the following parameters may require intensive care support; assess the patient’s goals of
care and suitability for intensive care management:
signs of severe acute respiratory insufficiency:
respiratory rate 30 breaths/minute or more

oxygen saturation less than 90% on room air, PaO2 less than 60 mmHg, or PaO2/FiO2 less than 250
multilobar or rapid progression of chest X-ray infiltrates
signs of acute extrapulmonary organ dysfunction:

poor peripheral perfusion or mottled skin
acute oliguria, elevated serum creatinine or uraemia (serum urea more than 7 mmol/L or BUN more than
19 mg/dL) (above baseline)
BUN = blood urea nitrogen; FiO2 = fraction of oxygen in inspired air; PaO2 = arterial partial pressure of oxygen
NB1: Many of the red flags are derived from formal pneumonia severity scoring tools.
A raised respiratory rate (eg 30 breaths/minute or more) is an early predictor of respiratory failure, and together
with hypoxaemia, may anticipate the need for mechanical ventilatory support. Blood lactate more than 2 mmol/L
and systolic blood pressure lower than 90 mmHg indicate circulatory failure and hypoperfusion, and impending
need for inotropic support. Do not misattribute hypotension to hypovolaemia, which is rare in this clinical setting.
Other parameters that indicate a worse prognosis include unstable cardiac function, leucopenia, thrombocytopenia,
and acidosis (pH less than 7.35). Closely monitor patients with these parameters for deterioration.
Consult local protocols or other references for comprehensive advice on nonantibiotic management of patients
with sepsis or septic shock; see also Early intervention for sepsis or septic shock.
Patients who require intensive care support, or who are anticipated to deteriorate and require intensive care
support, have high-severity CAP. For antibiotic therapy, see Empirical therapy: high-severity CAP in adults. For
patients in a tropical region of Australia [Note 1], see High-severity CAP in adults: tropical regions.
Patients in hospital (ie those that have at least one red flag for hospital admission listed in Box 2.15) who do not
meet the criteria for high-severity CAP, have moderate-severity CAP; for antibiotic regimens, see Empirical
therapy: moderate-severity CAP in adults. For patients in a tropical region of Australia [Note 1], see Moderate-
severity CAP in adults: tropical regions. Review patients with moderate-severity CAP regularly for signs of
deterioration.
The pneumonia severity scoring tools SMART-COP and CORB can also be used to identify patients at higher risk
of death or requiring intensive care support—see Pneumonia severity scoring tools for community-acquired
pneumonia in adults.
CAP in adults: clinical and microbiological investigations

Diagnosis and investigations for CAP
Community-acquired pneumonia (CAP) is usually suspected in patients with acute respiratory symptoms (eg
cough, dyspnoea, sputum production, pleuritic chest pain), fever and a new infiltrate on chest X-ray. In some
patients, nonrespiratory symptoms may be prominent (eg diarrhoea, headache). Diagnosis in the elderly can be
challenging because some patients present without acute respiratory symptoms. For further information on
diagnosis of pneumonia, see Pneumonia diagnosis.
In addition to a thorough history and examination, initial assessment of a patient with CAP should include:
chest X-ray, which usually establishes the diagnosis

oxygen saturation (on room air, if possible)
investigations for pneumonia severity (see CAP in adults: assessment of pneumonia severity).
This section includes information about the following investigations for patients with CAP:
sputum Gram stain and culture

nucleic acid amplification testing
arterial or venous blood gases
blood culture
pneumococcal urinary antigen assay
Legionella urinary antigen assay
serological testing
biomarker (C-reactive protein and procalcitonin) serum concentrations.
Investigations for unusual pathogens should be considered in immunocompromised patients with high-severity
CAP or those with significant immunosuppression (eg recent solid organ or haematopoietic stem cell transplant);
see Approach to pneumonia in immunocompromised patients.
Guidelines [Note 2] are available for recommended emergency department investigations for patients with
pneumonia who are being admitted to hospital.
Note 2: Australasian College for Emergency Medicine (ACEM) and the Royal College of Pathologists of
Australasia (RCPA). Pathology testing in the emergency department. Melbourne: ACEM & RCPA; 2013, revised
2018. [URL]
Sputum Gram stain and culture
At the onset of CAP, many patients are not able to produce sputum. If a sputum sample can be collected before
starting antibiotic therapy, sputum Gram stain and culture can indicate the likely pathogen (up to 40% yield),
provided good quality samples (presence of polymorphs, but few or no squamous epithelial cells on microscopy)
are collected. Always correlate the results of culture with the Gram stain.
The results of culture of good quality sputum samples should be correlated with the Gram stain.
The identification of potential pathogens via sputum Gram stain and culture can enable directed antibiotic therapy.
Examples include identification of Streptococcus pneumoniae in any severity of CAP and identification of
Klebsiella pneumoniae in high-severity CAP. However, growth of enteric Gram-negative bacteria (eg K.
pneumoniae, Escherichia coli) in sputum culture from patients with low- to moderate-severity CAP is less reliable
to guide therapy because it often reflects colonisation. Culture of sputum collected after antibiotic treatment has
been started has poor specificity and leads to over-interpretation and inappropriate antibiotic choice. The results of
culture of poor quality samples are frequently misleading.
Nucleic acid amplification testing
Nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]) technology is evolving rapidly.
At the time of writing, although the use of nose and throat swabs for NAAT (eg PCR) to screen for respiratory
pathogens is promising, the impact on patient outcomes and antibiotic use for CAP is not established. The utility of
these tests in practice is likely to improve as they become more readily available and the test turnaround time
decreases.
Increasingly, NAAT (eg PCR) can be performed as a rapid (1- to 2-hour) real-time assay that includes a varied
range of targets. Some current rapid assays are specific for influenza A and B, and respiratory syncytial virus
(RSV). Other commercial assays multiplex together a broader range of virus targets including influenza, RSV,
human metapneumovirus (hMPV), parainfluenza viruses and adenovirus, as well as selected bacterial pathogens.
NAAT (eg PCR) tests for bacteria such as Chlamydophila (Chlamydia) pneumoniae, Mycoplasma pneumoniae and
Legionella species are becoming available selectively.
The primary aim of NAAT (eg PCR) in the context of patients with CAP is to confirm or exclude a viral diagnosis
(eg influenza) and aid decisions on antiviral therapy. It is also used for hospital infection control management to
prevent viral cross-transmission. If available, sputum samples, endotracheal aspirates and bronchial lavage samples
provide greater yield for NAAT (eg PCR) than nose and throat swab samples.
Arterial or venous blood gases
Venous blood gas analysis to estimate blood lactate and pH can help to assess pneumonia severity; however,
venous blood gas analysis is not accurate for assessing gas exchange (eg arterial partial pressure of oxygen [PaO2]
and partial pressure of carbon dioxide [PaCO2]). Arterial blood gas analysis is appropriate for patients with high-
severity CAP, hypoxaemia or comorbid lung disease.
Blood culture
Before starting antibiotic therapy, blood samples for culture should be collected in patients with CAP who are
being admitted to hospital. Collect two samples of blood from two different peripheral sites, or one site on two
separate occasions. Identification of a pathogen often enables de-escalation of antibiotic therapy and provides
useful information on local epidemiology. Importantly, blood culture sometimes identifies alternative diagnoses in
septic patients who have been misdiagnosed as having CAP.
Pneumococcal urinary antigen assay
The pneumococcal urinary antigen assay is used to identify S. pneumoniae infection in patients with confirmed
CAP. It should not be used to establish a diagnosis of CAP. Particularly in patients with low-severity CAP, the
pneumococcal urinary antigen assay has limited utility because of low yield—hence cost outweighs benefit.
The pneumococcal urinary antigen assay is easily performed on routine urine samples (either before or after
starting antibiotic therapy), so is useful for the early identification of S. pneumoniae. Sensitivity for S. pneumoniae
is increased in high-severity CAP, and pneumococcal pneumonia with bacteraemia.
Consider this test in hospitalised adults either with high-severity CAP, or when therapy will be altered by a
positive result and results are tied to a stewardship strategy of antibiotic de-escalation. However, the result may not
alter treatment decisions in patients already treated with benzylpenicillin or amoxicillin.
Legionella urinary antigen assay

The Legionella urinary antigen assay only detects Legionella pneumophila serogroup 1, which accounted for 98%
of L. pneumophila cases in Australia in 2014. The test does not detect other Legionella species, such as other L.
pneumophila serogroups or L. longbeachae. The prevalence of different Legionella species varies with
geographical region.
The Legionella urinary antigen assay should be reserved for patients with high-severity CAP and those with risk
factors for Legionella infection (see Table 2.56), and for use during suspected outbreaks. The test can be
performed either before or after starting antibiotics.
Serological testing
Available serological tests include immunoglobulin M (IgM) serology for M. pneumoniae, and acute and
convalescent serology for M. pneumoniae, Legionella species, C. pneumoniae, Chlamydophila (Chlamydia)
psittaci, Coxiella burnetii and influenza. For patients from tropical regions of Australia [Note 3], Burkholderia
pseudomallei serology is also available. While the M. pneumoniae IgM result can assist in making a diagnosis
during the acute phase of the illness, false-positive results can occur; carefully interpret the result. Acute and
convalescent serology usually only provides a retrospective diagnosis (looking for a change in immunoglobulin G
[IgG] titre between acute and convalescent serology).
In acute illness, interpret a low positive IgG result with caution, because it may reflect past infection rather than
current infection. Serological testing is therefore rarely helpful in the acute setting and results seldom change
initial patient management.
Serological testing is rarely helpful in the acute setting.
Serological testing for Legionella species can be useful to confirm the diagnosis retrospectively, particularly for
Legionella species and serotypes other than L. pneumophila serogroup 1. Interpret a single positive Legionella
serum IgG result with caution, because it may reflect past infection rather than current infection.
The approach to serological testing at some centres is to collect samples for acute serology but not complete the
test until a convalescent serology sample is also obtained.
Biomarker (C-reactive protein and procalcitonin) serum concentrations
Biomarker (C-reactive protein [CRP] and procalcitonin) serum concentration monitoring has been mainly studied
in CAP to guide decisions about:
whether to start antibiotic therapy

the duration of antibiotic therapy.
Elevated CRP and procalcitonin concentrations correlate with increased probability of infection caused by
bacterial pathogens, especially typical bacteria (eg S. pneumoniae). However, no single biomarker threshold alone
adequately discriminates viral from bacterial infection. At present, the utility of point-of-care biomarker testing to
guide decisions about whether to start antibiotic therapy is unclear, and its use is generally not recommended.
Biomarkers may have a role as part of initial clinical assessment, when a diagnosis of pneumonia has not been
confirmed, to guide whether antibiotic therapy is required. Biomarker testing is an area of investigation in primary
care management in Australia.
Biomarkers, particularly procalcitonin serum concentrations, have been used to determine when antibiotic therapy
can be stopped, which may allow a reduced duration of therapy (eg from 10 to 5 days). However, this can also be
achieved by assessment of clinical stability and adherence to the shorter-course regimens for CAP recommended in
these guidelines. Therefore, use of procalcitonin serum concentration to guide duration of antibiotic therapy is not
recommended when standard treatment duration is limited to 5 to 7 days. Biomarkers can be useful as an adjunct
to clinical judgment, or for reassurance when clinical improvement is not evident.
CAP in adults: rationale for empirical regimens

Australian studies show that penicillin-based regimens are effective and safe for the majority of patients with low-
or moderate-severity community-acquired pneumonia (CAP).
Patients with high-severity CAP requiring intensive care support have a high risk of adverse outcomes if they do
not receive appropriate initial treatment. Therefore, broader-spectrum empirical antibiotic therapy is recommended
initially for these patients until the results of investigations are available, even though penicillin-susceptible
Streptococcus pneumoniae is the most common cause of high-severity CAP. Identification of patients with high-
severity CAP, or at risk of progression to high-severity CAP, is an important step in the management of CAP (see
CAP in adults: assessment of pneumonia severity).
oropharynx. Therefore, initial management of suspected aspiration pneumonia should follow empirical therapy
for CAP. For further information, see Approach to managing aspiration pneumonia.
Based on current data, adjunctive corticosteroids are not recommended for patients with low- and moderate-
severity CAP. The benefit of adjunctive corticosteroids in patients with high-severity CAP is uncertain; therefore, a
definitive recommendation cannot be made at the time of writing.
Further background on the empirical antibiotic regimens for CAP in adults follows.
Doxycycline or a macrolide (oral clarithromycin or intravenous azithromycin) is used in CAP to treat

atypical bacteria such as Mycoplasma pneumoniae, Chlamydophila (Chlamydia) pneumoniae and Legionella
species. There is increasing resistance of S. pneumoniae isolates to doxycycline and macrolides, so these
drugs should not be used as monotherapy, except in patients with low-severity CAP who can be reviewed.
For moderate- or high-severity CAP, combination therapy with a beta lactam is recommended. Doxycycline
is not suitable for use in pregnant women; if an alternative to beta-lactam therapy is needed for pregnant
women with low-severity CAP, use oral azithromycin (see Pneumonia caused by Mycoplasma pneumoniae,
or Chlamydophila (Chlamydia) species) for dosage.
If an oral cephalosporin is required to treat CAP for a patient with immediate nonsevere or delayed
nonsevere hypersensitivity to penicillins, cefuroxime is preferred to cefalexin or cefaclor because of its
superior antipneumococcal activity.
At the recommended dosage, intravenous benzylpenicillin, amoxicillin and ampicillin have similar efficacy
against penicillin-susceptible Haemophilus influenzae isolates, but benzylpenicillin is preferred for
intravenous therapy because it has a narrower spectrum of activity. For oral therapy, amoxicillin is preferred
to phenoxymethylpenicillin because it has superior bioavailability, and therefore greater clinical activity
against H. influenzae.
For penicillin-susceptible infections, ceftriaxone and cefotaxime do not have superior activity against H.
influenzae and S. pneumoniae compared to penicillins. H. influenzae, including strains that produce beta-
lactamase enzymes, is an uncommon cause of CAP in Australia. At the recommended dose, benzylpenicillin
remains active and achieves satisfactory serum concentrations to treat strains of S. pneumoniae with
intermediate susceptibility to penicillin. S. pneumoniae strains with high-level penicillin resistance remain
uncommon in Australia. Therefore, ceftriaxone is not recommended for routine use in empirical treatment of
moderate-severity CAP or for directed therapy of S. pneumoniae pneumonia.
Once a patient with moderate-severity CAP has responded to benzylpenicillin therapy, switching to oral
amoxicillin is recommended to finish the course. Amoxicillin+clavulanate is not an appropriate alternative.
Compared with amoxicillin+clavulanate (875+125 mg, 12-hourly), amoxicillin:
is less selective for resistance
has fewer adverse effects
at the dosage recommended for CAP (1 g, 8-hourly), achieves significantly higher plasma
concentrations of amoxicillin (which is needed in case of infection due to S. pneumoniae with a higher
minimum inhibitory concentration [MIC] to penicillin).
Widespread use of quinolones has been associated with the development of resistant pathogens and with
Clostridium difficile infection. Consequently, moxifloxacin is reserved for patients with CAP who have
immediate severe or delayed severe hypersensitivity to penicillins. When a quinolone is necessary for
empirical therapy of CAP, monotherapy with moxifloxacin is preferred because it has better
antipneumococcal activity than ciprofloxacin. Moxifloxacin is not routinely recommended for use in
pregnant women—seek expert advice.
In tropical regions of Australia [Note 4], CAP may be caused by pathogens such as Burkholderia
pseudomallei and Acinetobacter baumannii (especially in the wet season), so the treatment regimens for
moderate- and high-severity CAP are different—see CAP in adults: tropical regions.
If a pathogen is identified, use directed antibiotic therapy (see Directed therapy for pneumonia). Some antibiotics
have poor or uncertain efficacy for the treatment of pneumonia, so should not be used even if susceptibility is
reported (eg daptomycin, tigecycline).
CAP in adults: role of community-based parenteral antimicrobial

therapy
Community-based parenteral antimicrobial therapy has a limited role in the management of patients with
community-acquired pneumonia (CAP). Patients with moderate- or high-severity CAP are at risk of deterioration
and should generally be managed in hospital while receiving parenteral antibiotics. When the patient is well
enough to go home, a switch to oral therapy is usually appropriate; however, if there are no options for oral therapy
(eg due to antibiotic resistance or drug intolerance), community-based parenteral antimicrobial therapy may be
suitable.
In selected residents of aged-care facilities, if treatment in hospital is not consistent with the patient’s goals of care,
intravenous therapy (eg an organised Residential In-Reach Program, a community-based parenteral antimicrobial
therapy program or similar) can avoid transfer to hospital (see Parenteral therapy for CAP in residents of aged-care
facilities).
Empirical therapy: low-severity CAP in adults
Assessment of pneumonia severity helps determine appropriate antibiotic treatment. For severity assessment, see
CAP in adults: assessment of pneumonia severity.
Patients with low-severity community-acquired pneumonia (CAP) are usually managed in the community with
oral antibiotic therapy. For residents of aged-care facilities who are being treated in the facility, see Community-
acquired pneumonia in aged-care facilities.
Patients with low-severity CAP who have been admitted to hospital for observation (eg due to comorbidities or
social circumstances) can also be managed with oral antibiotic therapy.
The choice of initial empirical monotherapy or combination therapy depends on whether the patient can be
reviewed within 48 hours. If patient follow-up may not occur, consider combination therapy.
Combination therapy is an option in patients who have not improved after 48 hours of monotherapy.
Antibiotic regimens for CAP in these guidelines can be used for initial treatment of aspiration pneumonia (see
Approach to managing aspiration pneumonia). If the patient has had an aspiration event, try to exclude aspiration
pneumonitis (see Table 2.57) before starting antibiotic therapy for pneumonia. If aspiration pneumonia is
suspected (eg pneumonia in a patient with recurrent aspiration), start empirical therapy for low-severity CAP.
Recommended empirical therapy (monotherapy)

Monotherapy is recommended for patients with low-severity CAP to minimise adverse effects and optimise
adherence to therapy. Clinical review of the patient within 48 hours is recommended in case modification of
therapy is required. If patient follow-up within 48 hours may not occur, consider using initial combination therapy
instead (see Combination empirical therapy).
Amoxicillin is the drug of choice for monotherapy because of increasing rates of Streptococcus pneumoniae
resistance to tetracyclines and macrolides. For patients with low-severity CAP, use:
amoxicillin 1 g orally, 8-hourly; see below for duration of therapy.
In rural and remote regions of Australia, supervised administration and clinical review through a community
management program is sometimes preferred. Use:
procaine benzylpenicillin 1.5 g intramuscularly, daily; see below for duration of therapy.
Initial monotherapy with doxycycline can be used if atypical pathogens (eg Mycoplasma pneumoniae,
Chlamydophila [Chlamydia] pneumoniae) are suspected based on epidemiology or the clinical presentation (eg a
young adult who presents with nonproductive cough for 5 or more days and bilateral lower zone infiltrates on chest
X-ray). Use:
1 doxycycline 100 mg orally, 12-hourly; see below for duration of therapy
OR if doxycycline is poorly tolerated
2 clarithromycin 500 mg orally, 12-hourly; see below for duration of therapy.
For patients with low-severity CAP who are hypersensitive to penicillins, use:
1 doxycycline 100 mg orally, 12-hourly; see below for duration of therapy
2 clarithromycin 500 mg orally, 12-hourly; see below for duration of therapy.
Modify treatment based on the results of investigations, including susceptibility testing, if possible (see Directed
therapy for pneumonia).
Duration of therapy: if the patient has significantly improved after 2 to 3 days of antibiotic therapy, treat for 5
days. If the clinical response is slow, treat for 7 days. If the patient is not improving after 48 hours of monotherapy,
reassess the diagnosis. Consider infective and noninfective diagnoses—see Approach to managing patients with
pneumonia who are not improving. If pneumonia remains the likely diagnosis, consider escalating to combination
therapy (see Combination empirical therapy), and reassess the need for hospital admission.
For information about recovery from pneumonia and strategies to prevent further episodes of pneumonia, see
Pneumonia diagnosis and follow-up.
Combination empirical therapy

Monotherapy is recommended initially for patients with low-severity CAP, unless there is a risk that follow-up
within 48 hours may not occur. Use initial combination therapy if patient follow-up may not occur.
Monotherapy is recommended initially, unless there is a risk that follow-up within 48 hours may not occur.
If the patient was treated with monotherapy initially but is not improving after 48 hours, consider escalating to
combination therapy and reassess the need for hospital admission.
For patients with low-severity CAP who require combination empirical therapy, use as a two-drug regimen:
amoxicillin 1 g orally, 8-hourly; see below for duration of therapy
PLUS
doxycycline 100 mg orally, 12-hourly; see below for duration of therapy.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use as a two-drug
regimen:
cefuroxime 500 mg orally, 12-hourly; see below for duration of therapy [Note 5]
PLUS
doxycycline 100 mg orally, 12-hourly; see below for duration of therapy.
If doxycycline is poorly tolerated, replace doxycycline in the above regimens with:
clarithromycin 500 mg orally, 12-hourly; see below for duration of therapy.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, use as monotherapy:
moxifloxacin 400 mg orally, daily; see below for duration of therapy.
Duration of therapy: if the patient has significantly improved after 2 to 3 days of combination therapy, continue
combination therapy for 5 days. If the clinical response to combination therapy is slow, continue combination
therapy for 7 days. If the patient is not improving after 48 hours of combination therapy, reassess the diagnosis.
Consider infective and noninfective diagnoses—see Approach to managing patients with pneumonia who are not
improving. If pneumonia remains the likely diagnosis, reassess the need for hospital admission.
Empirical therapy: moderate-severity CAP in adults

Patients with moderate-severity community-acquired pneumonia (CAP) require close clinical observation so are
usually managed in hospital. If the patient requires intensive care support, see Empirical therapy: high-severity
CAP in adults for regimens. For residents of aged-care facilities, if treatment in the facility is being considered, see
Community-acquired pneumonia in aged-care facilities. For patients with low-severity CAP who have been
admitted to hospital for observation (eg due to comorbidities or social circumstances), use oral therapy.
For patients with low-severity CAP who have been admitted to hospital for observation (eg due to comorbidities or social
circumstances), use oral therapy.
Identify the pathogen if possible. Collect blood, and if available, sputum for Gram stain and culture, ideally before
starting antibiotic therapy [Note 6]. Other investigations may also be required—see CAP in adults: clinical and
microbiological investigations.
If influenza is suspected (eg depending on the season), consider adding empirical antiviral therapy while awaiting
the results of nucleic acid amplification tests (NAAT) (eg polymerase chain reaction [PCR]). For antiviral
regimens, see Antiviral therapy for influenza. If transmissible respiratory pathogens are a likely diagnosis (eg
influenza, respiratory syncytial virus [RSV], human metapneumovirus [hMPV]), implement droplet precautions
and isolation according to local infection control guidelines.
If the patient has had an aspiration event, try to exclude aspiration pneumonitis (see Table 2.57) before starting
antibiotic therapy for pneumonia. If aspiration pneumonia is suspected (eg pneumonia in a patient with recurrent
aspiration), start empirical therapy for moderate-severity CAP.
Patients with moderate-severity CAP in a tropical region of Australia [Note 7] are managed as for nontropical
regions unless the patient has risk factors for Burkholderia pseudomallei and Acinetobacter baumannii, or Gram-
negative bacilli are identified by culture of sputum or blood. See CAP in adults: tropical regions for risk factors
and management.
Note 6: At the onset of CAP, many patients do not produce sputum. If a sputum sample can be collected before
starting antibiotic therapy, a good quality sample (presence of polymorphs, but few or no squamous epithelial
cells on microscopy) can assist in detection of the pathogen. See Sputum Gram stain and culture.
Empirical therapy
For patients with moderate-severity CAP, use as a two-drug regimen:
benzylpenicillin 1.2 g intravenously, 6-hourly; see Intravenous to oral switch and Duration
of therapy
PLUS EITHER
1 doxycycline 100 mg orally, 12-hourly; see Duration of therapy
2 clarithromycin 500 mg orally, 12-hourly; see Duration of therapy.
In patients who can take oral therapy and have appropriate clinical review, oral amoxicillin can be used as initial
therapy instead of benzylpenicillin because it has good bioavailability.
If oral therapy is not possible, consider giving doxycycline or clarithromycin enterally, or change to intravenous
azithromycin. If intravenous azithromycin is not available, seek expert advice; see also Antimicrobial drug
shortages.
management program is sometimes preferred. Use as a two-drug regimen:
procaine benzylpenicillin 1.5 g intramuscularly, daily; see Intravenous to oral switch and
Duration of therapy
PLUS EITHER
regimen:
1 ceftriaxone 1 g intravenously, daily; see Intravenous to oral switch and Duration of

therapy
OR
1 cefotaxime 1 g intravenously, 8-hourly; see Intravenous to oral switch and Duration of

therapy
PLUS EITHER
If oral therapy is not possible, consider giving doxycycline or clarithromycin enterally, or change to intravenous
azithromycin. If intravenous azithromycin is not available, seek expert advice; see also Antimicrobial drug
shortages.
moxifloxacin 400 mg orally, daily; see Duration of therapy.
If oral therapy is not possible, consider giving moxifloxacin enterally or intravenously.
Intravenous to oral switch

Once the patient has improved and is clinically stable, switch to oral therapy (see Box 2.35 for guidance on when
to switch to oral therapy).
Do not use amoxicillin+clavulanate for intravenous to oral switch.
Amoxicillin+clavulanate is not an appropriate choice for de-escalation of therapy. Compared with

amoxicillin+clavulanate (875+125 mg, 12-hourly), amoxicillin:

at the dosage recommended for CAP (1 g orally, 8-hourly), achieves significantly higher concentrations of
amoxicillin (which is needed in case of infection due to Streptococcus pneumoniae with a higher minimum
inhibitory concentration [MIC] to penicillin).
For intravenous to oral switch, use as a two-drug regimen:
amoxicillin 1 g orally, 8-hourly; see Duration of therapy

PLUS EITHER
regimen:
cefuroxime 500 mg orally, 12-hourly; see Duration of therapy [Note 8]
PLUS EITHER
2 clarithromycin 500 mg orally, 12-hourly; see below Duration of therapy.
Duration of therapy
If a patient with moderate-severity CAP improves within 2 to 3 days, treat for 5 days (intravenous + oral). Treat for
7 days (intravenous + oral) if clinical response is slow. Patients with lung abscess, empyema or large
parapneumonic effusion require a longer duration of therapy—see Lung abscess or Parapneumonic effusion and
empyema. If the patient is not improving after 48 hours, reassess the diagnosis. Consider infective and
noninfective diagnoses—see Approach to managing patients with pneumonia who are not improving. If
pneumonia remains the likely diagnosis, reassess disease severity (see CAP in adults: assessment of pneumonia
severity).
Empirical therapy: high-severity CAP in adults

High-severity community-acquired pneumonia (CAP) refers to patients with the highest risk of mortality. These
patients are usually managed in an intensive care unit because they are more likely to require intensive respiratory
or vasopressor support. This includes patients with sepsis or septic shock (see Early recognition of sepsis or septic
shock in adults for definitions).
For patients with sepsis or septic shock, start antibiotic therapy for high-severity CAP within 1 hour of
Identify the pathogen if possible. Collect blood and, if available, sputum for Gram stain and culture, ideally before
microbiological investigations. For immunocompromised patients, consider investigations for unusual pathogens
(see Approach to pneumonia in immunocompromised patients), and seek expert advice on whether to adjust
empirical antibiotic therapy while awaiting the results.
Penicillin-susceptible Streptococcus pneumoniae is the most common cause of high-severity CAP. However, the
empirical antibiotic regimens for high-severity CAP in these guidelines treat a broad range of pathogens
(S. pneumoniae, Legionella pneumophila and Gram-negative Enterobacteriaceae), because patients with high-
severity CAP have a high risk of adverse outcomes if they do not receive appropriate initial treatment. Some
patients require additional therapy for infection caused by Staphylococcus aureus, Pseudomonas aeruginosa,
multidrug-resistant Gram-negative bacteria or influenza. In patients with severe periodontal disease or putrid
sputum, consider infection caused by anaerobes such as Bacteroides or Prevotella species.
For management of high-severity CAP in tropical regions of Australia [Note 10], see CAP in adults: tropical
regions.
Empirical therapy
For patients with high-severity CAP, use as a two-drug regimen:
1 ceftriaxone 2 g intravenously, daily; for patients with septic shock or requiring intensive
care support, use ceftriaxone 1 g intravenously, 12-hourly. See Patient review, intravenous
to oral switch and duration of therapy
OR
1 cefotaxime 2 g intravenously, 8-hourly; for patients with septic shock or requiring

intensive care support, use cefotaxime 2 g intravenously, 6-hourly. See Patient review,
azithromycin 500 mg intravenously, daily; see Patient review, intravenous to oral switch
Some patients require additional therapy for infection caused by S. aureus, P. aeruginosa, multidrug-resistant
Gram-negative bacteria, anaerobes and influenza; see Additional therapy for high-severity CAP.
A three-drug regimen using benzylpenicillin, gentamicin and azithromycin is an alternative empirical therapy
regimen for patients with high-severity CAP. For more information on the use of gentamicin, see Principles of
aminoglycoside use.
cefotaxime plus azithromycin as above.
moxifloxacin 400 mg intravenously, daily; see Patient review, intravenous to oral switch
Some patients require additional therapy for infection caused by S. aureus, P. aeruginosa, multidrug-resistant
Gram-negative bacteria, anaerobes and influenza; see Additional therapy for high-severity CAP.
Additional therapy for high-severity CAP
Staphylococcus aureus
Consider adding empirical antistaphylococcal therapy in a patient with high-severity CAP if:
the clinical presentation is suggestive of staphylococcal pneumonia (eg rapid progression to sepsis, cavitary
or necrotising pneumonia, multilobar consolidation, postinfluenza pneumonia)
profuse Gram-positive cocci in clusters are identified by Gram stain of sputum [Note 11].
If treatment of S. aureus is considered necessary, vancomycin is the empirical antibiotic of choice because of
increased prevalence of community-associated methicillin-resistant S. aureus (CA-MRSA). Add to the empirical
therapy regimen:
intensive care support. See Patient review, intravenous to oral switch and duration of
therapy.
If staphylococcal pneumonia is confirmed by investigations, see Staphylococcal pneumonia. If S. aureus is not

identified, stop vancomycin and modify therapy based on the results of culture and susceptibility testing (see
Directed therapy for pneumonia).
Note 11: Gram stain of poor quality sputum samples can give misleading results. Ensure a good quality sample
(presence of polymorphs, but few or no squamous epithelial cells on microscopy), collected before starting
antibiotics, is used for adjusting therapy. The pathogen should be predominant in the Gram stain as well as the
culture.
Pseudomonas aeruginosa
For management of patients with cystic fibrosis, see Cystic fibrosis.
P. aeruginosa is a rare cause of CAP. Consider empirical antipseudomonal therapy for patients with known
colonisation of sputum with P. aeruginosa (eg patients with chronic suppurative lung disease such as
bronchiectasis) and one of the following:
Gram-negative bacilli predominant on Gram stain or identified by culture of sputum [Note 12] or blood
Do not use previous susceptibility results to guide current antipseudomonal therapy unless the sample was taken
recently (eg in the last month).
If empirical antipseudomonal therapy is indicated, replace the empirical therapy regimen with:
1 cefepime 2 g intravenously, 8-hourly; see Patient review, intravenous to oral switch and
duration of therapy
OR
1 piperacillin+tazobactam 4+0.5 g intravenously, 6-hourly; see Patient review, intravenous

and duration of therapy
PLUS for patients with sepsis or septic shock

first dose. See Principles of aminoglycoside use for subsequent dosing [Note 14] [Note
15].
If P. aeruginosa is confirmed, see Pseudomonas aeruginosa pneumonia for ongoing management and modification
of therapy. If P. aeruginosa is not identified, switch to an appropriate narrower-spectrum empirical regimen (see
Empirical therapy).
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, replace the
empirical therapy regimen with the cefepime-based regimen above.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, replace the empirical
therapy regimen with:
meropenem 1 g intravenously, 8-hourly; see Patient review, intravenous to oral switch and
duration of therapy [Note 16]
PLUS
PLUS for patients with sepsis or septic shock
gentamicin intravenously over 3 to 5 minutes. See Principles of aminoglycoside use for

first dose. See Principles of aminoglycoside use for subsequent dosing [Note 14] [Note
15].
If P. aeruginosa is confirmed, see Pseudomonas aeruginosa pneumonia for ongoing management and modification
of therapy. If P. aeruginosa is not identified, switch to an appropriate narrower-spectrum empirical regimen (see
Empirical therapy).
culture.
calculate the dose.
function.
treatment options.
Multidrug-resistant Gram-negative bacteria
Enteric Gram-negative bacilli (eg Enterobacteriaceae) are uncommon causes of high-severity CAP, which can
result in destructive or necrotising pneumonia. Ceftriaxone and cefotaxime provide empirical treatment for most
community-acquired Gram-negative Enterobacteriaceae. A change to patient management is not required unless
multidrug-resistant (MDR) Gram-negative bacteria are suspected as a cause of CAP.
Patients who have recently travelled to an area with a high prevalence of multidrug-resistant Gram-negative
bacteria are at increased risk of colonisation with these bacteria; for additional risk factors, see Box 2.30. Patients
with confirmed enteric or urinary colonisation with extended-spectrum beta-lactamase (ESBL)-producing
Enterobacteriaceae or carbapenemase-producing Enterobacteriaceae do not usually require an adjustment to
empirical therapy because these bacteria are uncommon causes of CAP. If a patient with high-severity CAP has
confirmed or suspected colonisation with multidrug-resistant Gram-negative bacteria, expert advice from an
infectious diseases physician or clinical microbiologist is recommended.
Perform routine rectal screening for multidrug-resistant Gram-negative bacteria in patients who have been
hospitalised overseas.
If multidrug-resistant Enterobacteriaceae are confirmed as the cause of CAP, see Multidrug-resistant

Enterobacteriaceae pneumonia for management.
Anaerobes
Antibiotic regimens for CAP in these guidelines can be used for initial treatment of aspiration pneumonia because
these regimens treat most pathogens aspirated from the oropharynx, including oral anaerobes (see Approach to
managing aspiration pneumonia). In rare cases, pneumonia following aspiration may be due to specific anaerobes,
such as Bacteroides or Prevotella species, that are not adequately treated with the cephalosporin-based regimens
for high-severity CAP. These pathogens are more likely in a patient who has severe periodontal disease or putrid
sputum.
aspiration), start empirical therapy for high-severity CAP. If the patient has severe periodontal disease or putrid
sputum and is being treated with either ceftriaxone or cefotaxime plus azithromycin for high-severity CAP,
consider adding metronidazole. Metronidazole is not necessary for suspected aspiration pneumonia if the patient is
receiving an empirical regimen containing meropenem, moxifloxacin or piperacillin+tazobactam because these
drugs treat a broader range of oral anaerobes, including Bacteroides and Prevotella species.
For patients with suspected aspiration pneumonia who have severe periodontal disease or putrid sputum,
consider adding to the ceftriaxone or cefotaxime plus azithromycin empirical regimen:
metronidazole 500 mg intravenously, 12-hourly; see Patient review, intravenous to oral

Review the patient within 24 to 48 hours. Consider stopping antibiotic therapy if the patient has significantly
improved and aspiration pneumonitis is a more likely diagnosis.
Pneumonia involving anaerobic pathogens can be necrotising or cavitary, and the infection may progress to lung
abscess or parapneumonic effusion and empyema—assess the patient for these complications.
Influenza and other viral respiratory pathogens
Patient review, intravenous to oral switch and duration of therapy
Patient review
therapy for pneumonia). If the response to initial empirical therapy is inadequate at 48 hours, reassess the
diagnosis. Consider infective and noninfective diagnoses—see Approach to managing patients with pneumonia
who are not improving. Consider if additional therapy for high-severity CAP is needed for S. aureus, P.
aeruginosa, anaerobes or influenza.
For management of complications of pneumonia, see Parapneumonic effusion and empyema or Lung abscess.
to switch to oral therapy). If a pathogen is not identified, use as a two-drug regimen:
amoxicillin 1 g orally or enterally, 8-hourly; see Duration of therapy
PLUS EITHER (unless the patient has had at least 3 days of azithromycin)
1 doxycycline 100 mg orally or enterally, 12-hourly; see Duration of therapy

2 clarithromycin 500 mg orally or enterally, 12-hourly; see Duration of therapy.
regimen:
cefuroxime 500 mg orally or enterally, 12-hourly; see Duration of therapy [Note 17]
moxifloxacin 400 mg orally or enterally, daily; see Duration of therapy.
If the patient was prescribed additional therapy for anaerobes and aspiration pneumonia remains the likely
diagnosis, consider continuing metronidazole orally (or enterally). Add to the amoxicillin- or cefuroxime-based
oral therapy regimens:
metronidazole 400 mg orally or enterally, 12-hourly; see Duration of therapy.
Duration of therapy
Review the patient’s response to therapy and results of investigations. The usual total treatment duration is 7 days
(intravenous + oral), except for azithromycin, which is only required for 3 to 5 days. If the patient has had at least
3 days of azithromycin, ongoing oral therapy with doxycycline or clarithromycin (to treat atypical bacteria) is not
required. If a pathogen is identified, see Directed therapy for pneumonia for duration of therapy. Patients with lung
abscess, empyema or large parapneumonic effusion require a longer duration of therapy—see Lung abscess or
Parapneumonic effusion and empyema.
CAP in adults: tropical regions

In tropical regions of Australia [Note 18], the Gram-negative bacteria Burkholderia pseudomallei and
Acinetobacter baumannii can cause community-acquired pneumonia (CAP); cases are also occasionally seen
further south. Risk factors for CAP caused by these pathogens are listed in Box 2.17.
Risk factors for community-acquired pneumonia caused by Burkholderia pseudomallei and
Acinetobacter baumannii in tropical regions of Australia (Box 2.17) [NB1]
Risk factors for B. pseudomallei and A. baumannii include:
diabetes
hazardous alcohol consumption
chronic kidney disease
chronic lung disease (including chronic obstructive pulmonary disease and bronchiectasis)
immunosuppressive therapy (including chronic corticosteroid use).
NB1: Tropical regions of Australia refer to regions north of 20°S latitude. This includes areas of Queensland north of Mackay, the Northern
Territory north of Tennant Creek, and Western Australia north of Port Hedland.
Assess pneumonia severity to determine appropriate antibiotic therapy; see CAP in adults: assessment of
pneumonia severity.
Patients with low-severity CAP in tropical regions of Australia are managed as for patients in nontropical regions.
For empirical therapy, see Empirical therapy: low-severity CAP in adults.
Patients with moderate-severity CAP in tropical regions of Australia may need adjustment to empirical therapy—
see Moderate-severity CAP in adults: tropical regions.
For patients with high-severity CAP in tropical regions of Australia, adjustment to empirical therapy is required—
see High-severity CAP in adults: tropical regions.
Low-severity CAP in adults: tropical regions

Patients with low-severity CAP in tropical regions of Australia are managed as for patients in nontropical regions;
see Empirical therapy: low-severity CAP in adults.
Moderate-severity CAP in adults: tropical regions
Patients with moderate-severity CAP require close clinical observation so are usually managed in hospital. If the
patient requires intensive care support, see High-severity CAP in adults: tropical regions for regimens.
For patients with low-severity CAP who have been admitted to hospital for observation (eg due to comorbidities or
social circumstances), use oral therapy as for Empirical therapy: low-severity CAP in adults.
Identify the pathogen if possible. Collect blood, and if available, sputum for Gram stain and culture, ideally before
microbiological investigations.
aspiration), start empirical therapy for moderate-severity CAP (see below).
Patients in tropical regions of Australia should be treated as for patients in nontropical regions unless they have risk factors for
B. pseudomallei and A. baumannii, or Gram-negative bacilli are identified by culture.
Patients with moderate-severity CAP in a tropical region of Australia [Note 20] are managed as for patients in
nontropical regions (see Empirical therapy: moderate-severity CAP in adults), unless:
the patient has risk factors for B. pseudomallei and A. baumannii (see Box 2.17), or
Gram-negative bacilli are identified by Gram stain or culture of sputum [Note 21] or blood.
north of Mackay, the Northern Territory north of Tennant Creek, and Western Australia north of Port Hedland
culture.
Empirical therapy
For patients with moderate-severity CAP in a tropical region of Australia who have risk factors for B.
pseudomallei and A. baumannii, or Gram-negative bacilli identified by culture, use as a three-drug regimen:

therapy
OR

therapy
PLUS
gentamicin intravenously, as a single dose initially, followed by further inpatient

assessment; see Principles of aminoglycoside use for dosage and principles of use
PLUS EITHER
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use either the
ceftriaxone- or cefotaxime-based regimen as above.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, use as a two-drug regimen:
gentamicin intravenously, as a single dose initially, followed by further inpatient

assessment; see Principles of aminoglycoside use for dosage and principles of use
PLUS
If B. pseudomallei pneumonia is confirmed, see Melioidosis for ongoing management. If A. baumannii pneumonia
or another pathogen is confirmed, see Directed therapy for pneumonia for ongoing management.
Do not use amoxicillin+clavulanate for intravenous to oral switch.
Amoxicillin+clavulanate is not an appropriate choice for de-escalation of therapy. Compared with

amoxicillin+clavulanate (875+125 mg, 12-hourly), amoxicillin:

at the dosage recommended for CAP (1 g orally, 8-hourly), achieves significantly higher concentrations of
amoxicillin (which is needed in case of infection due to Streptococcus pneumoniae with a higher minimum
inhibitory concentration [MIC] to penicillin).
For intravenous to oral switch, once B. pseudomallei and A. baumannii pneumonia have been excluded, use as a
two-drug regimen:
PLUS EITHER
OR if doxycyline is poorly tolerated
regimen:
PLUS EITHER
Duration of therapy
In patients with moderate-severity CAP who improve within 2 to 3 days, treat for 5 days (intravenous + oral). Treat
for 7 days (intravenous + oral) if clinical response is slow. Patients with lung abscess, empyema or large
empyema. If the patient is not improving after 48 hours, reassess the diagnosis. Consider infective and
noninfective diagnoses—see Approach to managing patients with pneumonia who are not improving. If
pneumonia remains the likely diagnosis, reassess disease severity (see CAP in adults: assessment of pneumonia
severity).
High-severity CAP in adults: tropical regions

High-severity CAP refers to patients with the highest risk of mortality. These patients are usually managed in an
intensive care unit because they are more likely to require intensive respiratory or vasopressor support. This
includes patients with sepsis or septic shock (see Early recognition of sepsis or septic shock in adults for
definitions).
For patients with sepsis or septic shock, start antibiotic therapy for high-severity CAP within 1 hour of
Identify the pathogen if possible. Collect blood, and if available, sputum for Gram stain, culture, ideally before
microbiological investigations. For immunocompromised patients, consider investigations for unusual pathogens
(see Approach to pneumonia in immunocompromised patients), and seek expert advice on whether to adjust
empirical antibiotic therapy while awaiting the results.
aspiration), start empirical therapy for high-severity CAP.
In tropical regions of Australia [Note 24], B. pseudomallei and A. baumannii are important causes of high-severity
CAP. B. pseudomallei is the second most common cause of high-severity CAP, after S. pneumoniae. In tropical
regions, empirical therapy depends on the season.
Empirical therapy
In the wet season [Note 25], use as a two-drug regimen:
duration of therapy [Note 26]
PLUS
In the dry season, use as a two-drug regimen:
PLUS one of the following
care support, use ceftriaxone 1 g intravenously, 12-hourly. See Patient review, intravenous
OR

intensive care support, use cefotaxime 2 g intravenously, 6-hourly. See Patient review,
OR

to oral switch and duration of therapy.
In the dry season, for patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins,
use the ceftriaxone- or cefotaxime-based regimen as above.
In the dry season, for patients with delayed severe or immediate severe hypersensitivity to penicillins, the
meropenem plus azithromycin regimen above may be suitable [Note 26].
treatment options.
Additional therapy for high-severity CAP in tropical regions
If the clinical presentation is suggestive of Staphylococcus aureus pneumonia, or profuse Gram-positive cocci in
clusters are identified by Gram stain of sputum, add vancomycin to the empirical regimen; see here for dosage.
If the patient is at high risk of Pseudomonas aeruginosa pneumonia (eg patients with colonisation of sputum with
P. aeruginosa who have sepsis or septic shock, or Gram-negative bacilli identified by Gram stain or culture of
sputum or blood), use the meropenem plus azithromycin or piperacillin+tazobactam plus azithromycin regimen
above (depending on the season). Consider adding an initial dose of gentamicin to these regimens, unless the
patient already received a dose before evacuation to hospital. See Principles of aminoglycoside use for gentamicin
dosage and principles of use.
If aspiration pneumonia is suspected in a patient with severe periodontal disease or putrid sputum, consider
adding metronidazole to the ceftriaxone- or cefotaxime-based regimen (eg to treat Bacteroides or Prevotella
species). For metronidazole dosage, see here. Metronidazole is not necessary if the patient is receiving a regimen
containing meropenem or piperacillin+tazobactam because these drugs are effective against most anaerobic
bacteria that cause aspiration pneumonia. Pneumonia involving anaerobic pathogens is usually necrotising or
cavitary and the infection may progress to lung abscess or parapneumonic effusion and empyema—assess the
patient for these complications.
Consider the need for additional empirical therapy for influenza; see here for further information.
Patient review
therapy for pneumonia). If B. pseudomallei pneumonia is confirmed, see Melioidosis for ongoing management. If
A. baumannii pneumonia is confirmed, see Acinetobacter baumannii pneumonia for ongoing management.
If the response to initial empirical therapy is inadequate at 48 hours, reassess the diagnosis. Consider infective and
noninfective diagnoses—see Approach to managing patients with pneumonia who are not improving. Consider
if additional therapy for high-severity CAP is needed for S. aureus, P. aeruginosa, anaerobes and influenza.
For management of complications of pneumonia, see Parapneumonic effusion and empyema and Lung abscess.
For intravenous to oral switch, once B. pseudomallei and A. baumannii pneumonia have been excluded, use as a
two-drug regimen:
amoxicillin 1 g orally or enterally, 8-hourly; see Duration of therapy
OR if doxycyclne is poorly tolerated
regimen:
cefuroxime 500 mg orally or enterally, 12-hourly; see Duration of therapy [Note 27]
moxifloxacin 400 mg orally or enterally, daily; see Duration of therapy.
If the patient was initially treated for aspiration pneumonia and this remains the likely diagnosis, consider adding
oral (or enteral) metronidazole to the amoxicillin- or cefuroxime-based oral therapy regimens (for dosage,
see here).
Duration of therapy
Treatment duration depends on patient response and the results of investigations. Provided B. pseudomallei and A.
baumannii have been excluded, a total treatment duration of 7 days (intravenous + oral) is sufficient for most
patients with high-severity CAP. However, azithromycin is only required for 3 to 5 days; if the patient has had at
least 3 days of azithromycin, ongoing oral therapy with doxycycline or clarithromycin (to treat atypical bacteria) is
not required. If a pathogen is identified, see Directed therapy for pneumonia for duration of therapy. Patients with
lung abscess, empyema or large parapneumonic effusion require a longer duration of therapy—see Lung abscess or
Parapneumonic effusion and empyema.
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CAP in neonates and children younger than 2 months
Aetiology
In neonates, the organisms associated with early-onset pneumonia (occurring within 72 hours of birth) are usually
acquired from the maternal perineal flora; common bacterial pathogens include Streptococcus agalactiae (group B
streptococcus) and Escherichia coli. When assessing neonatal pneumonia, it is helpful to review the results of
maternal bacterial screening and other maternal investigations for infection or colonisation.
Haemophilus influenzae can cause late-onset pneumonia (occurring more than 72 hours after birth) in neonates and
children up to 2 months of age.
Pneumonitis caused by herpes simplex virus (acquired from the mother) usually presents between days 3 and 7 of
life (see Neonatal herpes simplex infection).
Mycobacterium tuberculosis (acquired from the mother) presents as pneumonia in neonates. See Tuberculosis for
general information and seek expert advice for management of neonatal tuberculosis.
Listeria monocytogenes (acquired from the mother) is an uncommon cause of pneumonia in neonates. L.
monocytogenes pneumonia rarely occurs after 1 month of age. L. monocytogenes infection in the mother is
associated with a prodromal illness or evidence of intra-amniotic infection (chorioamnionitis) during labour.
Chlamydia trachomatis is an uncommon cause of pneumonia in children aged 2 weeks to 5 months. As many as
50% of infants with C. trachomatis pneumonia also have conjunctivitis (see Chlamydial conjunctivitis).
Bordetella pertussis, which causes pertussis, is an uncommon cause of community-acquired pneumonia (CAP) in
young children. Suspect B. pertussis in children who present with paroxysmal cough associated with cyanosis or
apnoea.
After the neonatal period, up to 70% of CAP in children is viral. Influenza A virus, respiratory syncytial virus
(RSV), parainfluenza virus, human metapneumovirus (hMPV) and adenovirus are commonly identified by nucleic
acid amplification tests (NAAT) (eg polymerase chain reaction [PCR]). After viral causes, Streptococcus
pneumoniae and Mycoplasma pneumoniae are the most common bacterial pathogens in children older than 1
month.
Staphylococcus aureus can cause CAP in children of all ages. It is an important cause of high-severity CAP. Lung
abscess, empyema and large parapneumonic effusion are complications of staphylococcal pneumonia in children.
Burkholderia pseudomallei, which causes melioidosis, can cause pneumonia in children in tropical regions of
Australia [Note 1], though rarely in children less than 2 months of age. Consider performing culture and serology
testing for B. pseudomallei in children less than 2 months of age in tropical regions of Australia who are not
improving (see Melioidosis for test details).

Acute viral bronchiolitis is a differential diagnosis of CAP in young children and is the most likely diagnosis in
children younger than 12 months who present with cough and respiratory distress. See Acute bronchiolitis.
In children younger than 2 months, the clinical signs of serious infection are usually nonspecific. Therefore, treat
suspected CAP as for sepsis or septic shock initially until differential diagnoses such as meningitis and encephalitis
are excluded.
Use the antibiotic regimens for sepsis or septic shock as initial management of suspected CAP in children younger than 2
months.
For antibiotic regimens:

for term neonates (gestational age 37 weeks or older)
see here for early-onset infection (occurring within 72 hours of birth)
see here for late-onset infection (occurring more than 72 hours after birth)
for children 1 month to younger than 2 months, see here.
For antibiotic management of preterm neonates and neonates who have been hospitalised since birth, seek expert
advice.
The antibiotic regimens in this topic can be used once meningitis and encephalitis are excluded, provided the child
is improving on the empirical sepsis or septic shock regimen. Seek expert advice for management of children who
are not improving.
Ongoing management of early-onset CAP (occurring within 72 hours of birth) in term

neonates
For ongoing management of early-onset CAP (occurring within 72 hours of birth) in term neonates (gestational
age 37 weeks or older), use:
benzylpenicillin 60 mg/kg intravenously (neonates 7 days or younger: 12-hourly; neonates

older than 7 days: 6-hourly) for a total of 7 days
PLUS
of use. Review empirical use after 48 hours and monitor plasma concentration if
continuing gentamicin.
therapy for pneumonia). Seek expert advice for management of neonates with complications of pneumonia such as
lung abscess, large parapneumonic effusion or empyema.
Ongoing management of late-onset CAP (occurring more than 72 hours after birth) in
term neonates and CAP in children younger than 2 months
Antibiotic regimens
For ongoing management of late-onset CAP (occurring more than 72 hours after birth) in term neonates
(gestational age 37 weeks or older) and CAP in children younger than 2 months, use:
1 ampicillin 50 mg/kg intravenously (neonate 7 days or younger: 12-hourly; neonate older

than 7 days and infants 1 month or older: 6-hourly); see Intravenous to oral switch and
duration of therapy
OR
1 amoxicillin 50 mg/kg intravenously (neonate 7 days or younger: 12-hourly; neonate older

than 7 days and infants 1 month or older: 6-hourly); see Intravenous to oral switch and
duration of therapy
PLUS with either of the above regimens
of use. Review empirical use after 48 hours and monitor plasma concentration if
gentamicin continues; see Intravenous to oral switch and duration of therapy.
Ampicillin or amoxicillin are recommended in these guidelines because of the possibility of H. influenzae and
other Gram-negative pneumonia. However, if the child was initially treated with benzylpenicillin and is improving,
it is reasonable to continue therapy rather than changing to ampicillin or amoxicillin.
Add azithromycin to the above regimen if:
B. pertussis is suspected (eg children who have been in contact with a pertussis case, children with
paroxysmal cough associated with cyanosis or apnoea), while awaiting the results of NAAT (eg PCR)
performed on a nasopharyngeal sample
C. trachomatis is suspected (eg afebrile children with ‘staccato’ cough [single coughs separated by
inspiration], children with diffuse crackles on auscultation, presence of conjunctivitis).
If azithromycin is indicated, add to the above regimen:
azithromycin 10 mg/kg intravenously, daily; see Intravenous to oral switch and duration of
therapy.
If B. pertussis infection is confirmed, see Pertussis for management. If C. trachomatis infection is confirmed, see
Pneumonia caused by Mycoplasma pneumoniae, or Chlamydophila (Chlamydia) species.
If the clinical presentation is suggestive of staphylococcal pneumonia (eg cavitary or necrotising pneumonia,
pneumatoceles on chest X-ray, postinfluenza pneumonia), start therapy for methicillin-resistant S. aureus (MRSA),
because of increased prevalence of community-associated MRSA. Add to the above regimen:
OR
Consider replacing clindamycin or lincomycin with vancomycin if local epidemiology indicates that MRSA is
likely to be resistant to lincosamides. Use:
If the child has life-threatening pneumonia, add both a lincosamide (clindamycin or lincomycin) and vancomycin
to the regimen above.
Review therapy with clindamycin, lincomycin or vancomycin at 24 to 48 hours. If staphylococcal pneumonia is

confirmed by investigations, see Staphylococcal pneumonia.
Seek expert advice for management of children younger than 2 months with complications of pneumonia such as
lung abscess, large parapneumonic effusion or empyema.
Intravenous to oral switch and duration of therapy
For neonates, intravenous antibiotics are recommended for the full treatment course because oral absorption is
unreliable.
For children 1 to 2 months old, consider switching to oral therapy to complete the course when the child is
clinically stable and able to tolerate and absorb oral medicines (see Box 2.35 for guidance on when to switch to
oral therapy). If a pathogen is not identified, use:
amoxicillin 25 mg/kg orally, 8-hourly to complete 7 days (intravenous + oral).
If ongoing oral therapy with azithromycin is indicated, add:
azithromycin 10 mg/kg orally, daily to complete 5 days (intravenous + oral).
The total duration of therapy for ampicillin and amoxicillin is 7 days (intravenous + oral). Review empirical use of
gentamicin after 48 hours; if indicated continue for up to 7 days with plasma concentration monitoring. The total
duration of therapy for azithromycin is 5 days (intravenous + oral).
CAP in children 2 months or older: aetiology and management

approach
Clinical features
Typical clinical features of community-acquired pneumonia (CAP) in children include cough, tachypnoea,
tachycardia and increased work of breathing. Fever is usually, but not always, present. Clinical features help to
determine disease severity (see Assessing disease severity).
Aetiology
In children 2 months or older, up to 70% of CAP has a viral cause. Influenza A virus, respiratory syncytial virus
(RSV), parainfluenza virus, human metapneumovirus (hMPV) and adenovirus are commonly identified by nucleic
acid amplification tests (NAAT) (eg polymerase chain reaction [PCR]). However, is it difficult to differentiate
clinically between viral and bacterial CAP in children (see Is a viral diagnosis likely?).
Viruses are the most common cause of CAP in children 2 months or older.
Bacterial CAP in children is predominantly caused by Streptococcus pneumoniae. While Mycoplasma pneumoniae
can cause CAP, especially in school-aged children, the benefit of treatment is uncertain.
Chlamydia trachomatis is an uncommon cause of CAP in children up to 5 months of age. Suspect C. trachomatis
in children with low-severity CAP who are afebrile, have a ‘staccato’ cough (single coughs separated by
inspiration) with a subacute onset, and diffuse crackles on auscultation. C. trachomatis rarely causes more severe
disease.
Bordetella pertussis, which causes pertussis, is also an uncommon cause of CAP in young children. Suspect B.
pertussis in children who present with paroxysmal cough associated with cyanosis or apnoea.
Staphylococcus aureus can cause CAP in children of all ages. It is an important cause of high-severity CAP. Lung
abscess, empyema and large parapneumonic effusion are complications of staphylococcal pneumonia in children.
Children with chronic suppurative lung disease (eg bronchiectasis, cystic fibrosis) may be colonised with
Pseudomonas aeruginosa. For information about managing pneumonia in children with bronchiectasis, see
Approach to pneumonia in patients with COPD and bronchiectasis. For management of children with cystic
fibrosis, see Cystic fibrosis.
Although tuberculosis is uncommon in Australia, it should be considered in high-risk patient groups (such as
immigrants from high-prevalence countries), and children with an undiagnosed febrile or wasting illness or a
persistent cough (see Tuberculosis).
In tropical regions of Australia [Note 2], Burkholderia pseudomallei, which causes melioidosis, is a rare but
important cause of CAP in children. Empirical therapy active against B. pseudomallei is only needed for children
with high-severity CAP requiring intensive care support in the wet season (see CAP in children 2 months or older:
empirical therapy for high-severity CAP). For children with low- to moderate-severity CAP, perform culture and
serology testing for B. pseudomallei if the child does not improve with empirical antibiotic therapy (see
Melioidosis for test details).
Is a viral diagnosis likely?

Acute viral bronchiolitis is a differential diagnosis of CAP in young children and is the most likely diagnosis in
children younger than 12 months who present with cough and respiratory distress. See Acute bronchiolitis.
Viruses are the main cause of CAP in children 2 months or older but clinical features do not reliably distinguish
between viral and bacterial pathogens. A chest X-ray may help to differentiate between bacterial and viral CAP.
Children who have widespread pulmonary wheeze or crackles but no focal changes on chest X-ray are more likely
to have viral pneumonia. Consider performing NAAT (eg PCR) to detect respiratory viruses.
If a viral cause is suspected, treat symptoms with:
paracetamol or ibuprofen for fever or pain (see Pharmacological management of pain in children for dosing)
fluids to achieve and maintain adequate hydration.
Ask the carer to bring the child back for reassessment if symptoms are not improving after 48 to 72 hours, or
earlier if symptoms worsen.
Investigations
A chest X-ray is recommended to confirm the diagnosis of pneumonia and may help to differentiate between
bacterial and viral CAP.
Identification of the pathogen can be difficult in children with CAP because children rarely produce sputum and
some microbiological tests are unreliable in children. The pneumococcal urinary antigen assay has limited use in
children because nasal carriage of Streptococcus pneumoniae can lead to false-positive results. NAAT (eg PCR) is
useful to detect Bordetella pertussis (see Diagnosis of pertussis) or respiratory viruses. Investigations for atypical
bacteria (eg Mycoplasma pneumoniae) are not routinely recommended; positive NAAT (eg PCR) results can
represent asymptomatic carriage, and serological testing is rarely helpful in the acute setting.
Assessing disease severity

Clinical features of low-severity CAP in children include minimal tachypnoea, absence of tachycardia and oxygen
saturation 95% or higher on room air.
Clinical features of moderate-severity CAP in children include increased work of breathing, tachypnoea,
tachycardia and oxygen saturation 95% or lower on room air.
Clinical features of high-severity CAP in children include severe increase in work of breathing, grunting or nasal
flaring, marked tachypnoea and tachycardia, and oxygen saturation 90% or lower on room air.
Complications of pneumonia
Complications of pneumonia such as lung abscess, parapneumonic effusion and empyema can occur in children. If
the child’s signs and symptoms do not resolve as expected with appropriate antibiotic therapy, investigate for
complications of pneumonia. For management, see Lung abscess or Parapneumonic effusion and empyema.
For further information on assessment of patients with pneumonia who are not improving, see Approach to
managing patients with pneumonia who are not improving.
CAP in children 2 months or older: empirical therapy for low-severity

CAP
Clinical features of low–severity community-acquired pneumonia (CAP) in children include minimal tachypnoea,
absence of tachycardia and oxygen saturation 95% or higher on room air.
Viruses are the most common cause of CAP in children 2 months or older. Consider performing nucleic acid
amplification tests (NAAT) (eg polymerase chain reaction [PCR]) to detect respiratory viruses. It is difficult to
differentiate clinically between viral and bacterial CAP (see Is a viral diagnosis likely?).
Approach to managing aspiration pneumonia). If the patient has had an aspiration event, try to exclude aspiration
pneumonitis (see Table 2.57) before starting antibiotic therapy for pneumonia. If aspiration pneumonia is
suspected (eg pneumonia in a patient with recurrent aspiration), start empirical therapy for low-severity CAP.
For children 2 months or older with low-severity CAP, use:
amoxicillin 25 mg/kg up to 1 g orally, 8-hourly for 3 days.
For children 2 months or older with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins,
use:
cefuroxime (child 3 months or older) 15 mg/kg up to 500 mg orally, 12-hourly for 3 days
[Note 3].
For children 2 months or older with immediate severe or delayed severe hypersensitivity to penicillins, use:
1 azithromycin 10 mg/kg up to 500 mg orally, daily for 3 days
OR
1 clarithromycin 7.5 mg/kg up to 500 mg orally, 12-hourly for 3 days
OR (for children 8 years or older)
1 doxycycline orally, 12-hourly for 3 days [Note 4]

Doxycycline has not been associated with tooth discolouration, enamel hypoplasia or bone deposition, even in
children younger than 8 years, so is increasingly used in this age group. However, use is limited by the lack of a
suitable formulation.
If Chlamydia trachomatis is suspected (eg afebrile children up to 5 months of age with ‘staccato’ cough [single
coughs separated by inspiration], children with diffuse crackles on auscultation, presence of conjunctivitis), add to
amoxicillin or cefuroxime:
1 azithromycin 10 mg/kg up to 500 mg orally, daily for 3 days
OR
1 clarithromycin 7.5 mg/kg up to 500 mg orally, 12-hourly for 3 days.
therapy for pneumonia). For management of complications of pneumonia, see Lung abscess or Parapneumonic
effusion and empyema.
If the patient is not improving after 48 to 72 hours, reassess the diagnosis. Consider infective and noninfective
diagnoses—see Approach to managing patients with pneumonia who are not improving. If pneumonia remains the
likely diagnosis, reassess disease severity (see Assessing disease severity) and the need for hospital admission.
Note 4: An oral liquid formulation of doxycycline is not commercially available; for formulation options for
CAP in children 2 months or older: empirical therapy for moderate-

severity CAP
Clinical features of moderate–severity community-acquired pneumonia (CAP) in children include increased work
of breathing, tachypnoea, tachycardia and oxygen saturation 95% or lower on room air. Patients with moderate-
severity CAP require close clinical review so are usually managed in hospital.
In children hospitalised with CAP, the benefit of empirical therapy for atypical bacteria (eg Mycoplasma
pneumoniae) is uncertain. In most patients, routine therapy for atypical bacteria is not required.
Oral therapy is recommended because studies have shown equivalent outcomes to parenteral therapy for moderate-
severity CAP in children. Use parenteral therapy if oral therapy is not tolerated.
Use oral therapy because studies have shown equivalent outcomes to parenteral therapy for moderate-severity CAP in children.
Approach to managing aspiration pneumonia). If the patient has had an aspiration event (see Table 2.57), try to
exclude aspiration pneumonitis before starting antibiotic therapy for pneumonia. If aspiration pneumonia is
suspected (eg pneumonia in a patient with recurrent aspiration), start empirical therapy for moderate-severity CAP.
Oral therapy
Empirical therapy
Use oral therapy because studies have shown equivalent outcomes to parenteral therapy for moderate-severity CAP
in children.
For children 2 months or older with moderate-severity CAP who can tolerate oral therapy, use:
amoxicillin 25 mg/kg up to 1 g orally, 8-hourly; see Patient review and duration of

therapy.
For children 2 months or older with immediate nonsevere or delayed nonsevere hypersensitivity to
penicillins who can tolerate oral therapy, use:
cefuroxime (child 3 months or older) 15 mg/kg up to 500 mg orally, 12-hourly; see Patient
review and duration of therapy [Note 5].
For children 2 months or older with immediate severe or delayed severe hypersensitivity to penicillins who can
tolerate oral therapy, use:
1 azithromycin 10 mg/kg up to 500 mg orally, daily; see Patient review and duration of
therapy
OR
1 clarithromycin 7.5 mg/kg up to 500 mg orally, 12-hourly; see Patient review and duration
of therapy
1 doxycycline orally, 12-hourly; see Patient review and duration of therapy [Note 6]

suitable formulation.
In children hospitalised with CAP, the benefit of empirical therapy for atypical bacteria is uncertain. It is
reasonable to add therapy for atypical bacteria to amoxicillin or cefuroxime if:
Bordetella pertussis is suspected (eg children who have been in contact with a pertussis case, children with
performed on nasopharyngeal samples
M. pneumoniae is suspected (eg school-aged children with rash, children with a household contact who has
M. pneumoniae infection).
If therapy for atypical bacteria is indicated, add to amoxicillin or cefuroxime:
1 azithromycin 10 mg/kg up to 500 mg orally, daily; see Patient review and duration of
therapy
OR
of therapy
OR (for children 8 years or older, provided B. pertussis infection is not suspected)
1 doxycycline orally, 12-hourly; see Patient review and duration of therapy [Note 6]

Do not use doxycycline if B. pertussis infection is suspected. If B. pertussis infection is confirmed, see
Pertussis for management.
Patient review and duration of therapy
therapy for pneumonia). If infection with M. pneumoniae or Chlamydia species is confirmed, some clinicians add
therapy for atypical bacteria to amoxicillin or cefuroxime, rather than changing to directed therapy.
For management of complications of pneumonia, see Lung abscess or Parapneumonic effusion and empyema.
The duration of therapy for moderate-severity CAP is 5 to 7 days, except for azithromycin, which is only required
for 3 to 5 days. If the child significantly improves after 2 to 3 days of antibiotic therapy, treat for 5 days. If the
clinical response is slow, treat for 7 days.
likely diagnosis, reassess disease severity (see Assessing disease severity) and the need for parenteral therapy.
Consider adding therapy for atypical bacteria (azithromycin, clarithromycin or doxycycline) if the child is not
improving on amoxicillin or cefuroxime monotherapy (see dosages above).
For children in tropical regions of Australia [Note 7] who are not improving, perform culture and serology
testing for Burkholderia pseudomallei (see Melioidosis for details).
Parenteral therapy
Empirical therapy
Use oral therapy if possible because studies have shown equivalent outcomes to parenteral therapy for moderate-
severity CAP in children.
For children 2 months or older with moderate-severity CAP who cannot tolerate oral therapy, use:
benzylpenicillin 50 mg/kg intravenously, 6-hourly; see Patient review, intravenous to oral

If intravenous access cannot be established, consider using intramuscular procaine benzylpenicillin (see dosage
below).
management program is sometimes preferred. Use:
procaine benzylpenicillin 50 mg/kg up to 1.5 g intramuscularly, daily; see Patient review,

intravenous to oral switch and duration of therapy.
use:
1 cefotaxime 50 mg/kg up to 1 g intravenously, 8-hourly; see Patient review, intravenous to

oral switch and duration of therapy
OR
1 ceftriaxone 50 mg/kg up to 1 g intravenously, daily; see Patient review, intravenous to

oral switch and duration of therapy.
azithromycin 10 mg/kg up to 500 mg intravenously, daily; see Patient review, intravenous

reasonable to add therapy for atypical bacteria to the penicillin or cephalosporin regimens if:
B. pertussis is suspected (eg children who have been in contact with a pertussis case, children with
M. pneumoniae is suspected (eg school-aged children with rash, children with a household contact who has
M. pneumoniae infection).
If therapy for atypical bacteria is indicated, add to the penicillin or cephalosporin regimens above:

therapy for pneumonia). If B. pertussis infection is confirmed, see Pertussis for management. If infection with M.
pneumoniae or Chlamydia species is confirmed, some clinicians add atypical bacterial therapy to the penicillin or
cephalosporin regimens, rather than changing to directed therapy.
When the child can tolerate oral therapy, switch to an oral therapy regimen.
The duration of therapy for moderate-severity CAP is 5 to 7 days (intravenous + oral), except for azithromycin,
which is only required for 3 to 5 days (intravenous + oral). If the patient has significantly improved after 2 to 3
days of antibiotic therapy, treat for 5 days. If the clinical response is slow, treat for 7 days.
likely diagnosis, reassess disease severity (see Assessing disease severity). Consider adding azithromycin to treat
atypical bacteria if the child is not improving on the penicillin or cephalosporin regimens (see dosage above).
For children in tropical regions of Australia [Note 8] who are not improving, perform culture and serology
testing for B. pseudomallei (see Melioidosis for details).
CAP in children 2 months or older: empirical therapy for high-severity

CAP
Clinical features of high–severity community-acquired pneumonia (CAP) in children include severe increase in
work of breathing, grunting or nasal flaring, marked tachypnoea and tachycardia, oxygen saturation 90% or lower
on room air.
To treat children 2 months or older with high-severity CAP, use empirical intravenous therapy. Some children
require additional therapy for Staphylococcus aureus, atypical bacteria, Pseudomonas aeruginosa, Burkholderia
pseudomallei, influenza and, if aspiration pneumonia is suspected, anaerobes.
For children with sepsis or septic shock, see also Empirical regimens for community-acquired sepsis or septic
shock in children 2 months or older, source not apparent.
If the child is at high risk of colonisation with multidrug-resistant Gram-negative bacteria (see Box 2.30), seek
expert advice from an infectious diseases physician or clinical microbiologist.
For immunocompromised patients, consider investigations for unusual pathogens (see Approach to pneumonia in
immunocompromised patients), and seek expert advice on whether to adjust empirical antibiotic therapy while
awaiting the results.
For children with high-severity CAP in tropical regions of Australia [Note 9], perform culture and serology
testing for B. pseudomallei, ideally before starting antibiotic therapy (see Melioidosis for test details). Empirical
therapy for B. pseudomallei is only needed for children with high-severity CAP requiring intensive care support in
the wet season (see Burkholderia pseudomallei).
Empirical therapy
For children 2 months or older with high-severity CAP, use:
1 cefotaxime 50 mg/kg up to 2 g intravenously, 8-hourly; for children requiring intensive

care support, use cefotaxime 50 mg/kg up to 2 g intravenously, 6-hourly. See Patient
review, intravenous to oral switch and duration of therapy
OR
1 ceftriaxone 50 mg/kg up to 2 g intravenously, daily; for children requiring intensive care

support, use ceftriaxone 50 mg/kg up to 1 g intravenously, 12-hourly. See Patient review,
Some children require additional therapy for S. aureus, atypical bacteria, P. aeruginosa, B. pseudomallei, influenza
and, if aspiration pneumonia is suspected, anaerobes.
use ceftriaxone or cefotaxime as above.
1 ciprofloxacin 10 mg/kg up to 400 mg intravenously, 12-hourly; for children requiring

intensive care support, use ciprofloxacin 10 mg/kg up to 400 mg intravenously, 8-hourly.
See Patient review, intravenous to oral switch and duration of therapy [Note 10]
PLUS
use; see Patient review, intravenous to oral switch and duration of therapy
OR as a single drug
1 moxifloxacin 10 mg/kg up to 400 mg intravenously, daily; see Patient review, intravenous

to oral switch and duration of therapy [Note 11].
Some children require additional therapy for S. aureus, atypical bacteria, P. aeruginosa, B. pseudomallei, influenza
and, if aspiration pneumonia is suspected, anaerobes.
Additional therapy for high-severity CAP
S. aureus is an important cause of high-severity CAP in children.
If the clinical presentation is suggestive of staphylococcal pneumonia (eg cavitary or necrotising pneumonia,
pneumatoceles on chest X-ray, postinfluenza pneumonia), start therapy for methicillin-resistant S. aureus (MRSA),
because of increased prevalence of community-associated MRSA. Add to the empirical regimen:
OR
use.
to the empirical therapy regimen.
Review therapy with clindamycin, lincomycin or vancomycin at 24 to 48 hours. If staphylococcal pneumonia is

confirmed by investigations, see Staphylococcal pneumonia.
Assess the child for complications of staphylococcal pneumonia, such as lung abscess, empyema or a large
parapneumonic effusion. For management of these complications, see Lung abscess or Parapneumonic effusion
and empyema.
Atypical bacteria
reasonable to add therapy for atypical bacteria to the empirical regimen if:
Bordetella pertussis is suspected (eg children who have been in contact with a pertussis case, children with
Mycoplasma pneumoniae is suspected (eg school-aged children with rash, children with a household contact
who has M. pneumoniae infection)
the child is not improving on empirical therapy.
If therapy for atypical bacteria is indicated, add to the empirical therapy regimen:

If B. pertussis infection is confirmed, see Pertussis for management.
If infection with M. pneumoniae or Chlamydia species is confirmed, some clinicians add azithromycin to the
empirical regimen, rather than changing to directed therapy.
Pseudomonas aeruginosa
For management of children with cystic fibrosis, see Cystic fibrosis.
P. aeruginosa is a rare cause of CAP. Consider empirical antipseudomonal therapy in children with known
colonisation of sputum with P. aeruginosa (eg children with bronchiectasis) and one of the following:
Gram-negative bacilli predominant on Gram stain or identified by culture of sputum [Note 12] or blood
life-threatening pneumonia.
Do not use previous susceptibility results to guide current antipseudomonal therapy unless the sample was taken
recently (eg in the last month).
If empirical antipseudomonal therapy is indicated, replace the empirical therapy regimen with:
1 cefepime 50 mg/kg up to 2 g intravenously, 8-hourly; see Patient review, intravenous to

OR
1 piperacillin+tazobactam 100+12.5 mg/kg up to 4+0.5 g intravenously, 6-hourly; see

PLUS with either of the above regimens for patients with life-threatening pneumonia

child 2 months to younger than 10 years: 7.5 mg/kg up to 320 mg, for the first dose. See
Principles of aminoglycoside use for subsequent dosing [Note 14] [Note 15]
child 10 years or older requiring intensive care support: 7 mg/kg, for the first dose. See
Principles of aminoglycoside use for subsequent dosing [Note 15]
child 10 years or older not requiring intensive care support: 6 mg/kg up to 560 mg, for the
first dose. See Principles of aminoglycoside use for subsequent dosing [Note 15].
replace the empirical therapy regimen with the cefepime-based regimen above.
For children 2 months or older with immediate severe or delayed severe hypersensitivity to penicillins, replace
the empirical therapy regimen with:
meropenem 20 mg/kg up to 1 g intravenously, 8-hourly; see Patient review, intravenous to

oral switch and duration of therapy [Note 16] [Note 17]
PLUS for patients with life-threatening pneumonia

child 10 years or older requiring intensive care support: 7 mg/kg, for the first dose. See
Principles of aminoglycoside use for subsequent dosing [Note 15]
child 10 years or older not requiring intensive care support: 6 mg/kg up to 560 mg, for the
first dose. See Principles of aminoglycoside use for subsequent dosing [Note 15].
If P. aeruginosa is confirmed, modify therapy based on the results of culture and susceptibility testing if possible
(see Pseudomonas aeruginosa pneumonia). If P. aeruginosa is not identified, switch to an appropriate narrower-
spectrum empirical regimen (see Empirical therapy).
antibiotics, is used for adjusting therapy.
Note 14: The dose cap does not apply to children requiring intensive care support.
treatment options.
Note 17: Some centres use a meropenem dosage of 40 mg/kg up to 2 g intravenously, 8-hourly for children who
are very unwell; however, no data are available to support the use of this dosage for children who do not have
central nervous system infection.
The following advice applies to children in tropical regions of Australia [Note 18].
B. pseudomallei, which causes melioidosis, is a rare but important cause of CAP in children in tropical regions of
Australia (cases are also occasionally seen further south). Risk factors include diabetes, cystic fibrosis and
congenital or rheumatic heart disease; however, B. pseudomallei pneumonia can develop in children without these
risk factors. Melioidosis is more common in the wet season—around October to April.
For children with high-severity CAP in tropical regions of Australia, perform culture and serology testing for B.
pseudomallei, ideally before starting antibiotic therapy.
In the wet season, give children who require intensive care support empirical antibiotic therapy active against B. pseudomallei.
A change to the empirical therapy regimen for children with high-severity CAP is only needed in the wet season
[Note 19] for children who require intensive care support. Replace the empirical regimen with:

oral switch and duration of therapy [Note 20].
Meropenem may be suitable for children with immediate severe or delayed severe hypersensitivity to penicillins,
but seek expert advice [Note 21].
If B. pseudomallei pneumonia is confirmed, see Melioidosis for management. If B. pseudomallei is excluded,

switch to an appropriate narrower-spectrum empirical regimen (see Empirical therapy), or modify therapy based
on the results of culture and susceptibility testing (see Directed therapy for pneumonia).
treatment options.
Anaerobes
Antibiotic regimens for CAP in these guidelines can be used for initial treatment of aspiration pneumonia because
these regimens treat most pathogens aspirated from the oropharynx, including oral anaerobes (see Approach to
managing aspiration pneumonia). In rare cases, pneumonia following aspiration may be due to specific anaerobes,
such as Bacteroides or Prevotella species, that are not adequately treated with some of the empirical regimens for
high-severity CAP. Pneumonia involving anaerobic pathogens can be necrotising or cavitary, and the infection may
progress to lung abscess.
If the child has had an aspiration event, try to exclude aspiration pneumonitis (see Table 2.57) before starting
aspiration), consider adding metronidazole to the empirical regimen. Metronidazole is not necessary for suspected
aspiration pneumonia if the patient is receiving an empirical regimen containing clindamycin, lincomycin,
meropenem, moxifloxacin or piperacillin+tazobactam because these drugs treat a broader range of oral anaerobes,
including Bacteroides and Prevotella species.
If aspiration pneumonia is suspected, consider adding to the cefotaxime, ceftriaxone or ciprofloxacin plus
vancomycin empirical regimen:
metronidazole 12.5 mg/kg up to 500 mg intravenously, 12-hourly; see Patient review,

Review the patient within 24 to 48 hours. Consider stopping antibiotic therapy if the patient has significantly
improved and aspiration pneumonitis is a more likely diagnosis.
Influenza and other viral respiratory pathogens
If influenza is suspected (eg based on the season), consider adding empirical antiviral therapy while awaiting the
results of NAAT (eg PCR). For antiviral regimens, see Antiviral therapy for influenza.
Patient review
therapy for pneumonia). If infection with M. pneumoniae or Chlamydia species is confirmed, some clinicians add
azithromycin to the empirical regimen, rather than changing to directed therapy (see Atypical bacteria for dosage).
If the response to initial empirical therapy is inadequate at 48 hours, reassess the diagnosis. Consider infective and
noninfective diagnoses—see Approach to managing patients with pneumonia who are not improving. Consider if
additional therapy for high-severity CAP is needed for S. aureus, atypical bacteria, P. aeruginosa, B. pseudomallei,
anaerobes and influenza.
Once the patient is clinically stable and able to tolerate and absorb oral medication, switch to oral therapy (see Box
2.35 for guidance on when to switch to oral therapy). If a pathogen is not identified, use:
amoxicillin 25 mg/kg up to 1 g orally, 8-hourly; see Duration of therapy.
use:
cefuroxime (child 3 months or older) 15 mg/kg up to 500 mg orally, 12-hourly; see

Duration of therapy [Note 22].
If additional therapy for atypical bacteria was prescribed, unless the patient has had at least 3 days of
azithromycin, add to amoxicillin or cefuroxime:
1 azithromycin 10 mg/kg up to 500 mg orally, daily; see Duration of therapy
OR
1 clarithromycin 7.5 mg/kg up to 500 mg orally, 12-hourly; see Duration of therapy
1 doxycycline orally, 12-hourly; see Duration of therapy [Note 23]

For children 2 months or older with immediate severe or delayed severe hypersensitivity to penicillins, choosing
a safe and effective oral regimen is complex. Options may include ciprofloxacin, moxifloxacin or azithromycin—
seek expert advice.
If the child was prescribed additional therapy for anaerobes and aspiration pneumonia remains the likely
diagnosis, consider continuing metronidazole orally. Add to amoxicillin or cefuroxime:
metronidazole 10 mg/kg up to 400 mg orally, 12-hourly; see Duration of therapy.
Duration of therapy
If a pathogen is not identified, a total treatment duration of 7 days (intravenous + oral) is usually sufficient, except
for azithromycin, which is only required for 3 to 5 days. If the patient has had at least 3 days of azithromycin,
ongoing oral therapy with azithromycin, clarithromycin or doxycycline (to treat atypical bacteria) is not required.
If a pathogen is identified, see Directed therapy for pneumonia for duration of therapy.
Key references
CAP in neonates and children younger than 2 months
American Academy of Pediatrics. Committee on Infectious Diseases. Red Book (2018): Report of the Committee on
Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018.
ANMF Consensus Group. Benzylpenicillin (Penicillin G). v2.0 [neonatal drug information sheet]. Sydney: NSW
NeoMed Formulary; 2018. https://www.seslhd.health.nsw.gov.au/royal-hospital-for-women/neomed-formularies
Dis 2016;16(8):e139–52.
Nascimento-Carvalho CM, Andrade DC, Vilas-Boas AL. An update on antimicrobial options for childhood community-
acquired pneumonia: a critical appraisal of available evidence. Expert Opin Pharmacother 2016;17(1):53–78.
NeoMed Consensus Group. Ampicillin. v1.1 [neonatal drug information sheet]. Sydney: NSW NeoMed Formulary;
2017. https://www.seslhd.health.nsw.gov.au/royal-hospital-for-women/neomed-formularies.
Neonatal Medicines Formulary Consensus Group. Amoxycillin. v1.1 [neonatal drug information sheet]. Sydney: NSW
NeoMed Formulary; 2017. https://www.seslhd.health.nsw.gov.au/royal-hospital-for-women/neomed-formularies.
CAP in children 2 months or older: aetiology and management approach

Benet T, Sanchez Picot V, Messaoudi M, Chou M, Eap T, Wang J, et al. Microorganisms associated with pneumonia in
children <5 years of age in developing and emerging countries: The GABRIEL pneumonia multicenter, prospective,
case-control study. Clin Infect Dis 2017;65(4):604–12.
CAP in children 2 months or older: empirical therapy for low-severity CAP
Biondi E, McCulloh R, Alverson B, Klein A, Dixon A, Ralston S. Treatment of mycoplasma pneumonia: a systematic
review. Pediatrics 2014;133(6):1081–90.
Gardiner SJ, Gavranich JB, Chang AB. Antibiotics for community-acquired lower respiratory tract infections secondary
to Mycoplasma pneumoniae in children. Cochrane Database Syst Rev 2015;(1):CD004875.
Harris M, Clark J, Coote N, Fletcher P, Harnden A, McKean M, et al. British Thoracic Society guidelines for the
management of community acquired pneumonia in children: update 2011. Thorax 2011;66 Suppl 2:ii1–23.
Dis 2016;16(8):e139–52.
Williams DJ, Hall M, Shah SS, Parikh K, Tyler A, Neuman MI, et al. Narrow vs broad-spectrum antimicrobial therapy
for children hospitalized with pneumonia. Pediatrics 2013;132(5):e1141–8.
CAP in children 2 months or older: empirical therapy for moderate-severity CAP
Addo-Yobo E, Chisaka N, Hassan M, Hibberd P, Lozano JM, Jeena P, et al. Oral amoxicillin versus injectable penicillin
for severe pneumonia in children aged 3 to 59 months: a randomised multicentre equivalency study. Lancet
2004;364(9440):1141–8.
Atkinson M, Lakhanpaul M, Smyth A, Vyas H, Weston V, Sithole J, et al. Comparison of oral amoxicillin and
intravenous benzyl penicillin for community acquired pneumonia in children (PIVOT trial): a multicentre pragmatic
randomised controlled equivalence trial. Thorax 2007;62(12):1102–6.
Benet T, Sanchez Picot V, Messaoudi M, Chou M, Eap T, Wang J, et al. Microorganisms associated with pneumonia in
children <5 years of age in developing and emerging countries: The GABRIEL pneumonia multicenter, prospective,
case-control study. Clin Infect Dis 2017;65(4):604–12.
Hazir T, Fox LM, Nisar YB, Fox MP, Ashraf YP, MacLeod WB, et al. Ambulatory short-course high-dose oral amoxicillin
for treatment of severe pneumonia in children: a randomised equivalency trial. Lancet 2008;371(9606):49–56.
Dis 2016;16(8):e139–52.
CAP in children 2 months or older: empirical therapy for high-severity CAP
Harris M, Clark J, Coote N, Fletcher P, Harnden A, McKean M, et al. British Thoracic Society guidelines for the
management of community acquired pneumonia in children: update 2011. Thorax 2011;66 Suppl 2:ii1–23.
McLeod C, Morris PS, Bauert PA, Kilburn CJ, Ward LM, Baird RW, et al. Clinical presentation and medical
management of melioidosis in children: a 24-year prospective study in the Northern Territory of Australia and review of
the literature. Clin Infect Dis 2015;60(1):21–6.
Dis 2016;16(8):e139–52.
Community-acquired pneumonia in aged-care
facilities
Choosing the right empirical regimen for CAP in aged-care facility
residents
This topic covers management of community-acquired pneumonia (CAP) in aged-care facility residents who are
being treated in the aged-care facility. For aged-care facility residents with CAP who are managed in hospital, see
Community-acquired pneumonia in adults. The approach to choosing the right empirical regimen is outlined in
Figure 2.8.
Choosing the right empirical regimen for residents of aged-care facilities with community-
acquired pneumonia (Figure 2.8)
NB1: In this topic, CAP includes suspected aspiration pneumonia in residents of aged-care facilities.
Aetiology of CAP in residents of aged-care facilities

Community-acquired pneumonia (CAP) mortality is higher in aged-care facility residents than in the general
community. This is largely due to comorbidities and advanced age rather than infection with resistant pathogens.
The spectrum of pathogens in aged-care facility residents with pneumonia is similar to the general community, but atypical
bacterial pathogens are less common.
The spectrum of pathogens identified in aged-care facility residents with pneumonia does not vary greatly from the
general community. Streptococcus pneumoniae is the most common pathogen.
Atypical bacterial pathogens such as Mycoplasma pneumoniae and Chlamydophila (Chlamydia) pneumoniae are
uncommon. Therefore, empirical antibiotics for atypical pathogens are not routinely required, but may be
considered if atypical bacterial pathogens (especially Legionella species) are suspected on clinical history or risk
exposures (see CAP in adults: aetiology).
Although residents of aged-care facilities are at higher risk of being colonised with multidrug-resistant Gram-
negative bacteria such as extended-spectrum beta-lactamase (ESBL)-producing bacteria, these organisms rarely
cause CAP; for risk factors, see Box 2.30. If sputum samples are taken for Gram stain and culture, interpret with
care [Note 1]. The identification of enteric Gram-negative bacilli (eg Klebsiella pneumoniae) in sputum usually
reflects colonisation or prior antibiotic use, especially in patients with low- to moderate-severity CAP. For further
advice on interpreting sputum sample results, see Sputum Gram stain and culture.
Empirical treatment of CAP in residents of aged-care facilities is therefore largely the same as for treatment of
CAP in the general community.
culture.
Approach to managing CAP in residents of aged-care facilities

The management of community-acquired pneumonia (CAP) in residents of aged-care facilities can be challenging.
These patients can be difficult to assess, due to cognitive impairment or acute-onset confusion. In addition, patients
often present without fever or acute respiratory symptoms. Diagnosis may need to be based on clinical features
rather than investigations (because chest X-rays, for example, are not easy to obtain).
Assessing pneumonia severity and determining the site of care needs special consideration in residents of aged-
care facilities. Establish whether an advance care plan is in place, and if antibiotic therapy is appropriate for the
patient. Antibiotic therapy may be consistent with a declared palliative treatment plan. For information on advance
care plans, see Advance care planning.
Box 2.18 summarises the approach to managing CAP in residents of aged-care facilities.
Approach to managing community-acquired pneumonia in residents of aged-care facilities
(Box 2.18)
Printable box
Establish whether an advance care plan is in place and whether antibiotic therapy is appropriate for the
patient. Antibiotic therapy may be consistent with a declared palliative treatment plan.
Assess aspiration risk. If the patient has had an aspiration event, try to exclude aspiration pneumonitis
(see Table 2.57) before starting antibiotic therapy for pneumonia. If aspiration pneumonia is suspected (eg
pneumonia in a patient with recurrent aspiration), start empirical therapy for CAP.
Consider whether a viral respiratory infection, such as influenza, could be the cause of the patient’s
symptoms. Viral respiratory infections are common in aged-care facility residents and difficult to
differentiate from CAP. Do not rule out influenza in a vaccinated patient because circulating strains may
differ from the vaccine, and vaccine response can be suboptimal in elderly patients.
If a viral respiratory infection is suspected, consider performing nucleic acid amplification testing
(NAAT) (eg polymerase chain reaction [PCR]) to establish the diagnosis, guide appropriate
treatment and direct infection control measures (eg facility outbreak control and influenza
prophylaxis for other residents; see Influenza and local infection control guidelines)
If antibiotic therapy was started, review the results of investigations (eg NAAT [eg PCR], full blood
count, C-reactive protein) within 24 to 48 hours. If a respiratory viral infection is likely, consider
stopping antibiotic therapy.
Sputum samples can be difficult to obtain in residents of aged-care facilities. If sputum samples are taken
for Gram stain and culture, interpret with care [NB1].
Check that the patient is immunised against Streptococcus pneumoniae and influenza. For immunisation
and other strategies to prevent pneumonia, see Pneumonia prevention.
If antibiotic treatment is indicated and consistent with the patient’s goals of care, determine the appropriate
site of care by assessing:
severity of pneumonia (see CAP in adults: assessment of pneumonia severity) [NB2]
physiological status (eg hypoxaemia requiring supportive oxygen therapy)
comorbidities (particularly cardiac, respiratory and cognitive comorbidities)
functional status
ability to tolerate and absorb oral therapy (see Special considerations for antibiotic therapy in
residents of aged-care facilities).
Consider management in the aged-care facility with oral therapy if the patient can eat and drink, and the
following clinical parameters are met:
heart rate less than 100 beats/minute
systolic blood pressure higher than 90 mmHg
respiratory rate less than 25 breaths/minute
oxygen saturation higher than 92%
no evidence of acute-onset confusion.
If transfer to hospital is indicated (eg patients who do not meet the above criteria or who require
supportive oxygen therapy for hypoxaemia):
if transfer to hospital is consistent with the patient’s goals of care, transfer the patient and treat as for
CAP in adults (see Community-acquired pneumonia in adults).
if transfer to hospital is not consistent with the patient’s goals of care, consider parenteral therapy in
the aged-care facility (eg through an organised Residential In-Reach Program, community-based
parenteral antimicrobial therapy or similar).
Review the patient’s response to therapy within 24 to 48 hours and reassess the diagnosis if the patient is
not improving or an alternative diagnosis (eg aspiration pneumonitis, a respiratory virus) is more likely.
NB1: Gram stain of poor quality sputum samples can give misleading results. Ensure a good quality sample (presence of polymorphs, but few or no
squamous epithelial cells on microscopy), collected before starting antibiotics, is used for adjusting therapy.
NB2: Pneumonia severity scoring tools can overestimate disease severity in residents of aged-care facilities, leading to inappropriate broad-
spectrum therapy. These tools should be used as a guide, and are not a substitute for clinical judgment.
Special considerations for antibiotic therapy in residents of aged-care

facilities
Special considerations for antibiotic therapy in residents of aged-care facilities include:
reduced clearance of drugs (eg amoxicillin+clavulanate, cefuroxime) due to kidney impairment—check

kidney function and reduce dosage if necessary
increased vulnerability to adverse effects, particularly:
cardiac adverse effects including QT-interval prolongation, which can occur with macrolides (eg
azithromycin, clarithromycin) and quinolones (eg ciprofloxacin, moxifloxacin)
increased confusion (particularly with quinolones)
gastrointestinal adverse effects (eg nausea and diarrhoea with amoxicillin+clavulanate, oesophagitis
with doxycycline)
potential for drug interactions
altered pharmacokinetics (eg variable absorption from intramuscular injections due to low body mass index,
reduced drug clearance independent of kidney function)
impaired swallowing, especially following stroke, and in patients with neuromuscular disorders or impaired
consciousness.
Ability to tolerate oral medications
Check the patient’s ability to swallow. Even if the patient does not have impaired swallowing, some antibiotics are
difficult to administer (eg some regimens have a high pill burden; amoxicillin+clavulanate tablets are large and
difficult to swallow; the patient must remain upright after a dose of doxycycline). Ask whether alternative dose
forms or methods of administration are preferred by the patient or carer.
If the patient cannot swallow, consider enteral administration if the patient already has a percutaneous endoscopic
gastrostomy (PEG) tube in situ.
For information on modifying oral dose forms for patients with difficulty swallowing or enteral feeding tubes,
consult:
the Australian Don’t Rush to Crush Handbook (see The Society of Hospital Pharmacists of Australia
website)
the product information or a drug formulary
a pharmacist or medicines information service.
If oral or enteral therapy is not suitable, parenteral antibiotic therapy is indicated.
Oral therapy for CAP in residents of aged-care facilities

See Box 2.18 for the approach to managing community-acquired pneumonia (CAP) in residents of aged-care
facilities.
The antibiotic regimens below are for management of residents of aged-care facilities who are treated in the aged-
care facility. If the patient is managed in hospital, see Community-acquired pneumonia in adults.
Oral therapy for CAP in residents of aged-care facilities is suitable when the following clinical parameters are met:
heart rate less than 100 beats/minute

systolic blood pressure higher than 90 mmHg
respiratory rate less than 25 breaths/minute
oxygen saturation higher than 92%
no evidence of acute-onset confusion.
For patients who do not meet the above criteria or who require supportive oxygen therapy, consider transfer to
hospital. Functional status and goals of care should be reviewed when making decisions about site of care.
aspiration), start empirical therapy for CAP.
Residents of aged-care facilities with comorbid lung disease (eg chronic obstructive pulmonary disease [COPD])
usually do not require adjustment to empirical therapy for CAP. For further information, see Approach to
pneumonia in patients with COPD and bronchiectasis.
Empirical therapy
For empirical treatment of CAP in residents of an aged-care facility who are treated in the facility, use:
amoxicillin 1 g orally or enterally, 8-hourly; see Patient review and duration of therapy
[Note 2] .
doxycycline 100 mg orally or enterally, 12-hourly; see Patient review and duration of
therapy [Note 3] [Note 2].
If doxycycline is contraindicated or not tolerated (eg in bed-bound patients) and the patient has immediate
nonsevere or delayed nonsevere hypersensitivity to penicillins, use:
cefuroxime 500 mg orally or enterally, 12-hourly; see Patient review and duration of
If there is clinical suspicion of atypical bacterial pathogens (eg in patients with risk factors for Legionella
species; see CAP in adults: aetiology), add doxycycline to the amoxicillin or cefuroxime regimen while awaiting
results of microbiological tests.
If Legionella pneumonia is confirmed, see Legionella pneumonia in adults for management.
Note 2: For further information on antibiotic administration in patients with difficulty swallowing or who are
unable to tolerate oral therapy, see Special considerations for antibiotic therapy in residents of aged-care
facilities.
Note 3: Doxycycline can cause oesophagitis, which is more likely in bed-bound patients. Ensure doxycycline is
taken with food and a full glass of water, and that the patient remains upright after the dose.

Review the patient within 24 to 48 hours. Modify treatment based on the results of investigations, including
susceptibility testing, if possible (see Directed therapy for pneumonia). Consider stopping antibiotic therapy if
aspiration pneumonitis or a respiratory virus is a more likely diagnosis based on the results of investigations or the
speed of recovery.
Patients with pneumonia may improve slowly despite antibiotic therapy (see Expected clinical course of
pneumonia).
If the patient has significantly improved after 2 to 3 days of antibiotic therapy, treat for 5 days. If the clinical
response is slow, treat for 7 days.
If the patient is not improving after 48 hours of antibiotic therapy, reassess the diagnosis. Consider infective and
noninfective diagnoses such as heart failure—see Approach to managing patients with pneumonia who are not
improving. Ensure airway clearance strategies (eg chest physiotherapy) are optimised, particularly in patients with
comorbid lung disease. Reassess the patient’s need for hospital admission or parenteral antibiotic therapy (see Box
2.18). If pneumonia remains the likely diagnosis but the patient’s goals of care are not consistent with hospital
admission or parenteral antibiotic therapy in the aged-care facility, use of an alternative oral antibiotic is
reasonable.
Patients initially treated with amoxicillin who are not improving after 48 hours may have infection caused by a
beta-lactamase–producing strain of Haemophilus influenzae or Moraxella catarrhalis. These pathogens are more
likely in patients with comorbid lung disease. Adding clavulanate provides increased activity against these
pathogens. Use:
amoxicillin+clavulanate 875+125 mg orally, 12-hourly; see above for duration of therapy
amoxicillin+clavulanate 400+57 mg/5 mL oral liquid 11 mL orally or enterally, 12-hourly;

see above for duration of therapy.
For strategies to prevent further episodes of pneumonia, see Pneumonia prevention.
Parenteral therapy for CAP in residents of aged-care facilities

See Box 2.18 for the approach to managing community-acquired pneumonia (CAP) in residents of aged-care
facilities.
aspiration), start empirical therapy for CAP.
The antibiotic regimens below are for management of residents of aged-care facilities who are treated in the aged-
care facility. If the patient is managed in hospital, see Community-acquired pneumonia in adults.
If treatment with oral or enteral antibiotics is indicated but not possible, parenteral antibiotic therapy in the aged-
care facility can be used to avoid hospitalisation. Antibiotic choices include intravenous or intramuscular
ceftriaxone or, for short-term use in selected patients, intramuscular procaine benzylpenicillin. Intravenous therapy
(eg through an organised Residential In-Reach Program, community-based parenteral antimicrobial
therapy program or similar) is preferred to intramuscular injection to avoid painful administration and variable
absorption in frail patients. Although ceftriaxone is a practical choice due to its once-daily administration, it can
cause bacterial resistance; such broad-spectrum antibiotic therapy should only be used in this setting if there is no
alternative.
Ceftriaxone and procaine benzylpenicillin do not treat atypical bacterial pathogens (eg Legionella species). If the
patient cannot tolerate oral therapy and there is clinical suspicion of these pathogens (eg in patients with risk
factors for Legionella pneumonia; see CAP in adults: aetiology), seek expert advice.
Empirical therapy
If oral or enteral antibiotic therapy is not possible in an aged-care facility resident, use:
1 ceftriaxone 1 g intravenously, daily; see Patient review, switching to oral therapy and
duration of therapy
OR (if intravenous administration not possible)
2 ceftriaxone 1 g intramuscularly, daily; see Patient review, switching to oral therapy and
duration of therapy [Note 5].
Alternatively, procaine benzylpenicillin can be considered in patients able to tolerate intramuscular injections,
especially if it is expected that oral antibiotics can be resumed after two to three doses. Close clinical review is
necessary. Use:
procaine benzylpenicillin 1.5 g intramuscularly, daily; see Patient review, switching to oral
therapy and duration of therapy.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use ceftriaxone (see
dosage above).
Patient review, switching to oral therapy and duration of therapy

Review the patient within 24 to 48 hours and reassess the diagnosis. Modify treatment based on the results of
investigations, including susceptibility testing, if possible (see Directed therapy for pneumonia). If an alternative
diagnosis (eg heart failure, aspiration pneumonitis—see Table 2.57) is more likely based on the results of
investigations or the speed of recovery, consider stopping antibiotic therapy.
If the patient is not improving after 48 hours of antibiotic therapy, reassess the need for hospital admission, and
consider infective and noninfective diagnoses such as heart failure—see Approach to managing patients with
pneumonia who are not improving.
If the patient has improved with parenteral therapy, switch to oral or enteral therapy (see Box 2.35 for guidance on
when to switch to oral therapy). For oral or enteral regimens, see here.
If the patient has significantly improved after 2 to 3 days of antibiotic therapy, treat for 5 days (parenteral + oral).
If the clinical response is slow, treat for 7 days (parenteral + oral).
Key references
Aetiology of CAP in residents of aged-care facilities
Ayaz SI, Haque N, Pearson C, Medado P, Robinson D, Wahl R, et al. Nursing home-acquired pneumonia: course and
management in the emergency department. Int J Emerg Med 2014;7:19.
Faverio P, Aliberti S, Bellelli G, Suigo G, Lonni S, Pesci A, et al. The management of community-acquired pneumonia
in the elderly. Eur J Intern Med 2014;25(4):312–9.
Fukuyama H, Yamashiro S, Tamaki H, Kishaba T. A prospective comparison of nursing- and healthcare-associated

pneumonia (NHCAP) with community-acquired pneumonia (CAP). J Infect Chemother 2013.
Kang YS, Ryoo SR, Byun SJ, Jeong YJ, Oh JY, Yoon YS. Antimicrobial resistance and clinical outcomes in nursing
home-acquired pneumonia, compared to community-acquired pneumonia. Yonsei Med J 2017;58(1):180–6.
Liapikou A, Polverino E, Cilloniz C, Peyrani P, Ramirez J, Menendez R, et al. A worldwide perspective of nursing
home-acquired pneumonia compared with community-acquired pneumonia. Respir Care 2014;59(7):1078–85.
Ma HM, Ip M, Hui E, Chan PK, Hui DS, Woo J. Role of atypical pathogens in nursing home-acquired pneumonia. J Am
Med Dir Assoc 2013;14(2):109–13.
Marrie TJ, File TM, Jr. Bacterial Pneumonia in Older Adults. Clin Geriatr Med 2016;32(3):459–77.
Teramoto S, Yoshida K, Hizawa N. Update on the pathogenesis and management of pneumonia in the elderly-roles of
aspiration pneumonia. Respir Investig 2015;53(5):178–84.
Approach to managing CAP in residents of aged-care facilities
Carusone SC, Loeb M, Lohfeld L. A clinical pathway for treating pneumonia in the nursing home: part I: the nursing
perspective. J Am Med Dir Assoc 2006;7(5):271–8.
Dhawan N, Pandya N, Khalili M, Bautista M, Duggal A, Bahl J, et al. Predictors of mortality for nursing home-acquired
pneumonia: a systematic review. Biomed Res Int 2015;2015:285983.
Ewig S, Bauer T, Richter K, Szenscenyi J, Heller G, Strauss R, et al. Prediction of in-hospital death from community-
acquired pneumonia by varying CRB-age groups. Eur Respir J 2013;41(4):917–22.
Loeb M, Carusone SC, Goeree R, Walter SD, Brazil K, Krueger P, et al. Effect of a clinical pathway to reduce
hospitalizations in nursing home residents with pneumonia: a randomized controlled trial. JAMA 2006;295(21):2503–
10.
Ma HM, Ip M, Woo J. Effect of age and residential status on the predictive performance of CURB-65 score. Intern Med
J 2015;45(3):300–4.
Montalto M, Chu MY, Ratnam I, Spelman T, Thursky K. The treatment of nursing home-acquired pneumonia using a
medically intensive Hospital in the Home service. Med J Aust 2015;203(11):441–2.
Ugajin M, Yamaki K, Hirasawa N, Kobayashi T, Yagi T. Prognostic value of severity indicators of nursing-home-
acquired pneumonia versus community-acquired pneumonia in elderly patients. Clin Interv Aging 2014;9:267–74.
Oral therapy for CAP in residents of aged-care facilities
2008;46(10):1513–21.
2018;31(2):170–6.

Intern Med 2014;174(12):1894–901.
10.
Med Dir Assoc 2013;14(2):109–13.
J 2015;45(3):300–4.
(Larchmt) 2014;15(3):283–9.
2017;206(7):316–9.

2015;51(12):613–4.
Parenteral therapy for CAP in residents of aged-care facilities
2008;46(10):1513–21.
2018;31(2):170–6.

Intern Med 2014;174(12):1894–901.
10.
Med Dir Assoc 2013;14(2):109–13.
J 2015;45(3):300–4.
(Larchmt) 2014;15(3):283–9.
2017;206(7):316–9.

2015;51(12):613–4.
Pneumonia severity scoring tools for community-
acquired pneumonia in adults
This topic describes pneumonia severity scoring tools for community-acquired pneumonia (CAP) in adults
that can be used to:
decide whether to admit the patient to hospital (CRB-65, CURB-65, and Pneumonia Severity Index
[PSI])
identify patients at higher risk of death or requiring intensive care support (SMART-COP, CORB).
Tools for scoring pneumonia severity should not be used in isolation to decide management; but they are
useful as an aid to clinical judgment.
For the use of red flags in the assessment of pneumonia severity, see CAP in adults: assessment of pneumonia
severity.
Severity scoring tools for admission to hospital

Overview
Pneumonia severity scoring tools for community-acquired pneumonia (CAP) in adults that have been
evaluated to decide whether to admit the patient to hospital include CRB-65, CURB-65 and Pneumonia
Severity Index (PSI).
CRB-65 and CURB-65 identify low-risk patients who can usually be safely managed in the community and higher-risk
patients requiring admission to hospital.
For ease of use, the preferred tools for deciding whether to admit the patient to hospital are CRB-65 and
CURB-65. These tools identify low-risk patients who can usually be safely managed in the community and
higher-risk patients requiring admission to hospital. The CRB-65 tool does not require collection of blood
samples and can be used for patient assessment in primary care settings. The CURB-65 tool is recommended
for patient assessment in the emergency department. These tools are not designed to suggest likely pathogens.
Of note, CURB-65 and CRB-65 do not account for comorbidities and hypoxaemia. In younger patients (eg
under the age of 50 years) with hypoxaemia, pneumonia severity can be underestimated.
PSI [Note 1] has been used historically to determine the site of care and provide information about the
patient’s risk of mortality. It is more complex than the other pneumonia severity scoring tools and is not
routinely used in practice.
Note 1: Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify low-risk patients with
community-acquired pneumonia. N Engl J Med 1997;336(4):243-50. [URL]
CRB-65
The CRB-65 tool (see Figure 2.9) does not require collection of blood samples and can be used for patient
assessment in primary care settings. It is recommended by the British Thoracic Society, in conjunction with
clinical judgment, to decide whether to admit the patient to hospital.
CRB-65 tool for assessing severity of community-acquired pneumonia in adults (Figure 2.9)
NB1: When deciding if inpatient management is appropriate, consider the patient’s social circumstances (in particular the availability of home
support), age, comorbidities, ability to tolerate and absorb oral therapy, need for supportive oxygen therapy, functional status and goals of care.
Adapted from the following with permission from BMJ Publishing Group Ltd:
Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, et al. Defining community acquired pneumonia severity on
presentation to hospital: an international derivation and validation study. Thorax 2003;58(5):377-82. [URL]
Lim WS, Baudouin SV, George RC, Hill AT, Jamieson C, Le Jeune I, et al. BTS guidelines for the management of community acquired
pneumonia in adults: update 2009. Thorax 2009;64 Suppl 3:iii1-55. [URL]
CURB-65
The CURB-65 tool (see Figure 2.10) can be used for patient assessment in the emergency department. It is
recommended by the British Thoracic Society, in conjunction with clinical judgment, to decide whether to
admit the patient to hospital.
CURB-65 tool for assessing severity of community-acquired pneumonia in adults (Figure

2.10)
NB1: When deciding if inpatient management is appropriate, consider the patient’s social circumstances (in particular the availability of home
support), age, comorbidities, ability to tolerate and absorb oral therapy, need for supportive oxygen therapy, functional status and goals of care.
Adapted from the following with permission from BMJ Publishing Group Ltd:
Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, et al. Defining community acquired pneumonia severity on
presentation to hospital: an international derivation and validation study. Thorax 2003;58(5):377-82. [URL]
Lim WS, Baudouin SV, George RC, Hill AT, Jamieson C, Le Jeune I, et al. BTS guidelines for the management of community acquired
pneumonia in adults: update 2009. Thorax 2009;64 Suppl 3:iii1-55. [URL]
Severity scoring tools for risk of death and the need for intensive
care support
Overview
Pneumonia severity scoring tools for community-acquired pneumonia (CAP) in adults that have been
evaluated to identify patients at higher risk of death or requiring intensive care support are SMART-COP and
CORB.
SMART-COP and CORB identify patients that need assessment for intensive care support.
SMART-COP and CORB use clinical features that predict deterioration. SMART-COP uses more variables,
which generally increase sensitivity. CORB is a simple alternative to SMART-COP and can be used without
the collection of blood samples.
All severity scoring tools aid clinical judgment, rather than replace it. Always consider the patient’s goals of
care when deciding if intensive care support is appropriate. The use of these severity scores in isolation may
overestimate disease severity in the elderly, leading to inappropriate use of broad-spectrum treatment. These
scoring systems are not designed to suggest likely pathogens.
SMART-COP
The SMART-COP tool (see Figure 2.11) helps to assess the likelihood that a patient with CAP will require
intensive respiratory or vasopressor support (IRVS) (usually in an intensive care unit) and provides
information about the patient’s risk of mortality. SMART-COP can be modified for use by primary care
physicians, and is appropriate for pneumonia risk stratification in tropical Australia.
To calculate a SMART-COP score, use findings from the initial clinical assessment.
SMART-COP tool for assessing severity of community-acquired pneumonia in adults (Figure

2.11)
FiO2 = fraction of oxygen in inspired air; PaO2 = arterial partial pressure of oxygen; IRVS = intensive respiratory or vasopressor support
NB1: Peripheral venous blood gas measurements of pH are considered equivalent to arterial blood gas pH measurements.
NB2: In the Australian Community-Acquired Pneumonia Study (ACAPS) cohort, the accuracy for predicting patients who required IRVS (a
SMART-COP score of 3 or more points) was a sensitivity of 92%, specificity of 62%, positive predictive value of 22%, negative predictive value
of 99% and an area under the receiver operating characteristic curve = 0.87.
Adapted from Charles PG, Wolfe R, Whitby M, Fine MJ, Fuller AJ, Stirling R, et al. SMART-COP: a tool for predicting the need for intensive
respiratory or vasopressor support in community-acquired pneumonia. Clin Infect Dis 2008;47(3):375-84 [URL], by permission of Oxford
University Press.
CORB
The CORB tool (see Figure 2.12) helps to assess the likelihood that a patient with CAP will require intensive
respiratory or vasopressor support (IRVS) (usually in an intensive care unit) and provides information about
the patient’s risk of mortality. It is a simple tool that does not require invasive testing.
To calculate a CORB score, review findings from clinical assessments within 24 hours of the patient arriving
in hospital (or presenting to medical care) and use the most abnormal result.
CORB tool for assessing severity of community-acquired pneumonia in adults (Figure 2.12)
IRVS = intensive respiratory or vasopressor support
NB1: In the Australian CAP Study (ACAPS) cohort, the accuracy of CORB for predicting death or the need for IRVS (two or more features of
CORB present) was a sensitivity of 72%, specificity of 70%, positive predictive value of 27%, negative predictive value of 94% and an area
under the receiver operating characteristic curve = 0.72.
Adapted with permission from Buising KL, Thursky KA, Black JF, MacGregor L, Street AC, Kennedy MP, et al. Identifying severe community-
acquired pneumonia in the emergency department: a simple clinical prediction tool. Emerg Med Australas 2007;19(5):418-26. [URL]
Key references
Kolditz M, Braeken D, Ewig S, Rohde G. Severity assessment and the immediate and long-term prognosis in
community-acquired pneumonia. Semin Respir Crit Care Med 2016;37(6):886–96.
Ranzani OT, Taniguchi LU, Torres A. Severity scoring systems for pneumonia: current understanding and next
steps. Curr Opin Pulm Med 2018;24(3):227–36.
Waterer G. Severity scores and community-acquired pneumonia. Time to move forward. Am J Respir Crit Care
Med 2017;196(10):1236–8.
Pneumonia severity scoring tools for admission to hospital
Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify low-risk
patients with community-acquired pneumonia. N Engl J Med 1997;336(4):243–50.
Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, et al. Defining community acquired
pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax
2003;58(5):377–82.
Med 2017;196(10):1236–8.
Pneumonia severity scoring tools for risk of death and the need for intensive care support
Buising KL, Thursky KA, Black JF, MacGregor L, Street AC, Kennedy MP, et al. Identifying severe community-
acquired pneumonia in the emergency department: a simple clinical prediction tool. Emerg Med Australas
2007;19(5):418–26.
Byrne AL, Bennett M, Chatterji R, Symons R, Pace NL, Thomas PS. Peripheral venous and arterial blood gas
analysis in adults: are they comparable? A systematic review and meta-analysis. Respirology 2014;19(2):168–75.
Charles PG, Wolfe R, Whitby M, Fine MJ, Fuller AJ, Stirling R, et al. SMART-COP: a tool for predicting the need
for intensive respiratory or vasopressor support in community-acquired pneumonia. Clin Infect Dis
2008;47(3):375–84.
Robins-Browne KL, Cheng AC, Thomas KA, Palmer DJ, Currie BJ, Davis JS. The SMART-COP score performs
well for pneumonia risk stratification in Australia's Tropical Northern Territory: a prospective cohort study. Trop Med
Int Health 2012;17(7):914–9.
Med 2017;196(10):1236–8.
What is HAP?
Hospital-acquired pneumonia (HAP) is pneumonia that develops in a patient who has been hospitalised in acute
care for longer than 48 hours. Prolonged rest and low inspiratory volume (eg due to pain), which are common in
hospitalised patients, can lead to basal atelectasis, which predisposes the patient to pneumonia.
oropharynx. Prolonged hospitalisation can result in changes to the oropharyngeal flora (eg the oropharynx can
become colonised with Gram-negative bacteria). As patients recover and become ambulant, the oropharyngeal
flora transitions back to that of patients in the community. If an ambulant patient develops pneumonia in a
subacute-care setting (eg rehabilitation), the aetiology is likely to be similar to community-acquired pneumonia
(CAP). However, if a patient who has had prolonged immobility (eg due to long-term spinal injury rehabilitation)
or frequent exposure to antibiotics develops pneumonia, the aetiology is likely to be similar to HAP. If unsure
whether to treat the patient for CAP or HAP, seek expert advice. For management of CAP, see Community-
acquired pneumonia in adults or Community-acquired pneumonia in children.
The empirical antibiotic regimens for HAP in these guidelines can be used for initial treatment of aspiration
pneumonia in hospitalised patients (see Approach to managing aspiration pneumonia). If the patient has had an
aspiration event, try to exclude aspiration pneumonitis (see Table 2.57) before starting antibiotic therapy for
pneumonia. If aspiration pneumonia is suspected (eg pneumonia in a patient with recurrent aspiration), start
empirical therapy for HAP.
Ventilator-associated pneumonia (VAP) is pneumonia that develops in a patient who has been mechanically
ventilated for longer than 48 hours (see Ventilator-associated pneumonia).
Aetiology of HAP
The most common cause of hospital-acquired pneumonia (HAP) is Streptococcus pneumoniae, which is part of the
usual respiratory flora. Although prolonged hospitalisation can result in the oropharynx becoming colonised with
aerobic Gram-negative bacilli, these bacteria are a less common cause of HAP.
Recent broad-spectrum antibiotic therapy is a risk factor for HAP caused by more resistant bacteria (eg methicillin-
resistant Staphylococcus aureus [MRSA], multidrug-resistant [MDR] Gram-negative bacteria such as
Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter species). In many Australian hospitals,
nosocomial MRSA infections are uncommon.
Atypical pathogens (eg Legionella species) are a much less common cause of HAP than community-acquired
pneumonia (CAP). Legionella infection, although rare, can be acquired from a contaminated environmental
reservoir in the hospital. Although influenza and other respiratory viruses are uncommon causes of HAP, they can
be easily acquired from other patients, visitors or staff. Aspergillus and Pneumocystis jirovecii cause HAP rarely,
most often in immunocompromised patients. Although Candida species can colonise the respiratory tract of
patients in hospital, they rarely, if ever, cause HAP.
For aetiology of ventilator-associated pneumonia (VAP), see Ventilator-associated pneumonia.
Diagnosis and investigations for HAP

Diagnosis
There are no universally accepted diagnostic criteria for hospital-acquired pneumonia (HAP). The isolation of
bacteria from culture of sputum or a lower respiratory tract sample often represents colonisation; it is not sufficient
to diagnose HAP.
Isolation of bacteria from a respiratory tract sample is not sufficient to diagnose HAP.
Many postoperative patients with shadowing on chest X-ray do not have pneumonia. Postoperative atelectasis is
common and usually noninfective. Management with chest physiotherapy is recommended.
A diagnosis of HAP is suggested in patients who have a new, progressive, or persistent infiltrate on chest X-ray
(not explained by other causes), plus at least one of the following features:
fever above 38°C

total white cell count above or below the normal range
presence, or increased amount, of purulent sputum or lower respiratory tract secretions
worsening gas exchange (eg desaturation, increased oxygen requirement).
Investigations
The results of investigations can enable directed therapy or de-escalation of antibiotic treatment. Collect blood and,
if available, sputum samples (or for intubated patients, lower respiratory tract samples) for Gram stain and culture,
ideally before starting antibiotic therapy.
At the onset of HAP, many patients do not produce sputum. If a sputum sample can be collected before starting
antibiotic therapy, a good quality sample (presence of polymorphs, but few or no squamous epithelial cells on
microscopy) can assist in detection of the pathogen. Always correlate the results of culture with the Gram stain.
See Sputum Gram stain and culture for further information.
Investigations for Legionella species and respiratory viruses (eg influenza) are not routinely required for patients
with HAP. Consider performing investigations for these pathogens when the response to empirical antibiotic
therapy is inadequate.
For immunocompromised patients with high-severity HAP or those with significant immune compromise (eg
recent solid organ or haematopoietic stem cell transplant), consider performing investigations for unusual
pathogens (see Approach to pneumonia in immunocompromised patients).
Severity assessment of HAP

Empirical therapy for hospital-acquired pneumonia (HAP) is stratified according to disease severity.
The criteria for diagnosing high-severity HAP are not well defined. In these guidelines, high-severity HAP
includes patients with any of the following features:
septic shock (for definitions, see here for adults or here for children)
respiratory failure, particularly if requiring mechanical ventilation
rapid progression of infiltrates on chest X-ray.
For patients with high-severity HAP, empirical antibiotic therapy active against a broad range of pathogens,
including Pseudomonas aeruginosa, is recommended. For regimens, see Empirical therapy: high-severity HAP.
For antibiotic therapy in patients without high-severity HAP, see Empirical therapy: low- to moderate-severity
HAP.
Monitor patients closely for signs of deterioration.
Empirical therapy: low- to moderate-severity HAP

Empirical therapy for hospital-acquired pneumonia (HAP) is stratified according to disease severity. For severity
assessment, see Severity assessment of HAP.
Empirical therapy for low- to moderate-severity hospital-acquired pneumonia (HAP) is directed against
Streptococcus pneumoniae and aerobic Gram-negative bacilli. Treatment for atypical bacterial pathogens (eg
Legionella species) is not routinely required for patients with HAP. The results of investigations can enable
directed therapy or de-escalation of antibiotic treatment (see Investigations).
The parameters listed in Box 2.19 (red flags) are considered by the Antibiotic Expert Groups to indicate adults
with low- to moderate-severity HAP who need close observation, and reassessment by an experienced clinician to
identify deterioration early. If patients deteriorate, consider escalating to broader-spectrum antibiotic therapy (see
Empirical therapy: high-severity HAP for regimens).
Recognition of clinical deterioration in children is difficult. For discussion on early recognition of sepsis in
children, see Early recognition of sepsis or septic shock in neonates, infants and children.
Red flags for deterioration in adults with low- to moderate-severity hospital-acquired
pneumonia (Box 2.19)
Any of the following parameters are red flags for deterioration in patients with low- to moderate-severity
hospital-acquired pneumonia:
tachypnoea (respiratory rate higher than 22 breaths/minute)

heart rate higher than 100 beats/minute
oxygen saturation lower than 92% on room air (or lower than baseline in patients with comorbid lung
disease)
multilobar involvement on chest X-ray
Close observation, and reassessment of these patients by an experienced clinician is essential.
Oral therapy is recommended for patients with low- to moderate-severity HAP, if tolerated. If oral therapy is not
tolerated, consider enteral administration (eg via nasogastric or percutaneous endoscopic gastrostomy [PEG] tube).
If oral or enteral therapy is not possible, use parenteral therapy.
If a patient develops HAP while being treated with antibiotics, consider escalating therapy to broader-spectrum
antibiotic therapy. For example, if the patient is being treated with ceftriaxone, consider treating as for high-
severity HAP (see Empirical therapy: high-severity HAP for regimens).
pneumonia in hospitalised patients (see Approach to managing aspiration pneumonia). If the patient has had an
aspiration event, try to exclude aspiration pneumonitis (see Table 2.57) before starting antibiotic therapy for
pneumonia. If aspiration pneumonia is suspected (eg pneumonia in a patient with recurrent aspiration), start
empirical therapy for low- to moderate-severity HAP.
Oral therapy
For low- to moderate-severity HAP in patients who can tolerate oral or enteral therapy, use:

875+125 mg) orally or enterally, 12-hourly; the usual duration of therapy is 7 days. See
below for patient review [Note 1].
cefuroxime 500 mg (child 3 months or older: 15 mg/kg up to 500 mg) orally or enterally,
12-hourly; the usual duration of therapy is 7 days. See below for patient review [Note 2].
moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally or enterally, daily; the usual
duration of therapy is 7 days. See below for patient review [Note 3] [Note 4].
An alternative regimen for children with immediate severe or delayed severe hypersensitivity to penicillins is:
ciprofloxacin 12.5 mg/kg up to 500 mg orally or enterally, 12-hourly; the usual duration of
therapy is 7 days. See below for patient review [Note 5] [Note 6]
PLUS
clindamycin 10 mg/kg up to 450 mg orally or enterally, 8-hourly; the usual duration of

therapy is 7 days. See below for patient review [Note 7].
Patient review: review the patient within 24 to 48 hours and reassess the diagnosis. If an alternative diagnosis (eg
heart failure, aspiration pneumonitis—see Table 2.57) is more likely based on the results of investigations or the
speed of recovery, consider stopping antibiotic therapy. If the response to initial empirical therapy is inadequate at
48 hours, consider infective and noninfective diagnoses—see Approach to managing patients with pneumonia who
are not improving.
Note 1: Amoxicillin+clavulanate may be suitable for children aged 1 month to younger than 2 months, but a
Parenteral therapy
Oral (or enteral) therapy is recommended for low- to moderate-severity HAP, if tolerated.
For low- to moderate-severity HAP in patients who cannot tolerate oral or enteral therapy, use:

below for patient review and intravenous to oral switch. The usual total duration of
therapy is 7 days (intravenous + oral)
OR
1 cefotaxime 1 g (child: 50 mg/kg up to 1 g) intravenously, 8-hourly; see below for patient

review and intravenous to oral switch. The usual total duration of therapy is 7 days
(intravenous + oral)
OR
2 amoxicillin+clavulanate intravenously; see below for patient review and intravenous to

oral switch. The usual total duration of therapy is 7 days (intravenous + oral)
adult: 1+0.2 g 8-hourly
child 3 months or older: 25+5 mg/kg up to 1+0.2 g 8-hourly [Note 8].
cefotaxime (see dosage above).
moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, daily; see below for
patient review and intravenous to oral switch. The usual total duration of therapy is 7 days
(intravenous + oral) [Note 9].
Alternative regimens for children with immediate severe or delayed severe hypersensitivity to penicillins are:
ciprofloxacin 10 mg/kg up to 400 mg intravenously, 12-hourly; see below for patient

review and intravenous to oral switch. The usual total duration of therapy is 7 days
(intravenous + oral) [Note 10]
PLUS EITHER
1 clindamycin 15 mg/kg up to 600 mg intravenously, 8-hourly; see below for patient review
and intravenous to oral switch. The usual total duration of therapy is 7 days (intravenous
+ oral)
OR
2 lincomycin 15 mg/kg up to 600 mg intravenously, 8-hourly; see below for patient review
and intravenous to oral switch. The usual total duration of therapy is 7 days (intravenous
+ oral).
Patient review: review the patient within 24 to 48 hours and reassess the diagnosis. If an alternative diagnosis (eg
heart failure, aspiration pneumonitis—see Table 2.57) is more likely based on the results of investigations or the
speed of recovery, consider stopping antibiotic therapy. If the response to initial empirical therapy is inadequate at
48 hours, consider infective and noninfective diagnoses—see Approach to managing patients with pneumonia who
are not improving.
Intravenous to oral switch: once the patient has improved and is clinically stable, switch to oral antibiotic
therapy (see Box 2.35 for guidance on when to switch to oral therapy). For regimens, see Oral therapy.
Note 8: Intravenous amoxicillin+clavulanate may be suitable for children aged 1 month to younger than 3
months but a different dosage is required.
Empirical therapy: high-severity HAP

Empirical therapy for hospital-acquired pneumonia (HAP) is stratified according to disease severity. For severity
assessment, see Severity assessment of HAP.
For patients with high-severity HAP, identify the pathogen if possible. Collect blood and, if available, sputum
samples (or for intubated patients, lower respiratory tract samples) for Gram stain and culture, ideally before
starting antibiotic therapy [Note 11]. Other investigations may also be required—see Investigations. For
immunocompromised patients, consider investigations for unusual pathogens (see Approach to pneumonia in
immunocompromised patients), and seek expert advice on whether to adjust empirical antibiotic therapy while
awaiting the results.
For patients with sepsis or septic shock (for definitions, see here for adults and here for children), start antibiotic
therapy for high-severity HAP within 1 hour of development of sepsis or septic shock immediately after
appropriate samples are taken for culture. For nonantibiotic management of patients with sepsis or septic shock,
see Early intervention for sepsis or septic shock.
The empirical therapy regimens for high-severity HAP are active against a broad range of pathogens, including
Pseudomonas aeruginosa. Consider the need for additional therapy in patients with septic shock, suspected
staphylococcal pneumonia, suspected Gram-negative pneumonia or suspected aspiration pneumonia. Initial
therapy for atypical bacterial pathogens (eg Legionella) is not routinely required for patients with HAP.
If a patient develops high-severity HAP while being treated with broad-spectrum antibiotics (eg
piperacillin+tazobactam), seek expert advice.
Note 11: At the onset of HAP, many patients do not produce sputum. If a sputum sample can be collected before
cells on microscopy) can assist in detection of the pathogen. See Sputum Gram stain and cultures.
Empirical therapy
For high-severity HAP, use:

hourly; see Patient review, intravenous to oral switch and duration of therapy.
When prescribing empirical therapy, consider the need for additional therapy for patients with:
septic shock
suspected staphylococcal pneumonia
suspected Gram-negative pneumonia
suspected aspiration pneumonia.
cefepime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly; see Patient review,

1 ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 8-hourly; see Patient
review, intravenous to oral switch and duration of therapy [Note 12]
PLUS
requiring intensive care support. See Patient review, intravenous to oral switch and
duration of therapy
1 meropenem 1 g (child: 20 mg/kg up to 1 g) intravenously, 8-hourly; see Patient review,

intravenous to oral switch and duration of therapy [Note 13] [Note 14].
Also consider the need for additional therapy for high-severity HAP when prescribing the above regimens.
treatment options.
Additional therapy for high-severity HAP
Septic shock
For patients with septic shock, consider adding vancomycin for methicillin-resistant Staphylococcus aureus
(MRSA) and an aminoglycoside for multidrug-resistant (MDR) Gram-negative bacteria.
Consider adding both vancomycin and gentamicin to the empirical therapy regimen:

PLUS

The antibiotic susceptibility of multidrug-resistant Gram-negative bacteria varies—use local epidemiology to

guide the choice of aminoglycoside (eg gentamicin, amikacin, tobramycin). For amikacin or tobramycin dosing,
see here.
Review therapy with gentamicin and vancomycin at 24 to 48 hours and consider stopping therapy based on the
results of investigations—see Patient review, intravenous to oral switch and duration of therapy.
calculate the dose.
function.
Suspected staphylococcal pneumonia
For patients who have microbiological evidence suggestive of staphylococcal pneumonia (eg profuse Gram-
positive cocci resembling staphylococci identified on Gram stain of a respiratory tract sample [Note 19]), consider
adding vancomycin.
Consider adding to the empirical therapy regimen:
Review therapy with vancomycin at 24 to 48 hours and consider stopping therapy based on the results of
investigations—see Patient review, intravenous to oral switch and duration of therapy.
Suspected Gram-negative pneumonia

For patients with suspected Gram-negative pneumonia, consider adding an aminoglycoside. Gram-negative
pneumonia may be suspected:
if Gram-negative bacilli are identified on blood culture or culture of lower respiratory tract samples obtained
by more invasive methods (eg bronchoalveolar lavage [BAL] or mini-BAL)
in patients who have chronic suppurative lung disease (eg bronchiectasis) and known respiratory
colonisation with Gram-negative pathogens, such as Pseudomonas aeruginosa.
Consider adding to the empirical therapy regimen:


see here.
Review therapy with gentamicin at 24 to 48 hours and consider stopping therapy based on the results of
investigations—see Patient review, intravenous to oral switch and duration of therapy.
calculate the dose.
function.
Suspected aspiration pneumonia
pneumonia in hospitalised patients because these regimens treat most pathogens aspirated from the oropharynx,
including oral anaerobes (see Approach to managing aspiration pneumonia). In rare cases, pneumonia following
aspiration may be due to specific anaerobes, such as Bacteroides or Prevotella species, that are not adequately
treated with some of the empirical regimens for high-severity HAP. These pathogens are more likely in a patient
who has severe periodontal disease or putrid sputum.
aspiration), start empirical therapy for high-severity HAP. If the patient has severe periodontal disease or putrid
sputum and is being treated with either cefepime, or ciprofloxacin plus vancomycin, for high-severity HAP,
consider adding metronidazole to the empirical regimen. Metronidazole is not necessary for suspected aspiration
pneumonia if the patient is receiving an empirical regimen containing meropenem or piperacillin+tazobactam
because these drugs treat a broader range of oral anaerobes, including Bacteroides and Prevotella species.
For patients with suspected aspiration pneumonia who have severe periodontal disease or putrid sputum,
consider adding to the cefepime, or ciprofloxacin plus vancomycin empirical regimens:
Patient review, intravenous to oral switch and duration of therapy.
Pneumonia involving anaerobic pathogens can be necrotising or cavitary, and the infection may progress to lung
abscess or parapneumonic effusion and empyema—assess the patient for these complications.
Patient review
Review the patient within 24 to 48 hours and reassess the diagnosis. If an alternative diagnosis (eg heart failure,
aspiration pneumonitis—see Table 2.57) is more likely based on the results of investigations or the speed of
recovery, consider stopping antibiotic therapy.
therapy for pneumonia). Await the results of culture before narrowing therapy to treat staphylococcal or Gram-
negative pneumonia.
Review ongoing therapy with gentamicin and vancomycin at 24 to 48 hours.
If gentamicin and vancomycin were added to the empirical therapy regimen, review the need for ongoing therapy
at 24 to 48 hours. If microbiological investigations exclude methicillin-resistant Staphylococcus aureus (MRSA),
multidrug-resistant Gram-negative bacteria and Pseudomonas aeruginosa and the patient is improving, stop
gentamicin and vancomycin.
If the response to initial empirical therapy is inadequate at 48 hours, reassess the diagnosis and seek expert advice.
improving.
De-escalation of therapy and intravenous to oral switch
Once the patient has improved and is clinically stable, de-escalate therapy to narrower-spectrum antibiotics, even if
a pathogen is not identified. Many patients can switch to oral (or enteral) therapy as for low- to moderate-severity
HAP—see Box 2.35 for guidance on when to switch to oral therapy. If parenteral therapy is still necessary (eg due
to impaired gastrointestinal function), switch to narrower-spectrum parenteral therapy as for low- to moderate-
severity HAP.
For patients with suspected aspiration pneumonia, the oral therapy regimens for low- to moderate-severity HAP
can be used; however, for patients with immediate nonsevere or delayed nonsevere hypersensitivity to
penicillins, consider adding clindamycin or metronidazole to cefuroxime.
Duration of therapy
The usual total duration of therapy is 7 days (intravenous plus oral). Patients with lung abscess, empyema or large
empyema. Patients with necrotising or cavitary pneumonia usually need a longer duration of therapy—seek expert
advice.
Prevention of HAP
For general measures to prevent pneumonia, see Pneumonia prevention.
There are no specific recommendations to prevent hospital-acquired pneumonia (HAP) in nonventilated patients.
However, good oral hygiene and early mobilisation during the hospital stay is associated with a reduced risk of
HAP. It is also important to identify patients with dysphagia so management strategies to minimise the risk of
aspiration can be implemented (see Management of recurrent aspiration).
For prevention of pneumonia in ventilated patients, see Prevention of ventilator-associated pneumonia (VAP).
Key references
What is HAP?
Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. Management of adults with hospital-
acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of
America and the American Thoracic Society. Clin Infect Dis 2016;63(5):e61–e111.
Torres A, Niederman MS, Chastre J, Ewig S, Fernandez-Vandellos P, Hanberger H, et al. International

ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated
pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia
(VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European
Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociacion Latinoamericana del Torax (ALAT).
Eur Respir J 2017;50(3).
Aetiology of HAP
Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial
pneumonia. Clin Infect Dis 2010;51 Suppl 1:S81–7.
Sievert DM, Ricks P, Edwards JR, Schneider A, Patel J, Srinivasan A, et al. Antimicrobial-resistant pathogens
associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network
at the Centers for Disease Control and Prevention, 2009-2010. Infect Control Hosp Epidemiol 2013;34(1):1–14.

Diagnosis and investigations for HAP
American Thoracic Society (ATS), Infectious Diseases Society of America (IDSA). Guidelines for the management of
adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med
2005;171(4):388–416.

Weiss E, Essaied W, Adrie C, Zahar JR, Timsit JF. Treatment of severe hospital-acquired and ventilator-associated
pneumonia: a systematic review of inclusion and judgment criteria used in randomized controlled trials. Crit Care
2017;21(1):162.
Severity assessment of HAP

2017;21(1):162.
Empirical therapy: low- to moderate-severity HAP
Pugh R, Grant C, Cooke RP, Dempsey G. Short-course versus prolonged-course antibiotic therapy for hospital-
acquired pneumonia in critically ill adults. Cochrane Database Syst Rev 2015;(8):CD007577.

Empirical therapy: high-severity HAP
O'Horo JC, Thompson D, Safdar N. Is the gram stain useful in the microbiologic diagnosis of VAP? A meta-analysis.
Clin Infect Dis 2012;55(4):551–61.

Prevention of HAP
Passaro L, Harbarth S, Landelle C. Prevention of hospital-acquired pneumonia in non-ventilated adult patients: a

narrative review. Antimicrob Resist Infect Control 2016;5:43.
What is VAP?
Ventilator-associated pneumonia (VAP) is pneumonia that develops in a patient who has been mechanically
ventilated for longer than 48 hours. Intubation significantly increases the risk of pneumonia because it interferes
with physiological mechanisms that limit bacterial contamination of the airways.
If a patient with community-acquired pneumonia (CAP) requires intubation and mechanical ventilation, continue
to manage the patient as CAP not VAP (see Community-acquired pneumonia in adults and Community-acquired
pneumonia in children).
Aetiology of VAP
In Australia, ventilator-associated pneumonia (VAP) is caused by similar pathogens to those implicated in hospital-
acquired pneumonia (HAP) (eg Streptococcus pneumoniae and Gram-negative pathogens; see Aetiology of HAP).
However, the aetiology of VAP can vary with location, so awareness of local epidemiology is useful. Some centres
have a higher prevalence of Pseudomonas aeruginosa and Staphylococcus aureus. In many Australian hospitals,
nosocomial methicillin-resistant S. aureus (MRSA) infections are uncommon.
Although Candida species can colonise the respiratory tract of hospitalised patients, they rarely, if ever, cause
VAP.
Diagnosis and investigations for VAP

Diagnosis of VAP
Bacteria often colonise the airways of patients who are intubated. Therefore, the presence of bacteria in tracheal
aspirates is not sufficient for diagnosis of ventilator-associated pneumonia (VAP). Furthermore, most intubated
patients with shadowing on chest X-ray do not have pneumonia—atelectasis is common and usually noninfective.
Management with physiotherapy is recommended.
Isolation of bacteria from a respiratory tract sample is not sufficient to diagnose VAP.
A diagnosis of VAP is suggested in patients who have a new, progressive, or persistent infiltrate on chest X-ray
(not explained by other causes), plus two or more of the following features:
fever above 38°C

total white cell count above or below the normal range
presence, or increased amount, of purulent sputum or lower respiratory tract secretions
worsening gas exchange (eg desaturation, increased oxygen requirement, increased ventilator demand).
Investigations for VAP

The results of investigations can enable directed therapy or de-escalation of antibiotic treatment. Collect blood and,
if possible, lower respiratory tract samples for Gram stain and culture, ideally before starting antibiotic therapy.
Interpret Gram-stain results of respiratory tract samples with care [Note 1].
Investigations for Legionella species and respiratory viruses (eg influenza) are not routinely required for patients
with VAP. Consider performing investigations for these pathogens if the response to empirical antibiotic therapy is
inadequate.
For immunocompromised patients with VAP, consider performing investigations for unusual pathogens (see
Approach to pneumonia in immunocompromised patients).
In patients who are severely unwell or not improving, there may be an advantage in obtaining samples for culture
with more invasive methods (eg bronchoalveolar lavage [BAL] or mini-BAL).
Note 1: Gram stain of poor quality respiratory tract samples can give misleading results. Ensure a good quality
sample (presence of polymorphs, but few or no squamous epithelial cells on microscopy), collected before
starting antibiotics, is used for adjusting therapy. The pathogen should be predominant in the Gram stain as well
as the culture.
Approach to managing VAP

To identify the pathogen, collect blood and, if possible, lower respiratory tract samples for Gram stain and culture,
ideally before starting antibiotic therapy. Other investigations may also be required—see Investigations for VAP.
For immunocompromised patients, consider performing investigations for unusual pathogens (see Approach to
pneumonia in immunocompromised patients), and seek expert advice on whether to adjust empirical antibiotic
therapy while awaiting the results.
For patients with sepsis or septic shock (for definitions, see here for adults or here for children), start antibiotic
therapy for VAP within 1 hour of development of sepsis or septic shock, immediately after appropriate samples
are taken for culture. For nonantibiotic management of sepsis or septic shock, see Early intervention for sepsis or
septic shock.
The empirical therapy regimens for ventilator-associated pneumonia (VAP) are active against a broad range of
pathogens, including Pseudomonas aeruginosa. Consider the need for additional therapy in patients with septic
shock, suspected staphylococcal pneumonia or suspected Gram-negative pneumonia.
If a patient develops VAP while being treated with broad-spectrum antibiotics (eg piperacillin+tazobactam), seek
expert advice.
Empirical therapy for VAP

For empirical therapy for ventilator-associated pneumonia (VAP), use:

hourly; see Patient review, intravenous to oral switch and duration of therapy for VAP.
When prescribing empirical therapy, consider the need for additional therapy for patients with:
septic shock
suspected staphylococcal pneumonia
suspected Gram-negative pneumonia.
cefepime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly; see Patient review,

intravenous to oral switch and duration of therapy for VAP.
1 ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 8-hourly; see Patient
review, intravenous to oral switch and duration of therapy for VAP [Note 2]
PLUS
use. Consider a 25 to 30 mg/kg loading dose for adults and children. See Patient review,
intravenous to oral switch and duration of therapy for VAP
1 meropenem 1 g (child: 20 mg/kg up to 1 g) intravenously, 8-hourly; see Patient review,

intravenous to oral switch and duration of therapy for VAP [Note 3] [Note 4].
Also consider the need for additional therapy for VAP when prescribing the above regimens.
treatment options.
Additional therapy for VAP

Septic shock
For patients with ventilator-associated pneumonia (VAP) who have septic shock, consider adding vancomycin for
methicillin-resistant Staphylococcus aureus (MRSA) and an aminoglycoside for multidrug-resistant (MDR) Gram-
negative bacteria.
Consider adding both vancomycin and gentamicin to the VAP empirical therapy regimen:

dose. See Principles of aminoglycoside use for subsequent dosing [Note 6] [Note 7]]
PLUS

Principles of vancomycin use for further dosage and principles of use.

see here.
Review therapy with gentamicin and vancomycin at 24 to 48 hours and consider stopping therapy based on the
results of investigations—see Patient review, intravenous to oral switch and duration of therapy for VAP.
calculate the dose.
function
Suspected staphylococcal pneumonia
For patients with VAP who have microbiological evidence suggestive of staphylococcal pneumonia (eg profuse
Gram-positive cocci resembling staphylococci identified on Gram stain of a lower respiratory tract sample [Note
9]), consider adding vancomycin.
Consider adding to the VAP empirical therapy regimen:
use. Consider a 25 to 30 mg/kg loading dose for adults and children.
Review therapy with vancomycin at 24 to 48 hours and consider stopping therapy based on the results of
investigations—see Patient review, intravenous to oral switch and duration of therapy for VAP.
Note 9: Gram stain of poor quality respiratory tract samples can give misleading results. Ensure a good quality
sample (presence of polymorphs, but few or no squamous epithelial cells on microscopy), collected before
starting antibiotics, is used for adjusting therapy.
Suspected Gram-negative pneumonia

For patients with VAP who have suspected Gram-negative pneumonia, consider adding an aminoglycoside. Gram-
negative pneumonia may be suspected:
if Gram-negative bacilli are identified on blood culture or culture of lower respiratory tract samples obtained
by more invasive methods (eg bronchoalveolar lavage [BAL] or mini-BAL)
in patients who have chronic suppurative lung disease (eg bronchiectasis) and known respiratory
colonisation with Gram-negative pathogens, such as Pseudomonas aeruginosa.
Consider adding to the VAP empirical therapy regimen:

for subsequent dosing [Note 13].

see here.
Review therapy with gentamicin at 24 to 48 hours and consider stopping therapy based on the results of
investigations—see Patient review, intravenous to oral switch and duration of therapy for VAP.
calculate the dose.
function.
Patient review, intravenous to oral switch and duration of therapy for

VAP
Patient review
Review patients with ventilator-associated pneumonia (VAP) within 24 to 48 hours and reassess the diagnosis. If
an alternative diagnosis (eg heart failure) is more likely based on the results of investigations, consider stopping
antibiotic therapy.
therapy for pneumonia). Await the results of culture before narrowing therapy to treat staphylococcal or Gram-
negative pneumonia. See also De-escalation of therapy and intravenous to oral switch.
Review ongoing therapy with gentamicin and vancomycin at 24 to 48 hours.
If gentamicin and vancomycin were added to the empirical therapy regimen, review the need for ongoing therapy
at 24 to 48 hours. If microbiological investigations exclude methicillin-resistant Staphylococcus aureus (MRSA),
multidrug-resistant Gram-negative bacteria and Pseudomonas aeruginosa and the patient is improving, stop
gentamicin and vancomycin.
If the response to initial empirical therapy is inadequate at 48 hours, reassess the diagnosis and seek expert advice.
improving.
De-escalation of therapy and intravenous to oral switch
Once the patient has improved and is clinically stable, de-escalate therapy to narrower-spectrum antibiotics, even if
a pathogen is not identified. Many patients can switch to oral (or enteral) therapy (see Box 2.35 for guidance on
when to switch to oral therapy). If parenteral therapy is still necessary (eg due to impaired gastrointestinal
function), switch to narrower-spectrum parenteral therapy.
The choice of oral therapy (or if needed, narrower-spectrum parenteral therapy) for VAP depends on the results of
microbiological investigations. If the pathogen is known, see Directed therapy for pneumonia.
If a pathogen is not identified, for oral or enteral therapy, use:

875+125 mg) orally or enterally, 12-hourly; see Duration of therapy [Note 14].
12-hourly; see Duration of therapy [Note 15].
moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally or enterally, daily; see
Duration of therapy [Note 16] [Note 17].
An alternative regimen for children with immediate severe or delayed severe hypersensitivity to penicillins is:
ciprofloxacin 12.5 mg/kg up to 500 mg orally or enterally, 12-hourly; see Duration of

PLUS
clindamycin 10 mg/kg up to 450 mg orally or enterally, 8-hourly; see Duration of therapy

[Note 20].
If a pathogen is not identified and parenteral therapy is still necessary, use:

patients still requiring intensive care support, consider using ceftriaxone 1 g (child 1
month or older: 50 mg/kg up to 1 g) intravenously 12-hourly. See Duration of therapy
OR
1 cefotaxime 1 g (child: 50 mg/kg up to 1 g) intravenously, 8-hourly; for patients still

requiring intensive care support, consider using cefotaxime 2 g (child: 50 mg/kg up to 2
g) intravenously, 8-hourly. See Duration of therapy
OR
2 amoxicillin+clavulanate intravenously; see Duration of therapy
adult: 1+0.2 g 8-hourly; for patients still requiring intensive care support, consider using
amoxicillin+clavulanate 1+0.2 g 6-hourly [Note 21]
child 3 months or older: 25+5 mg/kg up to 1+0.2 g 8-hourly; for children still requiring
intensive care support, consider using amoxicillin+clavulanate 25+5 mg/kg up to 1+0.2 g
6-hourly [Note 22] [Note 23].
cefotaxime (see dosage above).
moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, daily; see Duration of
therapy [Note 16].
Alternative regimens for children with immediate severe or delayed severe hypersensitivity to penicillins are:
ciprofloxacin 10 mg/kg up to 400 mg intravenously, 12-hourly; see Duration of therapy

[Note 18]
PLUS EITHER
1 clindamycin 15 mg/kg up to 600 mg intravenously, 8-hourly; see Duration of therapy
OR
2 lincomycin 15 mg/kg up to 600 mg intravenously, 8-hourly; see Duration of therapy.
Note 21: At the time of writing, there is limited clinical evidence to determine the optimal dosage regimen of
intravenous amoxicillin+clavulanate. For adults still requiring intensive care support, a reasonable alternative
regimen is 2+0.2 g intravenously, 8-hourly.
intravenous amoxicillin+clavulanate. For children still requiring intensive care support who weigh 40 kg or
more, a reasonable alternative regimen is 2+0.2 g intravenously, 8-hourly.
Duration of therapy
The usual total duration of therapy for VAP is 7 days (intravenous + oral). If the patient has rapidly improved and
is clinically stable by day 3, consider shortening the duration of therapy to 5 days (intravenous + oral).
Patients with lung abscess, empyema or large parapneumonic effusion require a longer duration of therapy—see
Lung abscess or Parapneumonic effusion and empyema. Patients with necrotising or cavitary pneumonia usually
need a longer duration of therapy—seek expert advice.
Role of biomarkers for management of VAP

Procalcitonin is a biomarker for acute inflammation and is elevated during bacterial infection. However, other
factors can also cause an elevation in procalcitonin concentration (eg trauma, burns, surgery, pancreatitis,
gastrointestinal tract ischaemia), so procalcitonin has poor utility as a diagnostic tool for ventilator-associated
pneumonia (VAP). Do not use procalcitonin to decide whether to start antibiotics in a patient with suspected VAP.
Procalcitonin monitoring can be used as an aid to clinical judgment when deciding whether to de-escalate or stop
antibiotic therapy in a patient with VAP. A number of randomised controlled trials for VAP demonstrated that
procalcitonin concentration can be used to reduce the duration of antibiotic therapy, and reduce overall antibiotic
exposure, without adversely affecting clinical outcomes. Studies used various procalcitonin algorithms to guide de-
escalating or stopping antibiotics; the algorithms presented in the ProVAP study [Note 24] or PRORATA study
[Note 25] may be useful. In general, procalcitonin concentration is measured when starting treatment, after 72
hours, and then 24-hourly thereafter. The algorithms compare the initial and subsequent procalcitonin results to
guide decisions about de-escalating or stopping antibiotics.
Note 24: Stolz D, Smyrnios N, Eggimann P, Pargger H, Thakkar N, Siegemund M, et al. Procalcitonin for
reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study. Eur Respir J
2009;34(6):1364-75. [URL]
Note 25: Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, et al. Use of procalcitonin to
reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised
controlled trial. Lancet 2010;375(9713):463-74. [URL]
Prevention of VAP
Intubation significantly increases the risk of pneumonia because it interferes with normal physiological
mechanisms that limit bacterial contamination of the airways. Intensive care units often implement ‘bundles’ of
interventions aimed at preventing ventilator-associated pneumonia (VAP). These include spontaneous awakening
trials, spontaneous breathing trials and head-of-bed elevation.
Antibiotic therapy for prevention of VAP (eg selective digestive and oral decontamination) is not currently
recommended in Australia outside of research settings.
Key references
What is VAP?

Aetiology of VAP?

Diagnosis and investigations for VAP
American Thoracic Society (ATS), Infectious Diseases Society of America (IDSA). Guidelines for the management of
adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med
2005;171(4):388–416.

2017;21(1):162.
Empirical therapy for VAP
Arthur LE, Kizor RS, Selim AG, van Driel ML, Seoane L. Antibiotics for ventilator-associated pneumonia. Cochrane
Klompas M, Li L, Menchaca JT, Gruber S, Centers for Disease Control Prevention Epicenters Program. Ultra-short-
course antibiotics for patients with suspected ventilator-associated pneumonia but minimal and stable ventilator
settings. Clin Infect Dis 2017;64(7):870–6.

Additional therapy for VAP

Patient review, intravenous to oral switch and duration of therapy for VAP

Role of biomarkers for management of VAP
Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, et al. Use of procalcitonin to reduce patients'
exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet
2010;375(9713):463–74.
Salluh JIF, Souza-Dantas VC, Povoa P. The current status of biomarkers for the diagnosis of nosocomial pneumonias.
Curr Opin Crit Care 2017;23(5):391–7.
Stolz D, Smyrnios N, Eggimann P, Pargger H, Thakkar N, Siegemund M, et al. Procalcitonin for reduced antibiotic
exposure in ventilator-associated pneumonia: a randomised study. Eur Respir J 2009;34(6):1364–75.

Prevention of VAP
Hellyer TP, Ewan V, Wilson P, Simpson AJ. The Intensive Care Society recommended bundle of interventions for the
prevention of ventilator-associated pneumonia. J Intensive Care Soc 2016;17(3):238–43.
Klompas M. What is new in the prevention of nosocomial pneumonia in the ICU? Curr Opin Crit Care 2017;23(5):378–
84.
Klompas M, Branson R, Eichenwald EC, Greene LR, Howell MD, Lee G, et al. Strategies to prevent ventilator-
associated pneumonia in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014;35(8):915–36.
What is aspiration pneumonia?
It is important to distinguish aspiration pneumonia from aspiration events and aspiration pneumonitis because
antibiotic therapy is only needed for aspiration pneumonia. Table 2.57 defines aspiration-related terms and
explains the role of antibiotic therapy.
Definitions of aspiration-related terms and the role of antibiotic therapy (Table 2.57)
Printable table
Term Definition Is antibiotic therapy required?

The inhalation of foreign material (eg food,
vomit, blood, saliva) into the lungs. Impaired No.
consciousness (eg due to trauma, stroke,
general anaesthetic, alcohol or drug Monitor the patient for signs of aspiration
aspiration intoxication) increases the risk of aspiration pneumonitis and aspiration pneumonia.
by compromising the swallowing reflex.
For advice on preventing recurrent
Recurrent aspiration can occur in patients aspiration, see Management of recurrent
with impaired swallowing or neurological aspiration.
disorders.
No.
A clear or witnessed episode of aspiration
aspiration event
(eg aspiration of vomit during a seizure). Monitor the patient for signs of aspiration
pneumonitis and aspiration pneumonia.
Acute chemical injury to the lung
parenchyma after aspiration of acidic
stomach contents.
No. Closely monitor the patient for
Also known as chemical pneumonitis or
deterioration.
Mendelson syndrome.
If unable to differentiate between aspiration
Symptom onset is rapid (usually within
pneumonitis and aspiration pneumonia, start
hours of aspiration). This is the key
antibiotic therapy and review within 24 to 48
difference between aspiration pneumonitis
hours (see Initial management of aspiration
aspiration and aspiration pneumonia. pneumonia). Consider stopping antibiotic
pneumonitis therapy if the patient has significantly
Clinical features can be difficult to
distinguish from aspiration pneumonia and improved and aspiration pneumonitis is a
more likely diagnosis.
the chest X-ray can appear similar to
pneumonia. For information on aspiration pneumonitis in
Severity ranges from mild symptoms such as cases of poisoning (overdose), see
cough or wheeze to severe acute respiratory Aspiration pneumonitis in cases of
poisoning.
distress syndrome (ARDS).
In most patients, symptoms improve quickly

(usually within 24 to 48 hours).
A bacterial infection caused by aspiration of
organisms from the oropharynx.
It can also follow aspiration pneumonitis,

particularly in patients taking gastric acid
suppression therapy or with bowel
obstruction.
Yes.
aspiration Symptom onset is delayed; this
pneumonia differentiates aspiration pneumonia from See Initial management of aspiration
aspiration pneumonitis. pneumonia.
Clinical features suggestive of pneumonia
include tachypnoea at rest, tachycardia,
persistent fever, rigors, hypoxaemia or
crepitations (crackles) on auscultation that
do not clear with coughing. For further
information, see Pneumonia diagnosis.
Approach to managing aspiration pneumonia

Initial management of aspiration pneumonia
oropharynx. Empirical therapy in these guidelines for community-acquired pneumonia (CAP) and hospital-
acquired pneumonia (HAP) treats most pathogens aspirated from the oropharynx, including oral anaerobes.
Therefore, initial management of suspected aspiration pneumonia should follow empirical therapy for CAP and
HAP. The need to treat more anaerobic organisms in patients with suspected aspiration pneumonia has been
overestimated; broader anaerobic therapy is not required unless the patient has high-severity or life-threatening
pneumonia.
Manage aspiration pneumonia as community- or hospital-acquired pneumonia initially.
antibiotic therapy for pneumonia.
For initial management of aspiration pneumonia in a patient from the community, or a patient who has been in
hospital for less than 48 hours, see:

Community-acquired pneumonia in children.
For initial management of aspiration pneumonia in a patient who has been in hospital for more than 48 hours, see
Hospital-acquired pneumonia.
Review the patient within 24 to 48 hours of starting antibiotic therapy. Consider stopping antibiotic therapy if
aspiration pneumonitis is a more likely diagnosis based on the results of investigations or the speed of recovery
(symptoms of aspiration pneumonitis usually improve within 24 to 48 hours).
Consider stopping antibiotic therapy if the patient has improved and aspiration pneumonitis is a more likely diagnosis.
If the response to initial empirical therapy is inadequate at 48 hours, see Management of aspiration pneumonia in
patients who are not improving on empirical therapy for CAP or HAP.
Management of aspiration pneumonia in patients who are not improving on empirical

therapy for CAP or HAP
Initial therapy for aspiration pneumonia is the same as empirical therapy for CAP or HAP, which treats most
pathogens aspirated from the oropharynx, including oral anaerobes. If the response to empirical therapy is
inadequate at 48 hours, reassess the diagnosis before adjusting the antibiotic regimen. Consider other infective and
noninfective diagnoses; see Approach to managing patients with pneumonia who are not improving.
For ongoing management of patients with high-severity pneumonia who are not improving, seek expert advice.
In rare cases, pneumonia following aspiration may be due to specific anaerobes such as Bacteroides or Prevotella
species that are not adequately treated with some empirical regimens for CAP or HAP. These pathogens are more
likely in a patient who has severe periodontal disease or putrid sputum. Pneumonia involving anaerobic pathogens
can be necrotising or cavitary, and the infection may progress to lung abscess or parapneumonic effusion and
empyema—assess the patient for these complications.
Anaerobic pathogens are difficult to detect using sputum samples but may be identified by blood culture or culture
of lower respiratory tract samples. If an anaerobic pathogen is identified by culture, the infection is often
polymicrobial. Consider using a regimen that also treats common aerobic respiratory pathogens (eg Streptococcus
pneumoniae), such as amoxicillin plus metronidazole, or clindamycin (rather than metronidazole monotherapy).
Antibiotic regimens for CAP and HAP in these guidelines that include amoxicillin+clavulanate, clindamycin,
lincomycin, meropenem, moxifloxacin or piperacillin+tazobactam are effective against a broader range of oral
anaerobes that cause pneumonia, including Bacteroides or Prevotella species. If the patient is taking one of these
drugs and the response is inadequate after 48 hours, seek expert advice. For patients taking other antibiotics for
pneumonia who have not improved after 48 hours and infection with anaerobes is likely (eg patients with severe
periodontal disease or putrid sputum), change the empirical regimen. If oral or enteral therapy is tolerated, change
to:
amoxicillin 1 g (child: 25 mg/kg up to 1 g) orally or enterally, 8-hourly; see below for

duration of therapy
PLUS
metronidazole 400 mg (child: 10 mg/kg up to 400 mg) orally or enterally, 12-hourly; see
below for duration of therapy.
Alternatively, if a single-drug regimen is preferred (eg to reduce toxicity or improve adherence), use:
1 amoxicillin+clavulanate 875+125 mg (child 2 months or older: 22.5+3.2 mg/kg up to

875+125 mg) orally or enterally, 12-hourly; see below for duration of therapy [Note 1]
OR
1 clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally or enterally, 8-hourly; see
below for duration of therapy [Note 2]
OR
2 moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally or enterally, daily; see below
for duration of therapy [Note 3] [Note 4].
For patients hypersensitive to penicillins, use clindamycin or moxifloxacin (see dosages above).
If the patient cannot tolerate oral (or enteral) therapy, change to:
1 benzylpenicillin 1.2 g (child: 50 mg/kg up to 1.2 g) intravenously, 6-hourly; see below for
PLUS
below for intravenous to oral switch and duration of therapy
OR (as a single preparation)
1 amoxicillin+clavulanate intravenously; see below for intravenous to oral switch and

duration of therapy
child 3 months or older: 25+5 mg/kg up to 1+0.2 g 8-hourly [Note 5].

below for intravenous to oral switch and duration of therapy
OR
1 cefotaxime 1 g (child: 50 mg/kg up to 1 g) intravenously, 8-hourly; see below for

below for intravenous to oral switch and duration of therapy.
for intravenous to oral switch and duration of therapy
OR
OR
2 moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, daily; see below for
intravenous to oral switch and duration of therapy [Note 3].
Intravenous to oral switch: Once the patient improves, switch to oral or enteral therapy as above (see Box
2.35 for guidance on when to switch to oral therapy).
Duration of therapy: The duration of therapy for aspiration pneumonia is guided by the setting (eg hospital- or
community-acquired pneumonia).
For community-acquired aspiration pneumonia, the total duration of therapy is 5 to 7 days (intravenous + oral). If
the patient has significantly improved after 2 to 3 days of antibiotic therapy, treat for 5 days. If the clinical
response is slow, treat for 7 days.
For hospital-acquired aspiration pneumonia, 7 days of therapy (intravenous + oral) is generally adequate.
Patients with lung abscess, empyema or large parapneumonic effusion complicating aspiration pneumonia
require a longer duration of therapy—see Lung abscess or Parapneumonic effusion and empyema. Patients with
necrotising pneumonia may also require a longer duration of therapy—seek expert advice. If the patient is not
improving and susceptibility results are not available, seek expert advice.
Management of recurrent aspiration

Recurrent aspiration can be difficult to manage because the cause (eg neuromuscular disorders, impaired
consciousness) often cannot be modified, putting the patient at ongoing risk of aspiration. Patients with recurrent
aspiration may develop multiple episodes of aspiration pneumonia, requiring antibiotic therapy. Harms associated
with repeated or prolonged courses of antibiotics include colonisation with increasingly resistant pathogens, and
Clostridium difficile infection.
Strategies to manage dysphagia and protect the upper airway are recommended to minimise further aspiration
events. These include:
swallowing rehabilitation with a speech pathologist

oral hygiene
immunisation against Streptococcus pneumoniae—see the Australian Immunisation Handbook [URL]
management of gastro-oesophageal reflux—see Gastro-oesophageal reflux
positioning the patient to minimise aspiration (eg elevating the head of the bed)
insertion of a percutaneous endoscopic gastrostomy (PEG) tube.
Key references
What is aspiration pneumonia?
Dragan V, Wei Y, Elligsen M, Kiss A, Walker SAN, Leis JA. Prophylactic antimicrobial therapy for acute aspiration
pneumonitis. Clinical Infectious Diseases 2018;67(4):513–8.
Lascarrou JB, Lissonde F, Le Thuaut A, Bachoumas K, Colin G, Henry Lagarrigue M, et al. Antibiotic therapy in
comatose mechanically ventilated patients following aspiration: Differentiating pneumonia from pneumonitis. Crit Care
Med 2017;45(8):1268–75.
Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 2001;344(9):665–71.
Marik PE. Pulmonary aspiration syndromes. Curr Opin Pulm Med 2011;17(3):148–54.
Approach to managing aspiration pneumonia
Akata K, Yatera K, Yamasaki K, Kawanami T, Naito K, Noguchi S, et al. The significance of oral streptococci in patients
with pneumonia with risk factors for aspiration: the bacterial floral analysis of 16S ribosomal RNA gene using
bronchoalveolar lavage fluid. BMC Pulm Med 2016;16(1):79.
Allewelt M. Aspiration pneumonia and primary lung abscess: diagnosis and therapy of an aerobic or an anaerobic
infection? Expert Rev Respir Med 2007;1(1):111–9.
Bartlett JG. How important are anaerobic bacteria in aspiration pneumonia: when should they be treated and what is
optimal therapy. Infect Dis Clin North Am 2013;27(1):149–55.
Jaoude P, Badlam J, Anandam A, El-Solh AA. A comparison between time to clinical stability in community-acquired
aspiration pneumonia and community-acquired pneumonia. Intern Emerg Med 2014;9(2):143–50.
Kwong JC, Howden BP, Charles PG. New aspirations: the debate on aspiration pneumonia treatment guidelines. Med
J Aust 2011;195(7):380–1.
Mandell LA, Marrie TJ, Grossman RF, Chow AW, Hyland RH. Canadian guidelines for the initial management of
community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the
Canadian Thoracic Society. The Canadian Community-Acquired Pneumonia Working Group. Clin Infect Dis
2000;31(2):383–421.
Management of recurrent aspiration
Australian and New Zealand Society for Geriatric Medicine. Position statement: dysphagia and aspiration in older
people. Australas J Ageing 2011;30(2):98–103.
Hua F, Xie H, Worthington HV, Furness S, Zhang Q, Li C. Oral hygiene care for critically ill patients to prevent
ventilator-associated pneumonia. Cochrane Database Syst Rev 2016;(10):CD008367.
Juthani-Mehta M, Van Ness PH, McGloin J, Argraves S, Chen S, Charpentier P, et al. A cluster-randomized controlled
trial of a multicomponent intervention protocol for pneumonia prevention among nursing home elders. Clin Infect Dis
2015;60(6):849–57.
Warusevitane A, Karunatilake D, Sim J, Lally F, Roffe C. Safety and effect of metoclopramide to prevent pneumonia in
patients with stroke fed via nasogastric tubes trial. Stroke 2015;46(2):454–60.
Directed therapy for pneumonia
Acinetobacter baumannii pneumonia
Community-acquired Acinetobacter baumannii pneumonia
Community-acquired Acinetobacter baumannii pneumonia particularly occurs in tropical regions of Australia
[Note 1] during the wet season (around October to April). Patients usually have risk factors such as hazardous
alcohol use, chronic lung disease or diabetes. Compared with hospital-acquired infection, community-acquired A.
baumannii causes severe pneumonia, but carbapenem resistance is less likely (see Hospital-acquired Acinetobacter
baumannii pneumonia).
For pneumonia caused by community-acquired A. baumannii, use the results of susceptibility testing to guide
therapy. If the results of susceptibility testing are not available, in adults use:
meropenem 1 g intravenously, 8-hourly.
Once the patient improves, switch to oral therapy (see Box 2.35 for guidance on when to switch to oral therapy). In
adults, use:
1 ciprofloxacin 500 mg orally or enterally, 12-hourly to complete 14 days total duration of

therapy (intravenous + oral)
OR (if the isolate is susceptible)
2 trimethoprim+sulfamethoxazole 160+800 mg orally or enterally, 12-hourly to complete

14 days total duration of therapy (intravenous + oral).
The duration of therapy is usually 14 days (intravenous + oral) but longer therapy may be required for those with
more extensive or complicated pneumonia.
For information about recovery from pneumonia, management of patients who are not improving and strategies to
prevent further episodes of pneumonia, see Pneumonia diagnosis and follow-up.
Hospital-acquired Acinetobacter baumannii pneumonia

Acinetobacter baumannii can cause pneumonia in hospitalised patients, especially patients requiring intensive care
support. It also frequently colonises the upper respiratory tract in hospitalised patients. Hospital-acquired A.
baumannii pneumonia is often multidrug resistant—seek expert advice for local susceptibility data and guidance
on the results of susceptibility testing. Consider if the patient has risk factors for infection with multidrug-resistant
bacteria (see Box 2.30).
Multidrug-resistant Enterobacteriaceae pneumonia

Enterobacteriaceae that cause pneumonia include Citrobacter, Enterobacter, Escherichia, Klebsiella, Morganella,
Providencia, Serratia and Yersinia species.
Multidrug-resistant (MDR) Enterobacteriaceae include extended-spectrum beta-lactamase (ESBL)-producing

Enterobacteriaceae, AmpC beta-lactamase–producing Enterobacteriaceae and carbapenemase-producing
Enterobacteriaceae. For risk factors for infection with a multidrug-resistant Gram-negative bacterium, see Box
2.30.
For management of pneumonia caused by Klebsiella pneumoniae and Escherichia coli isolates that are
nonmultidrug-resistant (non-MDR), see Nonmultidrug-resistant Enterobacteriaceae pneumonia.
Consult a clinical microbiologist or infectious diseases physician for management of multidrug-resistant Enterobacteriaceae
pneumonia.
Management of pneumonia caused by ESBL-producing Enterobacteriaceae is complex—consult a clinical

microbiologist or infectious diseases physician. For initial therapy while awaiting further advice, use:
Management of pneumonia caused by AmpC beta-lactamase–producing Enterobacteriaceae (eg Citrobacter,

Enterobacter, Morganella, Providencia and Serratia species) is complex—consult a clinical microbiologist or
infectious diseases physician. For initial therapy while awaiting further advice, use:
OR if the patient is critically ill
Management of pneumonia due to carbapenemase-producing Enterobacteriaceae is extremely challenging and

beyond the scope of this topic—consult a clinical microbiologist or infectious diseases physician.
Nonmultidrug-resistant Enterobacteriaceae pneumonia

The following treatment recommendations apply to pneumonia caused by Klebsiella pneumoniae and Escherichia
coli isolates that are nonmultidrug-resistant (non-MDR). For management of pneumonia caused by other
Enterobacteriaceae, or multidrug-resistant isolates of K. pneumoniae or E. coli, see Multidrug-resistant
Enterobacteriaceae pneumonia.
For the treatment of pneumonia caused by nonmultidrug-resistant K. pneumoniae and E. coli isolates, use:

month or older: 50 mg/kg up to 1 g) intravenously, 12-hourly. See below for advice on
OR

septic shock or requiring intensive care support, use cefotaxime 2 g (child: 50 mg/kg up to
2 g) intravenously, 8-hourly. See below for advice on intravenous to oral switch and
ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 12-hourly; for obese
patients, patients with septic shock or those requiring intensive care support use
See below for advice on intravenous to oral switch and duration of therapy.
Modify therapy based on the results of susceptibility testing.
Intravenous to oral switch: consider a switch from intravenous to oral therapy once the patient improves (see
Box 2.35 for guidance on when to switch to oral therapy). If the pathogen is susceptible and the patient does not
have high-severity or necrotising pneumonia, use:
1 amoxicillin+clavulanate 875+125 mg (child 2 months or older: 22.5+3.2 mg/kg up to

875+125 mg) orally or enterally, 12-hourly; see below for duration of therapy [Note 4]
OR

160+800 mg) orally or enterally, 12-hourly; see below for duration of therapy
OR
2 ciprofloxacin 500 mg (child: 12.5 mg/kg up to 500 mg) orally or enterally, 12-hourly; see
below for duration of therapy [Note 5] [Note 3].
For intravenous to oral switch in patients with high-severity or necrotising pneumonia, use ciprofloxacin if the
isolate is susceptible:
ciprofloxacin 500 mg (child: 12.5 mg/kg up to 500 mg) orally or enterally, 12-hourly; see
Duration of therapy: the total duration of therapy is usually 7 days (intravenous + oral). Patients with lung
abscess, empyema or large parapneumonic effusion complicating pneumonia require a longer duration of therapy
—see Lung abscess or Parapneumonic effusion and empyema. Patients with necrotising pneumonia may also
require a longer duration of therapy—seek expert advice.
Haemophilus influenzae pneumonia

Introduction
Approximately 25% of Haemophilus influenzae isolates produce beta-lactamase enzymes.
Phenoxymethylpenicillin is ineffective against H. influenzae, and macrolides have poor activity against H.
influenzae, so these drugs are not recommended for H. influenzae pneumonia.
Oral therapy for Haemophilus influenzae pneumonia

Oral therapy for H. influenzae pneumonia is recommended whenever possible. Use parenteral therapy for patients
with more severe H. influenzae pneumonia (eg patients with complications such as bacteraemia or pericarditis), or
patients who are unable to tolerate oral (or enteral) therapy. Use the results of susceptibility testing to guide
treatment.
If the isolate is susceptible to penicillin, use:
amoxicillin 1 g (child: 25 mg/kg up to 1 g) orally or enterally, 8-hourly; see Duration of

therapy.
If the isolate is resistant to penicillin (ie beta-lactamase–producing), or if the results of susceptibility testing are not
available, use:

875+125 mg) orally or enterally, 12-hourly; see Duration of therapy [Note 6].
12-hourly; see Duration of therapy.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, treatment depends on the
results of susceptibility testing. Options include:
doxycycline orally or enterally, 12-hourly; see Duration of therapy [Note 7]

adult: 100 mg
OR if the isolate is not susceptible to doxycycline, or the patient has high-severity pneumonia
ciprofloxacin 500 mg (child: 12.5 mg/kg up to 500 mg) orally or enterally, 12-hourly; see
Duration of therapy [Note 8] [Note 9].
In children younger than 8 years with immediate severe or delayed severe hypersensitivity to penicillins who do
not have high-severity pneumonia, use:

orally or enterally, 12-hourly; see Duration of therapy.
Parenteral therapy for Haemophilus influenzae pneumonia

Oral therapy is recommended whenever possible. Use parenteral therapy for patients with more severe H.
influenzae pneumonia (eg patients with complications such as bacteraemia or pericarditis), or patients who are
unable to tolerate oral (or enteral) therapy. Use the results of susceptibility testing to guide treatment.
If the isolate is susceptible to penicillin, use:
If the isolate is resistant to penicillin (ie beta-lactamase–producing), or if the results of susceptibility testing are not
available, use:

below for intravenous to oral switch
OR

For patients with immediate severe or delayed severe hypersensitivity to penicillins, treatment depends on the
results of susceptibility testing. If the isolate is susceptible to ciprofloxacin, oral (or enteral) therapy is preferred
because ciprofloxacin has excellent bioavailability (see Oral therapy for dosage). If oral therapy is not possible, or
the patient has complications of H. influenzae pneumonia (eg bacteraemia, pericarditis), use:
ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 12-hourly; see below
for intravenous to oral switch [Note 10].
Intravenous to oral switch: once the patient improves, switch to oral therapy (see Box 2.35 for guidance on when
Duration of therapy for Haemophilus influenzae pneumonia

The total duration of therapy for H. influenzae pneumonia is guided by the setting (eg hospital or community-
acquired pneumonia) and pneumonia severity. For information on severity assessment, see here for hospital-
acquired pneumonia, here for community-acquired pneumonia in adults or here for community-acquired
pneumonia in children.
For low- to moderate-severity community-acquired H. influenzae pneumonia the total duration of therapy is 5 to
7 days (intravenous + oral). If the patient has significantly improved after 2 to 3 days of antibiotic therapy, treat for
5 days. If the clinical response is slow, treat for 7 days. For children with low-severity community-acquired H.
influenzae pneumonia, a shorter treatment duration of 3 days therapy is recommended.
For high-severity community-acquired H. influenzae pneumonia and hospital-acquired H. influenzae

pneumonia, the total duration of therapy is 7 days (intravenous + oral).
Patients with empyema or large parapneumonic effusion complicating pneumonia require a longer duration of
therapy; see Parapneumonic effusion and empyema for duration of therapy. Patients with pericarditis may also
require a longer duration of therapy—seek expert advice.
Legionella pneumonia in adults

Report cases of Legionella pneumonia to the local public health authority [Note 11] [Note 12]. For further
information, see Legionellosis: CDNA National Guidelines for Public Health Units [URL].
For assessment of pneumonia severity in adults, see here for community-acquired pneumonia or here for hospital-
acquired pneumonia.
For low- to moderate-severity Legionella pneumonia in adults, use:
1 azithromycin 500 mg orally or enterally, daily for 3 to 7 days. If the patient has low-
severity pneumonia and has clinically improved, treat for 3 days. For other patients, treat
for up to 7 days based on clinical response
OR
2 ciprofloxacin 750 mg orally or enterally, 12-hourly for 5 to 7 days; treat for 5 days if
clinical response is rapid
OR
3 doxycycline 100 mg orally or enterally, 12-hourly for 10 to 14 days.
In vitro, Legionella longbeachae isolates appear to be more resistant to doxycycline. There is a lack of clinical data
on outcomes with doxycycline—consider using azithromycin or ciprofloxacin for directed therapy of L.
longbeachae pneumonia.
If oral therapy is not tolerated, consider giving azithromycin or ciprofloxacin intravenously (see dosage for high-
severity Legionella pneumonia below).
For high-severity Legionella pneumonia in adults, use:
1 azithromycin 500 mg intravenously, daily; see below for intravenous to oral switch and
duration of therapy
OR
2 ciprofloxacin 400 mg intravenously, 8-hourly; see below for intravenous to oral switch
For patients with high-severity Legionella pneumonia requiring intensive care support, combination therapy with
azithromycin plus ciprofloxacin, or with rifampicin plus either azithromycin or ciprofloxacin, is sometimes used.
There is limited evidence for this approach, and combination therapy has an increased potential for drug toxicity
and significant drug interactions—seek expert advice.
Intravenous to oral switch: once the patient improves, switch to oral (or enteral) azithromycin or ciprofloxacin;
see dosage above for low- to moderate-severity Legionella pneumonia. See Box 2.35 for guidance on when to
switch to oral therapy.
Duration of therapy for high-severity disease: the optimal duration of therapy for high-severity Legionella
pneumonia is uncertain. A total treatment duration of 7 to 10 days (intravenous + oral) is generally recommended.
Some immunocompromised patients may require a longer duration of therapy—seek expert advice. Prolonged
treatment (eg longer than 14 days) with azithromycin should generally be avoided because it has a long
intracellular half-life.
are available here.
Pneumonia caused by Mycoplasma pneumoniae or Chlamydophila

(Chlamydia) species
Report cases of Chlamydophila (Chlamydia) psittaci pneumonia to the local public health authority [Note 13]
[Note 14]. For further information, see Psittacosis (Ornithosis): CDNA National Guidelines for Public Health
Units [URL].
For pneumonia caused by Mycoplasma pneumoniae, Chlamydophila (Chlamydia) pneumoniae or C. psittaci, use:
adult: 100 mg
OR
2 azithromycin 500 mg (child: 10 mg/kg up to 500 mg) orally, daily for 3 days
OR
2 clarithromycin 500 mg (child: 7.5 mg/kg up to 500 mg) orally, 12-hourly for 7 days.
If oral therapy is not tolerated, use:
azithromycin 500 mg (child: 10 mg/kg up to 500 mg) intravenously, daily for 3 days.
For Chlamydia trachomatis pneumonia in infants aged 2 weeks to 5 months, use:

Neonates with C. trachomatis pneumonia may also have chlamydial conjunctivitis; see Chlamydial conjunctivitis.
are available here.
Pneumococcal pneumonia
Introduction
A penicillin is the drug of choice for pneumonia caused by Streptococcus pneumoniae (pneumococcal pneumonia).
At the dosages recommended below, benzylpenicillin and amoxicillin remain active against strains of S.
pneumoniae with intermediate susceptibility to penicillin (minimum inhibitory concentration [MIC] less than 4
mg/L). At the time of writing, S. pneumoniae strains with high-level penicillin resistance are currently uncommon
in Australia.
Consider testing patients with recurrent pneumococcal infections for an immune system disorder (eg HIV).
Oral therapy for pneumococcal pneumonia

Oral therapy is recommended whenever possible. Use parenteral therapy for patients with more severe
pneumococcal pneumonia (eg patients with bacteraemia), or patients who are unable to tolerate oral (or enteral)
therapy.
For pneumococcal pneumonia in patients who can tolerate oral (or enteral) therapy, use:
amoxicillin 1 g (child: 25 mg/kg up to 1 g) orally or enterally, 8-hourly; see Duration of

therapy for pneumococcal pneumonia .
12-hourly; see Duration of therapy for pneumococcal pneumonia.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, use the results of
susceptibility testing to guide therapy. While awaiting results, use:
1 doxycycline orally or enterally, 12-hourly; see Duration of therapy for pneumococcal

pneumonia [Note 16]
adult: 100 mg
OR
2 moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally or enterally, daily; see
Duration of therapy for pneumococcal pneumonia [Note 17] [Note 18]
OR
2 azithromycin 500 mg (child: 10 mg/kg up to 500 mg) orally or enterally, daily; see
Duration of therapy for pneumococcal pneumonia.
Modify therapy when susceptibility results are available.

Parenteral therapy for pneumococcal pneumonia

Oral therapy is recommended whenever possible. Use parenteral therapy for patients with more severe
pneumococcal pneumonia (eg patients with bacteraemia), or patients who are unable to tolerate oral (or enteral)
therapy.
If the patient has S. pneumoniae bacteraemia and signs of sepsis or septic shock (for definitions, see here for adults
or here for children), use the antibiotic regimens for Streptococcus pneumoniae sepsis or septic shock.
For patients with more severe pneumococcal pneumonia (eg patients with bacteraemia), or patients who are unable
to tolerate oral (or enteral) therapy, use:

below for intravenous to oral switch
OR

1 moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, daily; see below for
intravenous to oral switch [Note 19]
OR
use; see below for intravenous to oral switch.
Duration of therapy for pneumococcal pneumonia
The duration of therapy for pneumococcal pneumonia is guided by the setting (eg hospital- or community-acquired
pneumonia) and pneumonia severity. For information on severity assessment, see here for hospital-acquired
pneumonia, here for community-acquired pneumonia in adults or here for community-acquired pneumonia in
children.
In adults with low- to moderate-severity community-acquired pneumococcal pneumonia, the total duration of
therapy (except for patients treated with azithromycin) is 5 to 7 days (intravenous + oral). If the patient has
significantly improved after 2 to 3 days of antibiotic therapy, treat for 5 days. If the clinical response is slow, treat
for 7 days. For patients treated with azithromycin, 3 to 5 days of therapy is sufficient.
In children with low-severity community-acquired pneumococcal pneumonia, 3 days of treatment (intravenous
+ oral) is recommended. In children with moderate-severity community-acquired pneumococcal pneumonia, the
total duration of therapy (except for patients treated with azithromycin) is 5 to 7 days (intravenous + oral). If the
child has significantly improved after 2 to 3 days of antibiotic therapy, treat for 5 days. If the clinical response is
slow, treat for 7 days. For children with moderate-severity community-acquired pneumococcal pneumonia
treated with azithromycin, 3 to 5 days of therapy is sufficient.
For high-severity community-acquired pneumococcal pneumonia and hospital-acquired pneumococcal

pneumonia, 7 days of therapy (intravenous + oral) is generally adequate.
Patients with lung abscess, empyema or large parapneumonic effusion complicating pneumonia require a longer
duration of therapy—see Lung abscess or Parapneumonic effusion and empyema. Patients with persistent
bacteraemia may also require a longer duration of therapy—seek expert advice.
Pseudomonas aeruginosa pneumonia

For treatment of Pseudomonas-related exacerbations of bronchiectasis or cystic fibrosis, see Antibiotic
management of bronchiectasis or Lower airways infection in cystic fibrosis.
Patients with Pseudomonas aeruginosa pneumonia are initially treated with one or two antipseudomonal drugs,
depending on the severity of pneumonia and whether the patient has bacteraemia, until susceptibility results are
available. Combination therapy is not necessary once susceptibility results are known. Aminoglycosides (eg
gentamicin) and quinolones (eg ciprofloxacin) are not used as initial monotherapy unless there is no alternative, as
resistance can develop rapidly.
The use of inhaled antibiotics for P. aeruginosa pneumonia is not recommended, except in the setting of
multidrug-resistant infection under specialist supervision.
For assessment of pneumonia severity, see here for hospital-acquired pneumonia, here for community-acquired
pneumonia in adults or here for community-acquired pneumonia in children.
For initial treatment of P. aeruginosa pneumonia, use:
1 ceftazidime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly; see below for

OR

hourly; see below for intravenous to oral switch and duration of therapy
PLUS with either of the above regimens in patients with high-severity pneumonia or bacteraemia, EITHER
1 gentamicin intravenously over 3 to 5 minutes; see Principles of aminoglycoside use for

principles of use. See below for intravenous to oral switch and duration of therapy [Note
20]
first dose. See Principles of aminoglycoside use for subsequent dosing [Note 21] [[Note
23]]
aminoglycoside use for subsequent dosing [[Note 24]] [[Note 25]]
subsequent dosing [[Note 25]]
OR
2 ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 8-hourly; see below
for intravenous to oral switch and duration of therapy [Note 26].
For patients with septic shock or those requiring intensive care support, some centres administer ceftazidime or
piperacillin+tazobactam as a continuous or extended infusion—seek expert advice and consult local protocols.
Gentamicin is the preferred drug for combination empirical therapy because current epidemiology suggests
susceptibility to aminoglycosides is more likely than susceptibility to ciprofloxacin. However, aminoglycosides are
not recommended as ongoing monotherapy if appropriate alternative drugs are available, because clinical
outcomes may be inferior with gentamicin compared to an antipseudomonal beta lactam. Modify treatment when
susceptibility results are available.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use the ceftazidime-
based regimen above.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, meropenem may be suitable
[Note 27]. Use:
meropenem 1 g (child: 20 mg/kg up to 1 g) intravenously, 8-hourly; see below for

intravenous to oral switch and duration of therapy [Note 28]
PLUS with either of the above regimens in patients with high-severity pneumonia or bacteraemia
1 gentamicin intravenously over 3 to 5 minutes; see Principles of aminoglycoside use for

principles of use. See below for intravenous to oral switch and duration of therapy [Note
20]
the first dose. See Principles of aminoglycoside use for subsequent dosing [[Note 25]]
OR
2 ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 8-hourly; see below
for intravenous to oral switch and duration of therapy [Note 26].
For patients with septic shock or those requiring intensive care support, some centres administer meropenem as a
continuous or extended infusion—seek expert advice and consult local protocols.
Gentamicin is the preferred drug for combination empirical therapy because current epidemiology suggests
susceptibility to aminoglycosides is more likely than susceptibility to ciprofloxacin. However, aminoglycosides are
not recommended as ongoing monotherapy if appropriate alternative drugs are available, because clinical
outcomes may be inferior with gentamicin compared to an antipseudomonal beta lactam. Modify treatment when
susceptibility results are available.
Combination antipseudomonal therapy is not necessary once susceptibility results are known.
Intravenous to oral switch: a switch from intravenous to oral therapy is often possible after the patient
significantly improves, provided the isolate is susceptible to ciprofloxacin. See Box 2.35 for guidance on when to
switch to oral therapy. Use:
ciprofloxacin 750 mg (child: 20 mg/kg up to 750 mg) orally or enterally, 12-hourly; see
For severe infections, some experts continue intravenous therapy for the full course. In stable patients, if there is
no suitable oral therapy, consider community-based parenteral antimicrobial therapy.
Duration of therapy: the duration of therapy in patients with uncomplicated P. aeruginosa pneumonia requires
individual assessment; a total duration of therapy of 7 days (intravenous + oral) is usually adequate. Patients with
high-severity pneumonia, necrotising pneumonia or bacteraemia may require up to 14 days of therapy (intravenous
+ oral). Patients with lung abscess, empyema or large parapneumonic effusion complicating pneumonia require a
longer duration of therapy—see Lung abscess or Parapneumonic effusion and empyema.
calculate the dose.
function.
treatment options.
Staphylococcal pneumonia
Introduction
Staphylococcus aureus is an uncommon cause of community-acquired pneumonia (CAP). It usually causes high-
severity CAP or cavitary pneumonia. Staphylococcal pneumonia caused by methicillin-resistant S. aureus (MRSA)
or methicillin-susceptible S. aureus (MSSA) can occur as a primary infection, or secondary to influenza. It can also
occur as a metastatic complication of S. aureus bacteraemia or right-sided endocarditis, particularly in people with
a history of injecting drugs.
In patients with hospital-acquired pneumonia (HAP), staphylococcal pneumonia is most commonly associated
with intubation or prolonged hospital stays. It usually causes high-severity HAP.
Approach to managing staphylococcal pneumonia
S. aureus pneumonia is suspected when Gram stain of sputum shows profuse Gram-positive cocci in clusters [Note
30]. However, the identification of S. aureus (including MRSA) by sputum culture may represent colonisation.
Staphylococcal pneumonia is usually a severe and cavitary infection—consider the clinical context of the patient
when interpreting the results of investigations.
Consider if the identification of S. aureus in sputum represents colonisation.
Collect two sets of blood samples for culture to investigate for S. aureus bacteraemia, because S. aureus
bacteraemia has significant morbidity and mortality. If S. aureus bacteraemia is suspected, other investigations,
such as echocardiography, may be required (see Approach to managing Staphylococcus aureus bacteraemia). If
Gram-positive cocci in clusters are identified in the blood, consider both the recommendations in this topic and the
recommendations in Staphylococcus aureus bacteraemia.
Some strains of S. aureus (including both MSSA and MRSA) are particularly virulent, causing rapidly progressive
high-severity pneumonia even in young, previously healthy people. The following features suggest aggressive
staphylococcal infection in patients with pneumonia:
a short clinical course before requiring intensive care support

haemoptysis
early multilobar involvement on chest X-ray
progression to pulmonary cavitation
disseminated intravascular coagulation
a positive blood culture result for S. aureus.
Seek early advice from an infectious diseases physician for patients who have high-severity pneumonia or the
above clinical features. Treatment should include antibiotics for both MSSA and MRSA until the results of
susceptibility testing are available (see Directed therapy for high-severity staphylococcal pneumonia).
For patients with low- to moderate-severity pneumonia, consider whether the identification of S. aureus may
represent colonisation rather than infection. If staphylococcal pneumonia is the most likely diagnosis, ensure
empirical antibiotic therapy includes a drug with antistaphylococcal activity until the results of susceptibility
testing are available—seek expert advice for the adjustment to therapy.
For antibiotic management of staphylococcal pneumonia, see:
Directed therapy for high-severity staphylococcal pneumonia

Methicillin- and penicillin- susceptible S. aureus pneumonia
Methicillin-resistant S. aureus pneumonia.
culture.
Directed therapy for high-severity staphylococcal pneumonia
These recommendations are for patients with high-severity pneumonia when S. aureus has been identified by
culture of blood or sputum. When the results of susceptibility testing are available, see Methicillin- and penicillin-
susceptible S. aureus pneumonia or Methicillin-resistant S. aureus pneumonia for regimens.
When treating patients with S. aureus bacteraemia and staphylococcal pneumonia, consider both the
recommendations in this topic and the recommendations in Staphylococcus aureus bacteraemia.
Until the results of susceptibility testing are available, use combination therapy:
PLUS

Use a 4-hourly flucloxacillin dosing interval for patients with septic shock or requiring intensive care support.
flucloxacillin in the above regimen with cefazolin:
Use a 6-hourly cefazolin dosing interval for adults (but not children) with septic shock or requiring intensive care
support.
monotherapy (see dosage above) [Note 31].
Staphylococcal pneumonia can be secondary to influenza; consider the need for influenza testing (see Diagnosis of
influenza).
Note 31: In a critical situation, a cefazolin-containing regimen can be considered in patients with immediate
severe hypersensitivity, after undertaking a risk–benefit analysis and assessment of potential side-chain cross-
reactivity (see Cross-reactivity between beta lactams). Seek expert advice.
Methicillin- and penicillin- susceptible S. aureus pneumonia

Methicillin-susceptible S. aureus (MSSA) pneumonia can be secondary to influenza; consider the need for
influenza testing (see Diagnosis of influenza).
For MSSA pneumonia, use:
flucloxacillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly. For patients with

endocarditis, septic shock or requiring intensive care support, use a 4-hourly dosing
interval. See below for intravenous to oral switch and duration of therapy.
Some MSSA isolates are susceptible to penicillin (eg benzylpenicillin); however, confirm reported susceptibility
with a clinical microbiologist before adjusting therapy. For penicillin-susceptible S. aureus (PSSA) pneumonia,
use:
antimicrobial hypersensitivity). Management depends on the type of hypersensitivity.
cefazolin 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly. For adults with septic

shock or requiring intensive care support, use a 6-hourly dosing interval. See below for
For patients with immediate severe hypersensitivity to penicillins, perform desensitisation, if possible—seek
possible.

Principles of vancomycin use for subsequent dosing and principles of use. See below for
If the isolate is susceptible and bacteraemia has been excluded, consider changing vancomycin to:
1 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly. See below
OR
2 lincomycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly. See below for
Intravenous to oral switch: for patients with bacteraemia, see Staphylococcus aureus bacteraemia for ongoing
management.
If bacteraemia has been excluded, consider switching to oral therapy once the patient improves (see Box 2.35 for
guidance on when to switch to oral therapy).
For methicillin-susceptible S. aureus (MSSA) pneumonia, use:
flucloxacillin 1 g (child: 25 mg/kg up to 1 g) orally or enterally, 6-hourly. See below for

Cefalexin is often preferred to flucloxacillin in children, because the liquid formulation is better tolerated. For
children with MSSA pneumonia, use:
cefalexin 25 mg/kg up to 1 g orally or enterally, 6-hourly. See below for duration of

therapy.
For penicillin-susceptible S. aureus (PSSA) pneumonia, seek expert advice for intravenous to oral switch.
Duration of therapy: seek expert advice about the optimal treatment duration. For patients with uncomplicated
staphylococcal pneumonia (absence of bacteraemia, metastatic spread, endocarditis, lung abscess or empyema) a
total treatment duration of 7 to 14 days (intravenous + oral) is usually required. Patients with lung abscess,
empyema or large parapneumonic effusion complicating pneumonia require a longer duration of therapy—see
Lung abscess or Parapneumonic effusion and empyema. For patients with bacteraemia, see Staphylococcus
aureus bacteraemia for duration of therapy and other management advice.
Methicillin-resistant S. aureus pneumonia
Methicillin-resistant S. aureus (MRSA) pneumonia can be secondary to influenza; consider the need for influenza
testing (see Diagnosis of influenza).
For MRSA pneumonia, use:
1 vancomycin (adult and child) 25 to 30 mg/kg intravenously, as a loading dose; see

OR
2 linezolid 600 mg intravenously, 12-hourly (child younger than 12 years: 10 mg/kg up to

600 mg intravenously, 8-hourly). See below for intravenous to oral switch and duration of
therapy.
For staphylococcal pneumonia caused by S. aureus strains with intermediate resistance to vancomycin (VISA or
heteroresistant VISA [hVISA]), use linezolid (see dosage above).
For life-threatening or necrotising pneumonia, consider adding clindamycin or lincomycin to vancomycin (see
dosage below), and seek expert advice.
If the isolate is susceptible and bacteraemia has been excluded, consider changing vancomycin or linezolid to:
1 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly. See below
OR
2 lincomycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly. See below for
Although daptomycin and tigecycline have activity against MRSA, these drugs are not recommended due to poor
or uncertain efficacy for the treatment of pneumonia.
Intravenous to oral switch: for patients with bacteraemia, see Staphylococcus aureus bacteraemia for ongoing
management.
If bacteraemia has been excluded, consider switching to oral therapy once the patient improves (see Box 2.35 for
guidance on when to switch to oral therapy).
The choice of oral therapy depends on disease severity and susceptibility results—seek expert advice. Oral therapy
options for uncomplicated MRSA pneumonia (absence of bacteraemia, metastatic spread, endocarditis, lung
abscess or empyema) include linezolid or rifampicin plus fusidate sodium. If the isolate is susceptible (eg some
community-associated MRSA strains), clindamycin or trimethoprim+sulfamethoxazole may be suitable.
Duration of therapy: seek expert advice about the optimal treatment duration. For patients with uncomplicated
staphylococcal pneumonia (absence of bacteraemia, metastatic spread, endocarditis, lung abscess or empyema) a
total treatment duration of 7 to 14 days (intravenous + oral) is usually required. Patients with lung abscess,
empyema or large parapneumonic effusion complicating pneumonia require a longer duration of therapy—see
Lung abscess or Parapneumonic effusion and empyema. For patients with bacteraemia, see Staphylococcus
aureus bacteraemia for duration of therapy and other management advice.
Stenotrophomonas maltophilia pneumonia

Stenotrophomonas maltophilia is frequently identified in sputum, though this almost always represents
colonisation. Rarely, S. maltophilia may cause pneumonia, which can usually be treated with
trimethoprim+sulfamethoxazole or minocycline—seek expert advice.
Overview of fungal pneumonia

Introduction
Although fungal species are often identified by culture of respiratory tract samples, this usually represents
colonisation. Antifungal therapy is rarely indicated for immunocompetent patients, even in intubated patients.
Isolation of fungal species from cultures of respiratory tract samples in immunocompromised patients is more
likely to be pathogenic.
For the treatment of fungal pneumonia, expert advice is essential. Duration of treatment depends on clinical
response and, if possible, resolution of immunosuppression.
For detailed information about fungal infections, including the management of infections not covered in this topic,
consult specialist guidelines (eg the Australian and New Zealand antifungal guidelines [Note 32] ).
For management of pneumonia when fungal organisms have been identified in respiratory tract samples, see:
Candida species identified from lower respiratory tract samples

Aspergillosis
Pulmonary cryptococcosis
Pneumonia Pneumocystis (PJP) .
Note 32: Australian and New Zealand Consensus Guidelines for the Use of Antifungal Agents in the
Haematology/oncology Setting 2014 [URL].
Candida species identified from respiratory tract samples

Pneumonia caused by Candida species is extremely rare. Isolation of Candida species from respiratory tract
samples almost always represents colonisation, especially in intubated patients—this is not sufficient to diagnose
Candida pneumonia.
Isolation of Candida species from respiratory tract samples usually represents colonisation, not infection.
A definitive diagnosis of Candida pneumonia requires histological evidence of invasive Candida infection in lung
tissue—seek expert advice for treatment. If the patient has clinical signs of candidaemia, see Candida species
sepsis (candidaemia).
Aspergillosis
Types of aspergillosis
This section includes management of Invasive pulmonary aspergillosis and Chronic pulmonary aspergillosis.
For management of allergic bronchopulmonary aspergillosis:
for patients with asthma, see Allergic bronchopulmonary aspergillosis

for patients with cystic fibrosis, see Allergic bronchopulmonary aspergillosis in cystic fibrosis.
Invasive pulmonary aspergillosis

Invasive pulmonary aspergillosis usually occurs in patients with prolonged severe neutropenia, solid organ
transplant patients and haematopoietic stem cell transplant (HSCT) patients. Rarely, this infection can occur in
immunocompetent patients following severe influenza. Consider testing immunocompetent patients for an immune
system disorder (eg HIV).
Invasive pulmonary aspergillosis usually progresses rapidly, so administer systemic antifungal treatment promptly.
Seek expert advice for management of invasive pulmonary aspergillosis.
Many factors influence the choice of therapy for invasive pulmonary aspergillosis—seek expert advice for patient
management. Considerations include:
whether the patient developed invasive pulmonary aspergillosis while being treated with antifungal
prophylaxis
anticipated drug interactions with antifungal therapy
kidney and liver function
cost of treatment.
Voriconazole is the preferred antifungal treatment for invasive pulmonary aspergillosis. Consider initial therapy
with amphotericin B liposomal if voriconazole is contraindicated (eg due to drug interactions) or the patient
developed invasive pulmonary aspergillosis while being treated with voriconazole or posaconazole for mould
prophylaxis—seek expert advice. Do not use liposomal amphotericin B for Aspergillus species with amphotericin
resistance (eg A. terreus, A. nidulans). For severe disease, some experts recommend combination therapy with
voriconazole and an echinocandin, but conclusive evidence of benefit is lacking.
For invasive pulmonary aspergillosis in adults, use:
1 voriconazole 6 mg/kg intravenously, 12-hourly for two doses, then 4 mg/kg intravenously,
12-hourly. See below for duration of therapy. Monitor plasma concentration (see
Monitoring antimicrobial blood concentrations) [Note 33]
OR
2 amphotericin B liposomal 3 mg/kg intravenously, daily; see below for duration of therapy.
Once the patient improves, switch to oral or enteral voriconazole (see Box 2.35 for guidance on when to switch to
oral therapy). Use:
voriconazole 4 mg/kg orally or enterally, 12-hourly; give a loading dose of 6 mg/kg orally,
12-hourly for two doses if voriconazole was not used as initial intravenous therapy. See
below for duration of therapy. Monitor plasma concentration (see Monitoring
antimicrobial blood concentrations) [Note 33].
For invasive pulmonary aspergillosis in children, use:
1 voriconazole (child 2 to 12 years, and child 12 to 14 years less than 50 kg) 9 mg/kg
intravenously, 12-hourly for two doses, followed by 8 mg/kg intravenously, 12-hourly.
See below for duration of therapy. Monitor plasma concentration (see Monitoring
antimicrobial blood concentrations) [Note 34]
OR
2 amphotericin B liposomal 3 mg/kg intravenously, daily; see below for duration of therapy.
Once the child improves, switch to oral or enteral voriconazole (see Box 2.35 for guidance on when to switch to
oral therapy). Use:
voriconazole (child 2 to 12 years, and child 12 to 14 years less than 50 kg) 9 mg/kg orally
or enterally, 12-hourly. See below for duration of therapy. Monitor plasma concentration
(see Monitoring antimicrobial blood concentrations) [Note 34] [Note 35].
For adults and children who do not tolerate voriconazole or amphotericin B liposomal, alternative treatment
options include posaconazole or isavuconazole. For patients who are not improving with voriconazole or
amphotericin B liposomal, options for salvage therapy are limited—seek expert advice.
The duration of therapy depends on the patient’s clinical and mycological response—seek expert advice.
Treatment is usually continued for 6 to 12 weeks, until immune recovery or until there is clinical or radiological
evidence of disease resolution.
Secondary prophylaxis is recommended for patients with ongoing significant immune compromise—seek expert
advice and consult specialist guidelines (eg the Australian and New Zealand antifungal guidelines [Note 36]).
Note 33: Studies have suggested that voriconazole does not distribute extensively into adipose tissue, so dosing
in obese patients should be based on either ideal body weight (IBW) (see Table 2.79 or Ideal body weight
calculator) or adjusted body weight (see Box 2.46).
Note 34: Studies have suggested that voriconazole does not distribute extensively into adipose tissue, so dosing
in obese children should be based on either ideal body weight (IBW) or adjusted body weight (see Box 2.46).
Note 35: If voriconazole was not used as initial intravenous therapy, give a voriconazole loading dose to achieve
therapeutic concentrations more quickly. An intravenous loading dose (9 mg/kg intravenously, 12-hourly for two
doses) is most commonly recommended. An oral loading dose (10 mg/kg orally, 12-hourly for two doses) can be
used instead, but there are fewer data for this regimen.
Note 36: Australian and New Zealand Consensus Guidelines for the Use of Antifungal Agents in the
Haematology/oncology Setting 2014 [URL].
Chronic pulmonary aspergillosis

Chronic pulmonary aspergillosis includes several types of pulmonary infection with Aspergillus species such as:
chronic cavitary pulmonary aspergillosis

chronic fibrosing pulmonary aspergillosis
aspergilloma
Aspergillus nodules.
These infections usually occur in immunocompetent patients with comorbid lung disease, and are less invasive
than invasive pulmonary aspergillosis.
For patients with aspergilloma, consult a thoracic surgeon to discuss surgical resection. Surgery is often
recommended to manage haemoptysis and may be curative for patients with a single lesion.
For chronic pulmonary aspergillosis in adults, use:
1 itraconazole (Lozanoc capsule) 100 mg orally, 12-hourly; see below for duration of
therapy. Monitor plasma concentration (see Monitoring antimicrobial blood
concentrations) [Note 37]
OR
1 voriconazole 200 to 300 mg orally, 12-hourly; see below for duration of therapy. Monitor
plasma concentration (see Monitoring antimicrobial blood concentrations)

2 itraconazole (Sporanox oral liquid) 200 mg orally or enterally, 12-hourly; see below for
duration of therapy. Monitor plasma concentration (see Monitoring antimicrobial blood
concentrations) [Note 37].
Compared to conventional itraconazole formulations, there are limited clinical data to support the use of the
Lozanoc itraconazole formulation for chronic pulmonary aspergillosis. However, due to superior bioavailability
and ease of use, many experts prefer this formulation in practice.
Duration of therapy: seek expert advice for duration of therapy. The goal of treatment is to improve symptoms
(eg haemoptysis) and prevent further fibrosis. A long duration of therapy is often required, but the benefits must be
weighed against the adverse effects of long-term treatment.
on the preparation.
Pulmonary cryptococcosis
Introduction
Cryptococcus neoformans and Cryptococcus gattii can cause pulmonary disease in immunocompromised patients
such as patients with HIV infection or malignancy. Pulmonary cryptococcosis is rare in immunocompetent
patients; it is important to exclude immune disorders (eg HIV) in apparently immunocompetent patients. In
patients who need to be started on therapy for HIV, see Pulmonary cryptococcosis in adults with HIV infection for
advice on starting antiretroviral therapy.
Signs of pulmonary cryptococcosis on chest imaging include single or multiple lung nodules, consolidation and
interstitial changes. Cryptococcus species can be cultured from respiratory tract samples from patients with
pulmonary cryptococcosis. However, if Cryptococcus species are identified in a patient without radiographic
evidence of pulmonary infection, this may represent asymptomatic colonisation. The following investigations are
recommended in all patients diagnosed with pulmonary cryptococcosis to exclude disseminated disease (especially
cryptococcal meningitis) and identify risk factors contributing to disease:
serum cryptococcal antigen

blood culture
lumbar puncture
HIV antibody/antigen
CD4:CD8 lymphocyte ratio.
Manage patients with extrapulmonary disease (eg central nervous system involvement, endophthalmitis) as for
cryptococcal meningitis.
Management of pulmonary cryptococcosis depends on whether the patient is immunocompromised, and the
burden of disease. Immunocompetent patients with low disease burden (eg single pulmonary cryptococcoma,
minimal symptoms) are managed with a single phase of therapy; see Immunocompetent patients with low disease
burden. Immunocompromised patients, and immunocompetent patients with a significant burden of disease, are
managed with induction therapy, followed by consolidation and maintenance (suppression or eradication) therapy.
A flare in symptoms can occur in HIV-positive patients when they start antiretroviral therapy (immune
reconstitution inflammatory syndrome [IRIS]) and in HIV-negative patients when they start antifungal therapy.
Treatment with corticosteroids does not benefit patients with pulmonary cryptococcosis, except possibly in the
setting of immune reconstitution inflammatory syndrome—seek expert advice.
For patients with large pulmonary cryptococcomas, surgery may be required—seek expert advice.
Induction therapy for pulmonary cryptococcosis

Induction therapy is not required for immunocompetent patients with low disease burden.
Once extrapulmonary disease has been excluded (see Introduction), for induction therapy of pulmonary
cryptococcosis in immunocompromised patients and immunocompetent patients with a significant burden of
disease, as a two-drug regimen use:
1 amphotericin B liposomal (adult and child) 3 to 4 mg/kg intravenously, daily
OR
1 amphotericin B lipid complex (adult and child) 5 mg/kg intravenously, daily
OR
1 amphotericin B desoxycholate (adult and child) 0.7 to 1 mg/kg intravenously, daily [Note
38]
flucytosine (adult and child) 25 mg/kg orally, 6-hourly. Monitor plasma concentration and
full blood count for bone marrow suppression (see Monitoring flucytosine) [Note 39]
OR (if oral therapy not tolerated)
flucytosine (adult and child) 25 mg/kg intravenously, 6-hourly. Monitor plasma

concentration and full blood count for bone marrow suppression (see Monitoring
flucytosine).
The duration of induction therapy is typically 2 to 6 weeks, depending on culture conversion, whether the
patient is immunocompromised or has pulmonary cryptococcomas, and the species of Cryptococcus (gattii or
neoformans). Seek expert advice and consult the Australian and New Zealand antifungal guidelines [Note 40].
After completing induction therapy, start consolidation and maintenance (suppression or eradication) therapy.
Note 38: Amphotericin B desoxycholate is not marketed in Australia but is available via the Special Access
Scheme.
Note 39: Oral flucytosine is not registered for use in Australia but is available via the Special Access Scheme.
2014;44(12b):1315-32. [URL]
Consolidation and maintenance (suppression or eradication) therapy for pulmonary

cryptococcosis
After completing induction therapy, use consolidation and maintenance (suppression or eradication) therapy.
For pulmonary cryptococcosis in immunocompromised patients and immunocompetent patients with a significant
burden of disease, use:
fluconazole 400 mg (child: 6 mg/kg up to 400 mg) orally, daily for 12 months.
The total duration of consolidation and maintenance (suppression or eradication) therapy depends on the degree of
immune compromise and response to therapy—seek expert advice.
Immunocompetent patients with low disease burden

For immunocompetent patients with low disease burden (eg single pulmonary cryptococcoma, minimal
symptoms), a single phase of therapy using fluconazole can be used for pulmonary cryptococcosis. Once
extrapulmonary disease has been excluded (see Introduction), use:
fluconazole 800 mg (child: 12 mg/kg up to 800 mg) orally for the first dose, then 400 mg
(child: 6 mg/kg up to 400 mg) orally, daily for 6 to 12 months.
If oral therapy is not tolerated, use:
fluconazole 800 mg (child: 12 mg/kg up to 800 mg) intravenously for the first dose, then
400 mg (child: 6 mg/kg up to 400 mg) intravenously, daily. Switch to oral fluconazole (see
dosage above) when possible.

Introduction
Pneumocystis jirovecii usually causes pneumonia in immunocompromised patients (eg patients with HIV
infection, organ transplant recipients, patients with malignancy). If an apparently immunocompetent patient
develops P. jirovecii pneumonia (PJP), investigations for an immune system disorder are recommended.
This section covers treatment and secondary prophylaxis (maintenance therapy) of P. jirovecii pneumonia.
For adults with HIV infection who need to be started on antiretroviral therapy, see Pneumocystis jirovecii
pneumonia (PJP) in adults with HIV infection for advice on starting antiretroviral therapy.
For primary prophylaxis of P. jirovecii pneumonia, see here for immunocompromised adults without HIV infection
or here for adults with HIV infection.
Assessment of PJP disease severity
Parameters of high-severity P. jirovecii pneumonia are:
arterial partial pressure of oxygen (PaO2) less than 70 mmHg on room air, or
oxygen saturation less than 94% on room air—if blood gas analysis is unavailable.
For management of patients with high-severity P. jirovecii pneumonia, see Treatment of high-severity PJP.
If the patient does not meet the parameters for high-severity P. jirovecii pneumonia, manage as low- to moderate-
severity PJP.
Treatment of low- to moderate-severity PJP
Preferred treatment
Trimethoprim+sulfamethoxazole is the most effective treatment for P. jirovecii pneumonia; it is recommended in

all patients unless contraindicated (eg in patients hypersensitive to trimethoprim+sulfamethoxazole).
Trimethoprim+sulfamethoxazole is the most effective treatment for P. jirovecii pneumonia.
For low- to moderate-severity P. jirovecii pneumonia, use:

480+2400 mg orally, 8-hourly for 21 days
OR (if oral therapy is not tolerated)

480+2400 mg intravenously, 8-hourly for 21 days.
After completing 21 days of therapy, maintenance therapy (secondary prophylaxis) for P. jirovecii pneumonia may
be required for immunocompromised patients (eg patients with HIV infection, organ transplant recipients)—see
Maintenance therapy for PJP.

expert advice if desensitisation is being considered. If desensitisation is not an option, see Alternative treatment for
adults or Alternative treatment for children.
Alternative treatment for adults
For adults with low- to moderate-severity P. jirovecii pneumonia who have nonsevere hypersensitivity to
trimethoprim+sulfamethoxazole, use:
1 clindamycin 450 mg orally, 8-hourly for 21 days

PLUS
primaquine 30 mg orally, daily for 21 days [Note 41] [Note 42]
OR
1 dapsone 100 mg orally, daily for 21 days [Note 43] [Note 44]
PLUS
trimethoprim 5 mg/kg orally, 8-hourly for 21 days
2 atovaquone 750 mg orally with fatty food or full-fat milk, 12-hourly for 21 days.
For adults with severe hypersensitivity to trimethoprim+sulfamethoxazole (eg anaphylaxis, DRESS, SJS/TEN),
use clindamycin plus primaquine, or atovaquone alone (see dosages above). Do not give dapsone because there is a
Note 41: Test for glucose-6-phosphate dehydrogenase (G6PD) deficiency before starting treatment with
primaquine—seek expert advice if the patient is G6PD deficient.
Note 42: Consider using primaquine 15 mg daily because this dose has a lower rate of methaemoglobinaemia.
hypersensitivity).
Alternative treatment for children
For children with low- to moderate-severity P. jirovecii pneumonia who have nonsevere hypersensitivity to
1 atovaquone
child younger than 3 months: 15 to 20 mg/kg orally with full-fat milk or feeds, 12-hourly
for 21 days
child 3 to 24 months: 22.5 mg/kg orally with fatty food or full-fat milk, 12-hourly for 21
days
child older than 24 months: 15 to 20 mg/kg up to 750 mg orally with fatty food or full-fat
milk, 12-hourly for 21 days
1 dapsone 2 mg/kg up to 100 mg orally, daily for 21 days [Note 45] [Note 46] [Note 47]
[Note 48]
PLUS
trimethoprim 5 mg/kg orally, 8-hourly for 21 days [Note 49].
For children with severe hypersensitivity to trimethoprim+sulfamethoxazole (eg anaphylaxis, DRESS, SJS/TEN),
use atovaquone alone (see dosage above). Do not give dapsone because there is a possibility of cross-reactivity
between dapsone and sulfamethoxazole (see Cross-reactivity between sulfonamides).
hypersensitivity).
Note 47: Reduce the maximum dapsone dosage to 50 mg daily in children who develop toxicity
(methaemoglobinaemia, chemical haemolysis).
Note 48: An oral liquid formulation of dapsone is not commercially available; for formulation options for
children, see the Don’t Rush to Crush Handbook, published by the Society of Hospital Pharmacists of Australia
[URL].
Note 49: An oral liquid formulation of trimethoprim is not commercially available; for formulation options for
[URL].
Treatment of high-severity PJP
To manage a patient with high-severity P. jirovecii pneumonia:
prescribe antimicrobial therapy (see Preferred antimicrobial therapy for high-severity PJP)
consider if adjunctive corticosteroid therapy is required (see Corticosteroid therapy for high-severity PJP)
consider if maintenance therapy (secondary prophylaxis) for P. jirovecii pneumonia is indicated (see
Maintenance therapy for PJP).
Preferred antimicrobial therapy for high-severity PJP
Trimethoprim+sulfamethoxazole is the most effective treatment for P. jirovecii pneumonia and is recommended in
all patients unless contraindicated (eg in patients hypersensitive to trimethoprim+sulfamethoxazole).
Trimethoprim+sulfamethoxazole is the most effective treatment for P. jirovecii pneumonia.
For high-severity P. jirovecii pneumonia, use:

480+2400 mg intravenously, 6- to 8-hourly.
For clinically unstable patients, 6-hourly dosing is preferred for initial therapy.
Once the patient improves, switch to oral therapy (see Box 2.35 for guidance on when to switch to oral therapy).
Use:

480+2400 mg orally or enterally, 8-hourly to complete 21 days total duration of therapy
(intravenous + oral).
Consider if adjunctive corticosteroid therapy is required (see Corticosteroid therapy for high-severity PJP).

expert advice if desensitisation is being considered. If desensitisation is not an option, see Alternative
antimicrobial therapy for adults or Alternative antimicrobial therapy for children.
Alternative antimicrobial therapy for adults
For adults with high-severity P. jirovecii pneumonia who are hypersensitive to trimethoprim+sulfamethoxazole,
use:
1 clindamycin 450 mg orally or enterally, 6-hourly for 21 days
PLUS
primaquine 30 mg orally or enterally, daily for 21 days [Note 50] [Note 51]
1 pentamidine 4 mg/kg up to 300 mg intravenously, daily; see below for advice on

If oral clindamycin is not tolerated, use:
clindamycin 900 mg intravenously, 8-hourly; see below for advice on intravenous to oral
switch
PLUS
primaquine 30 mg orally or enterally, daily for 21 days [Note 50] [Note 51].
to switch to oral therapy). Use oral clindamycin plus primaquine (see dosages above) to complete 21 days of
therapy (intravenous + oral).
Note 50: Test for glucose-6-phosphate dehydrogenase (G6PD) deficiency before starting treatment with
primaquine—seek expert advice if the patient is G6PD deficient.
Note 51: Consider using primaquine 15 mg daily because this dose has a lower rate of methaemoglobinaemia.
Alternative antimicrobial therapy for children
For children with high-severity P. jirovecii pneumonia who are hypersensitive to

pentamidine 4 mg/kg up to 300 mg intravenously, daily; see below for advice on

to switch to oral therapy). Use atovaquone alone or dapsone plus trimethoprim (see here for dosages) to complete
21 days of therapy (intravenous + oral).
Corticosteroid therapy for high-severity PJP
Use adjunctive corticosteroid therapy in addition to antimicrobial therapy for patients with HIV infection who have
high-severity P. jirovecii pneumonia (see Assessment of PJP disease severity). Although evidence is lacking,
corticosteroids are also often used for patients without HIV infection.
When indicated, start corticosteroids as soon as possible. For adults, use:
prednis(ol)one 40 mg orally or enterally, 12-hourly for 5 days, then 40 mg daily for 5

days, then 20 mg daily for 11 days or until antibiotic therapy is completed.
For children, use:
prednis(ol)one 1 mg/kg up to 40 mg orally or enterally, 12-hourly for 5 days, then 1 mg/kg

up to 40 mg daily for 5 days, then 0.5 mg/kg up to 20 mg daily for 11 days or until
antibiotic therapy is completed.
If oral or enteral therapy is not tolerated, use initially:
1 hydrocortisone 100 mg (child: 2 mg/kg up to 100 mg) intravenously, 6-hourly for up to 5

days; see below for advice on further dosing
OR
1 methylprednisolone sodium succinate 30 mg (child: 1 mg/kg up to 30 mg) intravenously,

12-hourly for up to 5 days; see below for advice on further dosing.
Switch to oral prednis(ol)one once tolerated to complete the 21-day course (intravenous + oral). If the patient is
unable to tolerate oral or enteral therapy after 5 days, taper the intravenous dosage (using the prednis(ol)one
dosage schedule as a guide).
Maintenance therapy for PJP
Preferred maintenance therapy
After an episode of PJP, immunocompromised patients (eg patients with HIV infection, transplant recipients) may
require maintenance therapy (secondary prophylaxis)—seek expert advice on the need for maintenance therapy.
Trimethoprim+sulfamethoxazole is the most effective prophylaxis against P. jirovecii pneumonia.
A Cochrane review [Note 52] found the regimens below to be effective for prevention of P. jirovecii pneumonia.
The choice of regimen depends on patient preference, adherence and tolerability. Use:
1 trimethoprim+sulfamethoxazole 80+400 mg (child 1 month or older: 2.5+12.5 mg/kg up

to 80+400 mg) orally, daily; see below for advice on duration of therapy
OR

160+800 mg) orally, daily; see below for advice on duration of therapy
OR

160+800 mg) orally, 3 times weekly; see below for advice on duration of therapy [Note
53].
Duration of therapy: For adults with HIV infection taking combination antiretroviral therapy with a suppressed
HIV viral load, stop maintenance therapy if CD4 count is greater than 200 cells/microlitre for 3 months. Continue
maintenance therapy indefinitely if an episode of P. jirovecii pneumonia occurred when CD4 count was more than
200 cells/microlitre. For children with HIV infection, see the Guidelines for the Prevention and Treatment of
Opportunistic Infections in HIV-Exposed and HIV-Infected Children [URL].
The duration of maintenance therapy in patients without HIV infection depends on the type of immune
compromise, the duration of immunosuppression and patient factors such as comorbidities—seek expert advice.

expert advice if desensitisation is being considered. If desensitisation is not an option, see Alternative maintenance
therapy for adults or Alternative maintenance therapy for children.
Note 52: Stern A, Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in
non-HIV immunocompromised patients. Cochrane Database Syst Rev 2014;(10):CD005590. [URL]
Alternative maintenance therapy for adults
For maintenance therapy of P. jirovecii pneumonia in adults with nonsevere hypersensitivity to

1 dapsone 100 mg orally, daily; see below for advice on duration of therapy [Note 54] [Note
55] [Note 56]
OR
2 pentamidine 300 mg via nebuliser, every 4 weeks; see below for advice on duration of
OR
3 atovaquone 1500 mg orally with fatty food or full-fat milk, daily; see below for advice on
For adults with severe hypersensitivity to trimethoprim+sulfamethoxazole (eg anaphylaxis, DRESS, SJS/TEN),
use pentamidine or atovaquone (see dosage above). Do not give dapsone because there is a possibility of cross-
Duration of therapy: for adults with HIV infection taking combination antiretroviral therapy with a suppressed
HIV viral load, stop maintenance therapy if CD4 count is greater than 200 cells/microlitre for 3 months. Continue
maintenance therapy indefinitely if an episode of P. jirovecii pneumonia occurred when CD4 count was greater
than 200 cells/microlitre. The duration of maintenance therapy in patients without HIV infection depends on the
type of immune compromise, the duration of immunosuppression and patient factors such as comorbidities—seek
expert advice.
hypersensitivity).
Alternative maintenance therapy for children
For maintenance therapy of P. jirovecii pneumonia in children with nonsevere hypersensitivity to

1 atovaquone - see below for advice on duration of therapy
child younger than 3 months: 30 mg/kg orally with full-fat milk or feeds, daily
child 3 to 24 months: 45 mg/kg orally with fatty food or full-fat milk, daily
child older than 24 months: 30 mg/kg up to 1500 mg orally with fatty food or full-fat milk,
daily
OR
1 dapsone 2 mg/kg up to 100 mg orally, daily; see below for advice on duration of therapy
[Note 59] [Note 60] [Note 61] [Note 62]
OR
2 pentamidine (child 5 years or older) 300 mg via nebuliser, every 4 weeks; see below for
advice on duration of therapy [Note 63] [Note 64].
For children with severe hypersensitivity to trimethoprim+sulfamethoxazole (eg anaphylaxis, DRESS, SJS/TEN),
use pentamidine or atovaquone (see dosage above). Do not give dapsone because there is a possibility of cross-
Duration of therapy: for children with HIV infection, see the Guidelines for the Prevention and Treatment of
Opportunistic Infections in HIV-Exposed and HIV-Infected Children [URL]. The duration of maintenance therapy
in children without HIV infection depends on the type of immune compromise, the duration of
immunosuppression and patient factors such as comorbidities—seek expert advice.
Note 60: Reduce the maximum dapsone dosage to 50 mg daily in children who develop toxicity
(methaemoglobinaemia, chemical haemolysis).
hypersensitivity).
Note 62: An oral liquid formulation of dapsone is not commercially available; for formulation options for
[URL].
Note 64: Use with caution in patients with lung disease (eg asthma) because nebulised pentamidine may cause
cough and bronchospasm.
Other pathogens that cause pneumonia

The following pathogens can cause pneumonia:
Bordetella pertussis—an uncommon cause of pneumonia in infants. For management, see Pertussis
Burkholderia pseudomallei—pneumonia is the most common presentation of melioidosis, which is caused
by the soil saprophyte B. pseudomallei. For management, see Melioidosis
Coxiella burnetii—pneumonia is an uncommon presentation of Q fever, a zoonosis caused by C. burnetii.
For management, see Q fever
Cytomegalovirus (CMV)—cytomegalovirus can cause pneumonitis in immunocompromised patients. For
management, see Cytomegalovirus (CMV) infection
Herpes simplex virus (HSV)—neonates can develop pneumonitis caused by herpes simplex virus. It usually
presents between days 3 and 7 of life. For management, see Neonatal herpes simplex infection
Nocardia species—nocardiosis, which can present with pulmonary disease, is caused by environmental
Gram-positive Actinobacteria of the Nocardia genus. For management, see Nocardiosis
Strongyloides stercoralis—in immunocompromised patients, strongyloidiasis hyperinfection syndrome and
disseminated strongyloidiasis can present with pulmonary disease. For management, see Strongyloidiasis.
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Legionella pneumonia
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Communicable Diseases Network Australia (CDNA). Legionellosis: CDNA national guidelines for public health units
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Pneumonia caused by Mycoplasma pneumoniae, or Chlamydophila (Chlamydia) species
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Communicable Diseases Network Australia (CDNA). Psittacosis (ornithosis): CDNA national guidelines for public
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Pneumococcal pneumonia
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Pseudomonas aeruginosa pneumonia
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Staphylococcal pneumonia
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Stenotrophomonas maltophilia pneumonia
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Aspergillosis
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invasive mould infections in haematological malignancy and haemopoietic stem cell transplantation, 2014. Intern Med J
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Carmona-Fonseca J, Alvarez G, Maestre A. Methemoglobinemia and adverse events in Plasmodium vivax malaria
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Pneumocystis jirovecii pneumonia
Carmona-Fonseca J, Alvarez G, Maestre A. Methemoglobinemia and adverse events in Plasmodium vivax malaria
patients associated with high doses of primaquine treatment. Am J Trop Med Hyg 2009;80(2):188–93.
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Other pathogens that cause pneumonia
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Parapneumonic effusion and empyema
Approach to managing parapneumonic effusion and empyema
Parapneumonic effusion is a pleural effusion secondary to pneumonia; it occurs in up to 50% of pneumonia cases.
Monitor patients with parapneumonic effusion closely because the presence of an effusion predicts poorer clinical
outcomes (eg increased 30-day mortality, prolonged hospital stay). If a large parapneumonic effusion is not
managed appropriately (eg with drainage), it can develop into a thoracic empyema. The management of
parapneumonic effusion is guided by the size of the effusion and the likelihood of progression to an empyema—
see Table 2.58 for definitions and management.
For information about the role of surgery for patients who do not improve with antibiotics and adequate drainage,
see here.
Definitions and management of parapneumonic effusion and empyema (Table 2.58)
Diagnosis Definition Management

Pleural fluid sampling and drainage is not required.
Hospital admission is not required, unless indicated for

small incidental small effusion (eg pneumonia.
parapneumonic depth less than 10 mm on lateral
effusion decubitus X-ray) No change to standard therapy for pneumonia is needed.
Monitor the patient to ensure the effusion does not

progress.
Pleural fluid sampling and drainage is often required
(see Pleural effusion).
clinically significant effusion (eg
large depth greater than 10 mm on Admit the patient to hospital for treatment with
parapneumonic lateral decubitus X-ray or greater intravenous antibiotics. The choice of regimen depends
effusion than 30 mm on CT; dyspnoea on the type of pneumonia; see here for community-
attributable to effusion) acquired pneumonia in adults, here for community-
acquired pneumonia in children or here for hospital-
acquired pneumonia.
Pleural fluid sampling and drainage is required (see
Pleural effusion).
Admit the patient to hospital for treatment with

intravenous antibiotics. The choice of regimen depends
a collection of pus in the pleural on the type of pneumonia; see here for community-
empyema space associated with active acquired pneumonia in adults, here for community-
infection acquired pneumonia in children or here for hospital-
acquired pneumonia.
Intrapleural enzyme therapy may be needed when

empyema is not resolving despite an adequately sited
intercostal catheter for drainage.
CT = computed tomography
Antibiotic management of small parapneumonic effusion

Patients with pneumonia who develop a small pleural effusion (parapneumonic effusion) (see Table 2.58) do not
require pleural fluid sampling and drainage.
No change is needed to standard pneumonia treatment regimens.
No change is needed to standard pneumonia treatment regimens, including the timing of intravenous to oral switch
and duration of therapy; continue standard empirical antibiotic therapy for the applicable type and severity of
pneumonia. Monitor the patient to ensure the effusion does not progress.
For antibiotic regimens, see:

Antibiotic management of large parapneumonic effusion or empyema

complicating community-acquired pneumonia in adults
Management approach
Adults with community-acquired pneumonia (CAP) who develop a large pleural effusion (parapneumonic
effusion) or empyema (see Table 2.58) require admission to hospital, pleural fluid sampling and drainage and
intravenous antibiotics.
If the patient has a small parapneumonic effusion, see Antibiotic management of small parapneumonic effusion for
management.
In adults with large parapneumonic effusion or empyema complicating CAP, the most likely pathogens are:
Streptococcus pneumoniae
the Streptococcus anginosus (milleri) group (S. anginosus, S. constellatus, S. intermedius)
anaerobes such as Bacteroides, Veillonella and Peptostreptococcus species.
Polymicrobial infection is common. Staphylococcus species cause less than 10% of cases. Atypical pathogens are
unlikely to cause parapneumonic effusion or empyema.
Collect pleural fluid samples for culture to identify the pathogen.
Collect pleural fluid samples for culture. Culturing pleural fluid in blood culture bottles, in addition to standard
culture, can increase microbial yield. Other investigations, such as nucleic acid amplification tests (NAAT) (eg
polymerase chain reaction [PCR]), are sometimes performed on pleural fluid samples.
If available, use the results of microbiological investigations to guide antibiotic therapy. If an anaerobic pathogen
is identified by culture, the infection is often polymicrobial—seek expert advice on adjusting therapy.
Culture results are often negative because of antibiotic use for pneumonia. If microbiological results are not
available or are negative, empirical therapy is stratified according to the severity of the underlying pneumonia (for
assessment of pneumonia severity, see CAP in adults: assessment of pneumonia severity). After assessing severity,
see Low- to moderate-severity disease or High-severity disease for antibiotic regimens for empyema and large
parapneumonic effusion.
Low- to moderate-severity disease

For antibiotic management of large parapneumonic effusion or empyema complicating low- to moderate-severity
CAP in adults, use:
benzylpenicillin 1.2 g intravenously, 6-hourly; see Intravenous to oral switch and Duration
of therapy
PLUS
metronidazole 500 mg intravenously, 12-hourly; see Intravenous to oral switch and


therapy
OR
therapy

moxifloxacin 400 mg intravenously, daily; see Intravenous to oral switch and Duration of
therapy.
High-severity disease
When treating adults with large parapneumonic effusion or empyema complicating high-severity CAP, consider
both the recommendations in this topic and management advice in Community-acquired pneumonia in adults.
Additional treatment may be needed for:
influenza
Pseudomonas aeruginosa.
Atypical pathogens are unlikely to cause parapneumonic effusion or empyema so the addition of azithromycin is
not required.
The regimens below are not suitable for adults in tropical regions of Australia [Note 1] unless Burkholderia
pseudomallei and Acinetobacter baumannii have been excluded. Until these pathogens are excluded, manage the
patient as for High-severity CAP in adults: tropical regions.
For antibiotic management of large parapneumonic effusion or empyema complicating high-severity CAP in
adults, use:
care support, use ceftriaxone 1 g intravenously, 12-hourly. See Intravenous to oral switch
and Duration of therapy
OR

intensive care support, use cefotaxime 2 g intravenously, 6-hourly. See Intravenous to oral
switch and Duration of therapy
PLUS

Duration of therapy for further advice.
For adults with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use ceftriaxone or
cefotaxime, plus metronidazole, as above.
moxifloxacin 400 mg intravenously, daily; see Intravenous to oral switch and Duration of
therapy.
Modify antibiotic therapy based on the results of microbiological investigations. If an anaerobic pathogen is
identified by culture, the infection is often polymicrobial—seek expert advice on adjusting therapy. Once the
patient has improved and the pleural space is adequately drained, switch to oral therapy (see Box 2.35 for guidance
on when to switch to oral therapy). For oral continuation therapy for adults with parapneumonic effusion or
empyema complicating CAP, use:
PLUS
metronidazole 400 mg orally, 12-hourly; see Duration of therapy.
Alternatively, if a single-drug regimen is preferred (eg to reduce toxicity, to improve adherence to prolonged
therapy), use:
amoxicillin+clavulanate 875+125 mg orally, 12-hourly; see Duration of therapy [Note 2].
PLUS
metronidazole 400 mg orally, 12-hourly; see Duration of therapy.
Note 2: Consider giving additional amoxicillin (eg 1 g orally, at midday) when prescribing amoxicillin+clavulanate for patients with large
parapneumonic effusion or empyema.
Duration of therapy
In adults with parapneumonic effusion or empyema complicating CAP, the total duration of therapy is 3 to 4 weeks
(intravenous + oral). Consider monitoring serum C-reactive protein (CRP) for response to treatment.

complicating community-acquired pneumonia in children
Management approach
Children with community-acquired pneumonia (CAP) who develop a large pleural effusion (parapneumonic
effusion) or empyema (see Table 2.58) require admission to hospital, pleural fluid sampling and drainage and
intravenous antibiotics.
management.
In children, Streptococcus pneumoniae is the most common pathogen, followed by Staphylococcus aureus
(including methicillin-resistant S. aureus [MRSA]). Therefore, empirical antistaphylococcal therapy is
recommended. Anaerobes are an uncommon cause of parapneumonic effusion and empyema in children, so
empirical anaerobic therapy is not required.
Collect pleural fluid samples for culture to identify the pathogen.
If available, use the results of microbiological investigations to guide antibiotic therapy.
available or are negative, use the empirical therapy regimens below.
Seek expert advice for managing children younger than 2 months with large parapneumonic effusion or empyema
complicating CAP.
Empirical therapy
When treating children 2 months or older with large parapneumonic effusion or empyema complicating high-
severity CAP, consider both the recommendations in this topic and management advice in Community-acquired
pneumonia in children. Additional treatment may be needed for:
influenza
Pseudomonas aeruginosa.
Atypical pathogens are unlikely to cause parapneumonic effusion or empyema so the addition of azithromycin is
not required.
For children in tropical regions of Australia [Note 4], see here to identify if therapy with activity against
Burkholderia pseudomallei pneumonia is required.
For antibiotic management of large parapneumonic effusion or empyema complicating CAP in children 2 months
or older, use:
1 cefotaxime 50 mg/kg up to 2 g intravenously, 8-hourly; for children requiring intensive

care support, use cefotaxime 50 mg/kg up to 2 g intravenously, 6-hourly. See Intravenous
to oral switch and Duration of therapy
OR
1 ceftriaxone 50 mg/kg up to 2 g intravenously, daily; for children requiring intensive care

support, use ceftriaxone 50 mg/kg up to 1 g intravenously, 12-hourly. See Intravenous to
oral switch and Duration of therapy
PLUS EITHER
1 clindamycin 15 mg/kg up to 600 mg intravenously, 8-hourly; see Intravenous to oral

OR
2 lincomycin 15 mg/kg up to 600 mg intravenously, 8-hourly; see Intravenous to oral switch

and Duration of therapy.
use. See Intravenous to oral switch and Duration of therapy.
to cefotaxime or ceftriaxone.
use ceftriaxone or cefotaxime in combination with clindamycin, lincomycin or vancomycin (as above).
ciprofloxacin 10 mg/kg up to 400 mg intravenously, 12-hourly; for children requiring

intensive care support, use ciprofloxacin 10 mg/kg up to 400 mg intravenously, 8-hourly.
See Intravenous to oral switch and Duration of therapy [Note 5]
PLUS EITHER
1 clindamycin 15 mg/kg up to 600 mg intravenously, 8-hourly; see Intravenous to oral

OR
2 lincomycin 15 mg/kg up to 600 mg intravenously, 8-hourly; see Intravenous to oral switch

and Duration of therapy.
use. See Intravenous to oral switch and Duration of therapy.
to ciprofloxacin.
choice.
Modify antibiotic therapy based on the results of microbiological investigations. If S. aureus or S. pneumoniae is
identified, use directed therapy (see Staphylococcal pneumonia or Pneumococcal pneumonia for antibiotic choice);
however, large parapneumonic effusion and empyema require a prolonged duration of therapy, see Duration of
therapy.
Once the patient has improved and the pleural space is adequately drained, switch to oral therapy (see Box 2.35 for
guidance on when to switch to oral therapy). If a pathogen is not identified, for oral continuation therapy for
children 2 months or older with parapneumonic effusion or empyema complicating CAP, use:
amoxicillin+clavulanate 22.5+3.2 mg/kg up to 875+125 mg orally, 12-hourly [Note 6].
use:
cefuroxime (child 3 months or older) 15 mg/kg up to 500 mg orally, 12-hourly [Note 7].
clindamycin 10 mg/kg up to 450 mg orally, 8-hourly [Note 8].
Note 6: Consider giving additional amoxicillin (eg 25 mg/kg up to 1 g orally, at midday) when prescribing amoxicillin+clavulanate for children with
large parapneumonic effusion or empyema.
Note 8: An oral liquid formulation of clindamycin is not commercially available; for formulation options, see the Don’t Rush to Crush Handbook,
published by the Society of Hospital Pharmacists of Australia [URL].
Duration of therapy
In children 2 months or older with parapneumonic effusion or empyema complicating CAP, the total duration of
therapy is usually 2 to 3 weeks (intravenous + oral). If clinical response is rapid, shorten duration to 7 days after
drainage of pleural fluid. Rarely, a longer duration of therapy (eg up to 6 weeks) is required—seek expert advice.
Consider monitoring serum C-reactive protein (CRP) for response to treatment.

complicating hospital-acquired or ventilator-associated pneumonia
Patients with hospital-acquired or ventilator-associated pneumonia who develop a large pleural effusion
(parapneumonic effusion) or empyema (see Table 2.58) require intravenous antibiotics and pleural fluid sampling
and drainage.
management.
The aetiology is similar to community-acquired parapneumonic effusion or empyema. However, Pseudomonas

aeruginosa is an important potential pathogen, and Staphylococcus aureus (including methicillin-resistant S.
aureus [MRSA]) is more common.
If available, use the results of microbiological investigations to guide antibiotic therapy. If an anaerobic pathogen
is identified by culture, the infection is often polymicrobial—seek expert advice on adjusting therapy.
available or are negative, use the empirical regimens below.
When treating patients with large parapneumonic effusion or empyema complicating high-severity hospital-
acquired pneumonia (HAP), or ventilator-associated pneumonia (VAP), consider both the recommendations in this
topic and management advice in Hospital-acquired pneumonia or Ventilator-associated pneumonia. Additional
treatment may be needed for patients with:
septic shock (see here for hospital-acquired pneumonia or here for ventilator-associated pneumonia)
suspected staphylococcal pneumonia (see here for hospital-acquired pneumonia or here for ventilator-
associated pneumonia)
suspected Gram-negative pneumonia (see here for hospital-acquired pneumonia or here for ventilator-
associated pneumonia).
For antibiotic management of large parapneumonic effusion or empyema complicating hospital-acquired

pneumonia or ventilator-associated pneumonia, use:

hourly; see below for advice on intravenous to oral switch and duration of therapy.
For patients with large parapneumonic effusion or empyema complicating HAP or VAP who have immediate
cefepime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly; see below for advice on

PLUS
below for advice on intravenous to oral switch and duration of therapy.
For patients with large parapneumonic effusion or empyema complicating HAP or VAP who have immediate
severe or delayed severe hypersensitivity to penicillins, meropenem may be suitable [Note 9]. Use:
meropenem 1 g (child: 20 mg/kg up to 1 g) intravenously, 8-hourly; see below for advice

on intravenous to oral switch and duration of therapy [Note 10].
For patients at increased risk of MRSA (see Box 2.31) add vancomycin to the above regimens. Use:
use. See below for advice on intravenous to oral switch and duration of therapy.
Intravenous to oral switch: modify antibiotic therapy based on the results of microbiological investigations. If an
anaerobic pathogen is identified by culture, the infection is often polymicrobial—seek expert advice on adjusting
therapy. Once the patient has improved and the pleural space is adequately drained, switch to oral therapy guided
by the results of susceptibility testing (see Box 2.35 for guidance on when to switch to oral therapy).
Duration of therapy: in adults, the total duration of therapy is 3 to 4 weeks (intravenous + oral).
In children, the total duration of therapy is usually 2 to 3 weeks (intravenous + oral). If clinical response is rapid,
shorten duration to 7 days after drainage of pleural fluid. Rarely, a longer duration of therapy (eg up to 6 weeks) is
required—seek expert advice.
For both adults and children, consider monitoring serum C-reactive protein (CRP) for response to treatment.
Key references
Davies HE, Davies RJ, Davies CW. Management of pleural infection in adults: British Thoracic Society Pleural Disease
Guideline 2010. Thorax 2010;65 Suppl 2:ii41–53.
Dean NC, Griffith PP, Sorensen JS, McCauley L, Jones BE, Lee YC. Pleural effusions at first ED encounter predict
worse clinical outcomes in patients with pneumonia. Chest 2016;149(6):1509–15.
Jerng JS, Hsueh PR, Teng LJ, Lee LN, Yang PC, Luh KT. Empyema thoracis and lung abscess caused by viridans
streptococci. Am J Respir Crit Care Med 1997;156(5):1508–14.
Mahon C, Walker W, Drage A, Best E. Incidence, aetiology and outcome of pleural empyema and parapneumonic
effusion from 1998 to 2012 in a population of New Zealand children. J Paediatr Child Health 2016;52(6):662–8.
Maskell NA, Davies CW, Nunn AJ, Hedley EL, Gleeson FV, Miller R, et al. U.K. Controlled trial of intrapleural
streptokinase for pleural infection. N Engl J Med 2005;352(9):865–74.
Dis 2016;16(8):e139–52.
Menzies SM, Rahman NM, Wrightson JM, Davies HE, Shorten R, Gillespie SH, et al. Blood culture bottle culture of
pleural fluid in pleural infection. Thorax 2011;66(8):658–62.
Tsujimoto N, Saraya T, Light RW, Tsukahara Y, Koide T, Kurai D, et al. A simple method for differentiating complicated
parapneumonic effusion/empyema from parapneumonic effusion using the split pleura sign and the amount of pleural
effusion on thoracic CT. PLoS One 2015;10(6):e0130141.
Antibiotic management of bronchiectasis
This topic focuses on management of exacerbations of bronchiectasis. It covers assessment of the exacerbation
(including severity and whether the exacerbation is caused by a bacterial infection) and empirical antibiotic
therapy. Antibiotic regimens for adults and children are stratified by severity of the exacerbation and whether the
patient has longstanding Pseudomonas aeruginosa colonisation.
This topic also discusses the harms and benefits of long-term antibiotic therapy for patients with frequent
exacerbations, and eradication therapy for P. aeruginosa.
For causes, clinical features, diagnosis and general management of bronchiectasis, see Bronchiectasis.
This topic does not cover bronchiectasis caused by cystic fibrosis; for management of cystic fibrosis, see Cystic
fibrosis.
Assessment of exacerbations of bronchiectasis

Is the exacerbation caused by infection?
An exacerbation of bronchiectasis is an acute deterioration of symptoms from the patient’s baseline that usually
develops over several days. Patients with bronchiectasis often produce sputum (which may be purulent)—the
presence of purulent sputum alone is not an indication of an exacerbation warranting antibiotic therapy.
In patients with bronchiectasis, the airways are often colonised with organisms such as Haemophilus influenzae,
Streptococcus pneumoniae, Moraxella catarrhalis, Pseudomonas aeruginosa and Staphylococcus aureus.
Exacerbations of bronchiectasis may be caused by colonising organisms or infection with a new organism,
including common respiratory viruses (eg coronavirus, rhinovirus, influenza). Consider performing nose and throat
swabs for nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]) for influenza and other
respiratory viruses.
Do not treat colonising organisms if the patient is clinically stable.
Antibiotics are only indicated for patients with clinical features of a bacterial infection. These features are listed in
Box 2.20.
Clinical features of bacterial infection in exacerbations of bronchiectasis (Box 2.20)
Antibiotics are not indicated unless all three of the following clinical features are present:
increased sputum volume or change in sputum viscosity

increased sputum purulence
increased cough, which may be associated with wheeze, breathlessness or haemoptysis.
Many patients with bronchiectasis easily expectorate sputum. Collect a sputum sample for culture in all patients
(including patients managed in the community) before starting antibiotic therapy. The results of sputum culture
and susceptibility testing are used to modify therapy in patients who are not improving on empirical antibiotic
therapy [Note 1]. If the patient is improving, adjustment of antibiotic therapy is not required.
Assessing the exacerbation severity

The clinical features listed in Box 2.21 indicate a severe exacerbation of bronchiectasis; patients with any of these
features need close clinical review and usually require hospital admission. When deciding if inpatient management
is appropriate, also consider the patient’s social circumstances (in particular, the availability of home support), age,
comorbidities, ability to tolerate and absorb oral therapy, need for supportive oxygen therapy or assistance with
airway clearance, functional status and goals of care.
Clinical features of severe exacerbations of bronchiectasis (Box 2.21)
Patients with any of the following features need close clinical review and usually require hospital admission:
worsening respiratory distress

worsening hypoxaemia from the patient’s baseline state
signs of sepsis or septic shock (for definitions, see here for adults or here for children).
The clinical features of severe exacerbations of bronchiectasis are similar to pneumonia—a chest X-ray is
recommended to exclude pneumonia (see Pneumonia diagnosis).
For febrile patients, or patients with signs of sepsis or septic shock, collect two sets of blood samples for culture
before starting antibiotic therapy.
Antibiotic therapy for bronchiectasis in adults not colonised with

Pseudomonas aeruginosa: nonsevere exacerbations
These recommendations apply to adults without longstanding Pseudomonas aeruginosa colonisation who do not
have clinical features of a severe exacerbation of bronchiectasis (see Box 2.21). Before prescribing antibiotic
therapy, confirm the patient has definitive clinical features of a bacterial infection (see Box 2.20).
Adults with nonsevere bacterial exacerbations of bronchiectasis can usually be managed in the community with
oral antibiotic therapy. However, when deciding if inpatient management is appropriate, consider the patient’s
social circumstances (in particular, the availability of home support), age, comorbidities, ability to tolerate and
absorb oral therapy, need for supportive oxygen therapy or assistance with airway clearance, functional status and
goals of care.
Ensure other aspects of bronchiectasis management are optimised, such as airway clearance, physical activity and,
if appropriate, bronchodilator therapy (see Nonantibiotic management of bronchiectasis).
Optimise airway clearance, physical activity and, if appropriate, bronchodilator therapy during exacerbations of bronchiectasis.
Collect a sputum sample for culture from all patients (including patients managed in the community) before
starting antibiotic therapy.
Antibiotic therapy
For nonsevere exacerbations of bronchiectasis in adults without longstanding P. aeruginosa colonisation, use:
1 amoxicillin 1 g orally, 8-hourly; see Patient review and duration of therapy
OR
1 doxycycline 100 mg orally, 12-hourly; see Patient review and duration of therapy.
If infection with a beta-lactamase–producing strain of Haemophilus influenzae or Moraxella catarrhalis is

suspected (eg because the patient had a recent exacerbation caused by one of these pathogens), while awaiting
culture results, use:
amoxicillin+clavulanate 875+125 mg orally, 12-hourly; see Patient review and duration of

therapy.
If the patient is improving, adjustment of antibiotic therapy based on the results of sputum culture is not required.
Data to guide the optimal duration of therapy are limited; expert consensus is to treat exacerbations of
bronchiectasis for 14 days. If clinical response is rapid and the current exacerbation is not caused by a resistant
isolate (such as P. aeruginosa), shorten duration to 10 days.
If the patient is not improving with initial antibiotic therapy, modify treatment based on the results of sputum
culture and susceptibility testing when available [Note 2]. If amoxicillin was used as first-line therapy and
susceptibility results are not available, consider changing therapy to amoxicillin+clavulanate (see dosage above).
If the patient is still not improving, reassess the diagnosis and severity of the exacerbation (see Box 2.21).
Consider the need for hospital admission and intravenous therapy (see Antibiotic therapy for bronchiectasis in
adults not colonised with Pseudomonas aeruginosa: severe exacerbations).
Refer patients who have frequent exacerbations that do not respond to empirical therapy to a respiratory physician.
Antibiotic therapy for bronchiectasis in adults not colonised with

Pseudomonas aeruginosa: severe exacerbations
These recommendations apply to adults without longstanding Pseudomonas aeruginosa colonisation who have
clinical features of a severe exacerbation of bronchiectasis (see Box 2.21). Before prescribing antibiotic therapy,
confirm the patient has definitive clinical features of a bacterial infection (see Box 2.20).
The clinical features of severe exacerbations of bronchiectasis are similar to pneumonia. A chest X-ray is
Oral therapy
For severe bacterial exacerbations of bronchiectasis in adults without longstanding P. aeruginosa colonisation, a
trial of oral antibiotic therapy should be considered, if tolerated. Oral therapy is recommended if the patient has
been admitted to hospital for reasons other than disease severity (eg social circumstances, need for supportive
oxygen therapy, assistance with airway clearance). Use:
1 amoxicillin 1 g orally, 8-hourly; see Patient review, intravenous to oral switch and
duration of therapy
OR
1 doxycycline 100 mg orally, 12-hourly; see Patient review, intravenous to oral switch and

amoxicillin+clavulanate 875+125 mg orally, 12-hourly; see Patient review, intravenous to
oral switch and duration of therapy.
Parenteral therapy
For severe bacterial exacerbations of bronchiectasis in adults without longstanding P. aeruginosa colonisation, if
parenteral therapy is required, use:
1 ceftriaxone 2 g intravenously, daily; see Patient review, intravenous to oral switch and
duration of therapy
OR
1 cefotaxime 2 g intravenously, 8-hourly; see Patient review, intravenous to oral switch and
duration of therapy
OR
1 amoxicillin+clavulanate 1+0.2 g intravenously, 8-hourly; see Patient review, intravenous

Patients with septic shock or requiring intensive care support may require antibiotic dose adjustment—seek expert
advice.
For adults with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use ceftriaxone or
moxifloxacin 400 mg intravenously, daily; see Patient review, intravenous to oral switch
For regimens, see Oral therapy.
bronchiectasis for 14 days (intravenous + oral). If clinical response is rapid and the current exacerbation is not
caused by a resistant isolate (such as P. aeruginosa), shorten duration to 10 days (intravenous + oral).
culture and susceptibility testing when available [Note 3]. Ensure other aspects of bronchiectasis management are
optimised, such as airway clearance, physical activity and, if appropriate, bronchodilator therapy (see
Nonantibiotic management of bronchiectasis).
Antibiotic therapy for bronchiectasis in adults colonised with

These recommendations apply to adults with longstanding Pseudomonas aeruginosa colonisation (ie the current
exacerbation is not the first time P. aeruginosa has been identified) who do not have clinical features of a severe
exacerbation of bronchiectasis (see Box 2.21). The presence of P. aeruginosa in the airways is associated with
more frequent exacerbations, increased risk of hospitalisation and greater mortality. For information about the role
of eradication therapy for newly identified P. aeruginosa, see Eradication therapy for Pseudomonas aeruginosa in
patients with bronchiectasis.
Before prescribing antibiotic therapy for exacerbations of bronchiectasis, confirm the patient has definitive clinical
features of a bacterial infection (see Box 2.20).
Adults with nonsevere bacterial exacerbations of bronchiectasis can usually be managed in the community with
social circumstances (in particular, the availability of home support), age, comorbidities, ability to tolerate and
absorb oral therapy, need for supportive oxygen therapy or assistance with airway clearance, functional status and
goals of care.
Antibiotic therapy
Exacerbations of bronchiectasis can be caused by colonising organisms or infection with a new organism. For this
reason, a trial of narrower-spectrum antibiotic therapy is recommended. For nonsevere bacterial exacerbations of
bronchiectasis in adults with longstanding P. aeruginosa colonisation, use:
1 amoxicillin 1 g orally, 8-hourly; see Patient review and duration of therapy
OR
1 doxycycline 100 mg orally, 12-hourly; see Patient review and duration of therapy.

amoxicillin+clavulanate 875+125 mg orally, 12-hourly; see Patient review and duration of

therapy.
culture and susceptibility testing when available [Note 4]. If P. aeruginosa is identified in sputum, change therapy
to ciprofloxacin if the isolate is susceptible. Use:
ciprofloxacin 750 mg orally, 12-hourly for 14 days.
If the patient is still not improving, reassess the diagnosis and severity of the exacerbation (see Box 2.21), and
consider the need for hospital admission and intravenous therapy (see Antibiotic therapy for bronchiectasis in
adults colonised with Pseudomonas aeruginosa: severe exacerbations).
Antibiotic therapy for bronchiectasis in adults colonised with

These recommendations apply to adults with longstanding Pseudomonas aeruginosa colonisation (ie not the first
time P. aeruginosa has been identified) who have clinical features of a severe exacerbation of bronchiectasis (see
Box 2.21). The presence of P. aeruginosa in the airways is associated with more frequent exacerbations, increased
risk of hospitalisation and greater mortality. For information about the role of eradication therapy for newly
identified P. aeruginosa, see Eradication therapy for Pseudomonas aeruginosa in patients with bronchiectasis.
Before prescribing antibiotic therapy for exacerbations of bronchiectasis, confirm the patient has definitive clinical
If the patient requires hospitalisation for reasons other than disease severity (eg social circumstances, need for
supportive oxygen therapy, assistance with airway clearance), treat as for Antibiotic therapy for bronchiectasis in
adults colonised with Pseudomonas aeruginosa: nonsevere exacerbations.
Antibiotic therapy
For patients with longstanding P. aeruginosa colonisation, use the results of susceptibility tests (if available) to
guide antibiotic therapy. There is limited evidence to inform the optimal empirical regimen and whether
combination antipseudomonal therapy is required initially (usually with an antipseudomonal beta lactam plus an
aminoglycoside). Aminoglycosides (gentamicin or tobramycin) are the preferred drugs for combination empirical
therapy because current epidemiology suggests susceptibility to aminoglycosides is more likely than susceptibility
to ciprofloxacin. Consider the harms and benefits of combination therapy and check for contraindications and
precautions before prescribing aminoglycosides (see Box 2.42). Combination therapy is not necessary once P.
aeruginosa antibiotic susceptibility is known.
For severe bacterial exacerbations of bronchiectasis in adults with longstanding P. aeruginosa colonisation, use:
1 ceftazidime 2 g intravenously, 8-hourly; see Patient review, intravenous to oral switch and
duration of therapy
OR

PLUS with either of the above regimens if using combination therapy
1 gentamicin intravenously; see Principles of aminoglycoside use for dosage and principles
of use. Review the need for ongoing therapy at 72 hours; monitor plasma concentration if
therapy is continued. See Patient review, intravenous to oral switch and duration of
therapy
OR
1 tobramycin intravenously; see Principles of aminoglycoside use for dosage and principles
therapy
OR
2 ciprofloxacin 400 mg intravenously, 8-hourly; see Patient review, intravenous to oral

For adults with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use the ceftazidime-
For adults with immediate severe or delayed severe hypersensitivity to penicillins, meropenem may be suitable
[Note 5]. Use:
duration of therapy
PLUS EITHER if using combination therapy
therapy
OR
therapy
OR
2 ciprofloxacin 400 mg intravenously, 8-hourly; see Patient review, intravenous to oral

treatment options.
Review the results of culture and susceptibility testing, and the patients’ response to initial therapy. Combination
therapy is not necessary once P. aeruginosa susceptibility results are known. Aminoglycosides are not
recommended as ongoing monotherapy if appropriate alternative drugs are available, because clinical outcomes
may be inferior with gentamicin compared to an antipseudomonal beta lactam.
If P. aeruginosa is not identified by culture, switch to an appropriate narrower-spectrum antibiotic regimen (see
here) or modify therapy based on the results of culture and susceptibility testing.
If P. aeruginosa is identified by culture, most experts continue intravenous therapy for the full treatment course,
rather than switching to oral ciprofloxacin. Once the patient has stabilised, consider community-based parenteral
antimicrobial therapy to complete the course.
If the P. aeruginosa isolate is susceptible to ciprofloxacin, consider switching to oral therapy once the patient has
improved (see Box 2.35 for guidance on when to switch to oral therapy). Use:
ciprofloxacin 750 mg orally, 12-hourly to complete 14 days of therapy (intravenous +

oral).
bronchiectasis caused by P. aeruginosa for 14 days (intravenous + oral).
culture and susceptibility testing when available [Note 6]. Consider using combination antipseudomonal therapy if
the patient is not improving on monotherapy. Ensure other aspects of bronchiectasis management are optimised,
such as airway clearance, physical activity and, if appropriate, bronchodilator therapy (see Nonantibiotic
management of bronchiectasis).
Antibiotic therapy for bronchiectasis in children not colonised with

These recommendations apply to children without longstanding Pseudomonas aeruginosa colonisation who do not
have clinical features of a severe exacerbation of bronchiectasis (see Box 2.21). Before prescribing antibiotic
therapy, confirm the child has definitive clinical features of a bacterial infection (see Box 2.20).
Children with nonsevere bacterial exacerbations of bronchiectasis can usually be managed in the community with
oral antibiotic therapy. However, when deciding if inpatient management is appropriate, consider the child’s social
circumstances, comorbidities, ability to tolerate and absorb oral therapy, need for supportive oxygen therapy or
assistance with airway clearance, functional status and goals of care.
Antibiotic therapy
For nonsevere exacerbations of bronchiectasis in children without longstanding P. aeruginosa colonisation, use:
amoxicillin 25 mg/kg up to 1 g orally, 8-hourly; see Patient review and duration of

therapy.

suspected (eg the child had a recent exacerbation caused by one of these pathogens), while awaiting culture results,
use:
amoxicillin+clavulanate (child: 2 months or older) 22.5+3.2 mg/kg up to 875+125 mg

orally, 12-hourly; see Patient review and duration of therapy [Note 7].
cefuroxime (child 3 months or older) 15 mg/kg up to 500 mg orally, 12-hourly; see Patient
review and duration of therapy.
of therapy
OR
orally, 12-hourly; see Patient review and duration of therapy.

culture and susceptibility testing when available [Note 8]. If amoxicillin was used as first-line therapy and
susceptibility results are not available, consider changing therapy to amoxicillin+clavulanate (see dosage above).
Assess adherence to antibiotic therapy and ensure other aspects of bronchiectasis management are optimised such
as airway clearance, physical activity and, if appropriate, bronchodilator therapy (see Nonantibiotic management
of bronchiectasis).
If patient is still not improving, reassess the diagnosis and severity of the exacerbation (see Box 2.21). Consider
the need for hospital admission and intravenous therapy (see Antibiotic therapy for bronchiectasis in children not
colonised with Pseudomonas aeruginosa: severe exacerbations).
Refer all children with bronchiectasis to a respiratory physician. Children with frequent exacerbations, or those
who do not respond to empirical therapy, should have regular specialist and physiotherapist review.
Antibiotic therapy for bronchiectasis in children not colonised with

These recommendations apply to children without longstanding Pseudomonas aeruginosa colonisation who have
clinical features of a severe exacerbation (see Box 2.21). Before prescribing antibiotic therapy, confirm the child
has definitive clinical features of a bacterial infection (see Box 2.20).
Antibiotic therapy
For severe exacerbations of bronchiectasis in children without longstanding P. aeruginosa colonisation, use:
1 cefotaxime 50 mg/kg up to 2 g intravenously, 8-hourly; see Patient review, intravenous to

OR
1 ceftriaxone (child 1 month or older) 50 mg/kg up to 2 g intravenously, daily; see Patient

review, intravenous to oral switch and duration of therapy
OR
1 amoxicillin+clavulanate (child 3 months or older) 25+5 mg/kg up to 1+0.2 g

intravenously, 8-hourly; see Patient review, intravenous to oral switch and duration of
therapy [Note 9].
Children with septic shock or requiring intensive care support may require antibiotic dose adjustment—seek expert
advice.
moxifloxacin 10 mg/kg up to 400 mg intravenously, daily; see Patient review, intravenous

to oral switch and duration of therapy [Note 10].

For regimens, see Antibiotic therapy for bronchiectasis in children not colonised with Pseudomonas aeruginosa:
nonsevere exacerbations.
bronchiectasis for 14 days (intravenous + oral). If clinical response is rapid and the current exacerbation is not
caused by a resistant isolate (such as P. aeruginosa), shorten duration to 10 days (intravenous + oral).
culture and susceptibility tests when available. Ensure other aspects of bronchiectasis management are optimised,
Antibiotic therapy for bronchiectasis in children colonised with

These recommendations apply to children with longstanding Pseudomonas aeruginosa colonisation (ie not the first
time P. aeruginosa has been identified) who do not have clinical features of a severe exacerbation of bronchiectasis
(see Box 2.21). For information about the role of eradication therapy for newly identified P. aeruginosa, see
Eradication therapy for Pseudomonas aeruginosa in patients with bronchiectasis.
Before prescribing antibiotic therapy for exacerbations of bronchiectasis, confirm the child has definitive clinical
Children with nonsevere bacterial exacerbations of bronchiectasis can usually be managed in the community with
social circumstances, comorbidities, ability to tolerate and absorb oral therapy, need for supportive oxygen therapy
or assistance with airway clearance, functional status and goals of care.
Antibiotic therapy
Children with bronchiectasis are less likely to have P. aeruginosa infection that adults, so the presence of P.
aeruginosa in the airways often indicates more advanced disease. Most experts recommend treating exacerbations
of bronchiectasis in these children with antipseudomonal therapy, based on experience managing children with
cystic fibrosis. A trial of narrower-spectrum antibiotic therapy can be considered; for regimens see Antibiotic
therapy for bronchiectasis in children not colonised with Pseudomonas aeruginosa: nonsevere exacerbations.
Ciprofloxacin is the only available oral drug treatment for P. aeruginosa. For nonsevere exacerbations of
bronchiectasis in children with longstanding P. aeruginosa colonisation, if the isolate is expected to be susceptible
to ciprofloxacin, use:
ciprofloxacin 20 mg/kg up to 750 mg orally, 12-hourly; see Patient review and duration of

Review the results of culture and susceptibility testing. If P. aeruginosa is not identified by culture, switch to an
appropriate narrower-spectrum antibiotic regimen (see here) or modify therapy based on the results of culture and
susceptibility testing.
culture and susceptibility tests when available [Note 13]. Assess adherence to antibiotic therapy and ensure other
aspects of bronchiectasis management are optimised such as airway clearance, physical activity and, if appropriate,
bronchodilator therapy (see Nonantibiotic management of bronchiectasis).
If the patient is still not improving, reassess the diagnosis and severity of the exacerbation (see Box 2.21), and
consider the need for hospital admission and intravenous therapy (see Antibiotic therapy for bronchiectasis in
children colonised with Pseudomonas aeruginosa: severe exacerbations).
Antibiotic therapy for bronchiectasis in children colonised with

These recommendations apply to children with longstanding Pseudomonas aeruginosa colonisation (ie not the first
time P. aeruginosa has been identified) who have clinical features of a severe exacerbation of bronchiectasis (see
Box 2.21). For information about the role of eradication therapy for newly identified P. aeruginosa, see
Eradication therapy for Pseudomonas aeruginosa in patients with bronchiectasis.
Before prescribing antibiotic therapy for exacerbations of bronchiectasis, confirm the child has definitive clinical
If the child requires hospitalisation for reasons other than disease severity (eg social circumstances, need for
supportive oxygen therapy, assistance with airway clearance), treat as for Antibiotic therapy for bronchiectasis in
children colonised with Pseudomonas aeruginosa: nonsevere exacerbations.
Antibiotic therapy
For children with longstanding P. aeruginosa colonisation, use the results of susceptibility tests (if available) to
guide antibiotic therapy. There is limited evidence to inform the optimal empirical regimen and whether
combination antipseudomonal therapy is required initially (usually with an antipseudomonal beta lactam plus an
aminoglycoside). Aminoglycosides (gentamicin or tobramycin) are the preferred drugs for combination empirical
therapy because current epidemiology suggests susceptibility to aminoglycosides is more likely than susceptibility
to ciprofloxacin. Consider the harms and benefits of combination therapy and check for contraindications and
precautions before prescribing aminoglycosides (see Box 2.42). Combination therapy is not necessary once P.
aeruginosa antibiotic susceptibility is known.
For severe bacterial exacerbations of bronchiectasis in children with longstanding P. aeruginosa colonisation, use:
1 ceftazidime 50 mg/kg up to 2 g intravenously, 8-hourly; see Patient review, intravenous to

OR
1 piperacillin+tazobactam 100+12.5 mg/kg up to 4+0.5 g intravenously, 6-hourly; see

PLUS with either of the above regimens if using combination therapy
therapy
OR
therapy
OR
2 ciprofloxacin 10 mg/kg up to 400 mg intravenously, 8-hourly; see Patient review,

For children with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use the ceftazidime-
For children with immediate severe or delayed severe hypersensitivity to penicillins, meropenem may be suitable
[Note 15]. Use:
oral switch and duration of therapy [Note 16]
PLUS EITHER if using combination therapy
therapy
OR
therapy
OR
2 ciprofloxacin 10 mg/kg up to 400 mg intravenously, 8-hourly; see Patient review,

treatment options.

Review the results of culture and susceptibility testing, and the patients’ response to initial therapy. Combination
therapy is not necessary once P. aeruginosa susceptibility results are known. Aminoglycosides are not
recommended as ongoing monotherapy if appropriate alternative drugs are available, because clinical outcomes
may be inferior with gentamicin compared to an antipseudomonal beta lactam.
If P. aeruginosa is not identified by culture, switch to an appropriate narrower-spectrum antibiotic regimen (see
here for oral regimens or here for parenteral regimens) or modify therapy based on the results of culture and
susceptibility testing.
If P. aeruginosa is identified by culture, most experts continue intravenous therapy for the full treatment course,
rather than switching to oral ciprofloxacin. Once the patient has stabilised, consider community-based parenteral
antimicrobial therapy to complete the course.
If the P. aeruginosa isolate is susceptible to ciprofloxacin, consider switching to oral therapy once the patient has
improved (see Box 2.35 for guidance on when to switch to oral therapy). Use:
ciprofloxacin 20 mg/kg up to 750 mg orally, 12-hourly to complete 14 days of therapy

(intravenous + oral) [Note 17] [Note 18].
bronchiectasis caused by P. aeruginosa for 14 days (intravenous + oral).
culture and susceptibility tests when available [Note 19]. Consider using combination antipseudomonal therapy if
the patient is not improving on monotherapy. Ensure other aspects of bronchiectasis management are optimised,
The role of long-term antibiotic therapy for bronchiectasis

Long-term oral and inhaled antibiotic therapy promote the development of antibiotic resistance. Long-term
antibiotic therapy for bronchiectasis is not appropriate, except in patients who have more than three exacerbations
per year when other aspects of management are optimised. General management strategies include treating the
cause of bronchiectasis, airway clearance and exercise therapy such as pulmonary rehabilitation (see Nonantibiotic
Do not consider long-term antibiotic therapy for bronchiectasis unless airway clearance and exercise therapy are optimised.
Refer to a respiratory physician and exclude nontuberculous mycobacterial infections before starting long-term
antibiotic therapy.
Avoid long-term use of quinolones to minimise the development of antibiotic resistance. Ciprofloxacin is the only
available oral drug treatment for Pseudomonas aeruginosa.
Although studies of long-term low-dose macrolide therapy have shown a reduction in the frequency of
exacerbations, patients had variable improvement in symptoms and quality of life, significantly increased
antibiotic resistance, and gastrointestinal adverse effects. The reduction in exacerbation frequency may be due in
part to an anti-inflammatory effect of macrolides.
Clinical data to support the use of long-term inhaled antibiotics for bronchiectasis, such as tobramycin,
colistimethate sodium (colistin) and aztreonam, are limited to a few studies of varying quality. Most studies
reported no improvement in exacerbation frequency, inconsistent effects on symptoms and quality of life, and
significant adverse effects (eg bronchospasm and wheeze).
If long-term macrolide therapy or inhaled antibiotics are started, review the benefit of therapy after 6 to 12 months.
The benefit of ongoing therapy should be reconsidered after each exacerbation.
Eradication therapy for Pseudomonas aeruginosa in patients with

bronchiectasis
In patients with bronchiectasis, the presence of Pseudomonas aeruginosa in the airways is associated with more
frequent exacerbations, increased risk of hospitalisation and higher mortality. On the first occasion P. aeruginosa is
identified—seek expert advice.
It has been hypothesised that eradication of newly identified P. aeruginosa may be beneficial in patients with non–
cystic fibrosis bronchiectasis, but randomised controlled trials to support this practice are lacking. Therefore, if a
patient is clinically stable, it is not appropriate to treat P. aeruginosa because this promotes the development of
antibiotic resistance. For patients with long-term P. aeruginosa colonisation, there is no evidence that eradication
therapy is able to eliminate P. aeruginosa or reduce the incidence of exacerbations.
Key references
Assessment of exacerbations of bronchiectasis
Chang AB, Bell SC, Torzillo PJ, King PT, Byrnes CA, Maguire GP, et al. Chronic suppurative lung disease and
bronchiectasis in children and adults in Australia and New Zealand. Sydney: Thoracic Society of Australia and New
Zealand; 2014. https://www.thoracic.org.au/journal
Finch S, McDonnell MJ, Abo-Leyah H, Aliberti S, Chalmers JD. A comprehensive analysis of the impact of
Pseudomonas aeruginosa colonization on prognosis in adult bronchiectasis. Ann Am Thorac Soc 2015;12(11):1602–
11.
Gao YH, Guan WJ, Xu G, Lin ZY, Tang Y, Lin ZM, et al. The role of viral infection in pulmonary exacerbations of
bronchiectasis in adults: a prospective study. Chest 2015;147(6):1635–43.
Pasteur MC, Bilton D, Hill AT, British Thoracic Society Bronchiectasis non-CF Guideline Group. British Thoracic
Society guideline for non-CF bronchiectasis. Thorax 2010;65 Suppl 1:i1–58.
Polverino E, Goeminne PC, McDonnell MJ, Aliberti S, Marshall SE, Loebinger MR, et al. European Respiratory
Society guidelines for the management of adult bronchiectasis. Eur Respir J 2017;50(3).
Antibiotic therapy for bronchiectasis in adults not colonised with Pseudomonas aeruginosa:
nonsevere exacerbations
Wurzel D, Marchant JM, Yerkovich ST, Upham JW, Masters IB, Chang AB. Short courses of antibiotics for children and
adults with bronchiectasis. Cochrane Database Syst Rev 2011;(6):CD008695.
Antibiotic therapy for bronchiectasis in adults not colonised with Pseudomonas aeruginosa:
severe exacerbations
Antibiotic therapy for bronchiectasis in adults colonised with Pseudomonas aeruginosa:

11.
Antibiotic therapy for bronchiectasis in adults colonised with Pseudomonas aeruginosa: severe
exacerbations
11.
Antibiotic therapy for bronchiectasis in children not colonised with Pseudomonas aeruginosa:
Antibiotic therapy for bronchiectasis in children not colonised with Pseudomonas aeruginosa:
Antibiotic therapy for bronchiectasis in children colonised with Pseudomonas aeruginosa:

Antibiotic therapy for bronchiectasis in children colonised with Pseudomonas aeruginosa:

The role of long-term antibiotic therapy for bronchiectasis
Fjaellegaard K, Sin MD, Browatzki A, Ulrik CS. Antibiotic therapy for stable non-CF bronchiectasis in adults - A
systematic review. Chron Respir Dis 2017;14(2):174–86.
Hnin K, Nguyen C, Carson KV, Evans DJ, Greenstone M, Smith BJ. Prolonged antibiotics for non-cystic fibrosis
bronchiectasis in children and adults. Cochrane Database Syst Rev 2015;(8):CD001392.
Serisier DJ, Martin ML, McGuckin MA, Lourie R, Chen AC, Brain B, et al. Effect of long-term, low-dose erythromycin
on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled
trial. JAMA 2013;309(12):1260–7.
Welsh EJ, Evans DJ, Fowler SJ, Spencer S. Interventions for bronchiectasis: an overview of Cochrane systematic
reviews. Cochrane Database Syst Rev 2015;(7).
Eradication therapy for Pseudomonas aeruginosa in patients with bronchiectasis
11.
Acute bronchitis
Definition and aetiology of acute bronchitis
Acute bronchitis is a self-limiting lower respiratory tract infection. It is the most common cause of cough in
the general practice setting. In patients without chronic lung disease, acute bronchitis is defined as cough
(productive or nonproductive) in the presence of other signs of a lower respiratory tract infection.
If a patient with chronic lung disease presents with signs of a lower respiratory tract infection, consider
pneumonia, or an exacerbation of chronic obstructive pulmonary disease (COPD) or bronchiectasis.
Common respiratory viruses are responsible for over 90% of acute bronchitis cases. Although the atypical
pathogens Mycoplasma pneumoniae and Chlamydophila pneumoniae are occasionally identified in patients
with acute bronchitis, the role of bacteria in this infection is unclear.
Assessment of acute bronchitis

Patients with acute bronchitis often present with nonspecific symptoms of upper or lower respiratory tract
infection. In addition to cough, symptoms of acute bronchitis include:
purulent or coloured sputum

dyspnoea
wheeze
chest discomfort or pain (due to frequent coughing)
nasal congestion
headache
fever.
In acute bronchitis, purulent or coloured sputum is not predictive of a bacterial infection.
The cough lasts on average 2 to 3 weeks and, in 90% of patients, resolves by 4 weeks. However, in 10% of
patients, the cough will persist for up to 8 weeks, due to the time taken for bronchial inflammation to resolve.
Persistent cough is the main reason patients seek medical treatment for acute bronchitis, reinforced by anxiety
about slow recovery time.
If cough is not the predominant clinical feature, consider the likelihood of upper respiratory tract infections
such as acute rhinosinusitis, acute tonsillitis and pharyngitis (see Sore throat).
Due to the nonspecific nature of symptoms, exclusion of more serious causes of cough is important.
Differential diagnoses include:
pneumonia—consider in patients with tachypnoea at rest, tachycardia, persistent fever, rigors,

hypoxaemia or crepitations (crackles) on auscultation that do not clear with coughing. See Pneumonia
diagnosis
influenza and other respiratory viruses—consider performing nose and throat swabs for nucleic acid
amplification testing (NAAT) (eg polymerase chain reaction [PCR]) to detect respiratory viruses
pertussis (whooping cough)—consider in patients with paroxysmal cough or recent exposure to a
pertussis case. Older children and adults often lack the classical signs of pertussis so consider
performing a nasopharyngeal swab for NAAT (eg PCR)
asthma—consider if wheeze could represent a new diagnosis of asthma. For further information, see
here for asthma in adults and adolescents or here for asthma in children
heart failure—consider if signs of oedema or weight gain are present in addition to cough.
For a summary of common or important causes of cough, see Table 9.29. For detailed advice on diagnosis and
assessment of cough, see the Cough in Children and Adults Diagnosis and Assessment (CICADA) guidelines
[Note 1].
Chest X-ray is not indicated for patients with acute bronchitis.
Chest X-ray is not indicated for patients with acute bronchitis. If pneumonia is suspected, consider chest X-
ray to confirm the diagnosis (see Pneumonia diagnosis).
Note 1: Gibson PG, Chang AB, Glasgow NJ, Holmes PW, Katelaris P, Kemp AS, et al. CICADA: Cough in Children and Adults: Diagnosis and
Assessment. Australian cough guidelines summary statement. Med J Aust 2010;192(5):265-71. [URL]
Management of acute bronchitis

As most cases of acute bronchitis are caused by a self-limiting viral illness, antibiotics are not indicated, as
confirmed by a recent Cochrane review [Note 2]. Despite this, antibiotics are frequently inappropriately
prescribed for acute bronchitis.
Antibiotics are not indicated for acute bronchitis.
Many patients have an expectation of treatment with antibiotics. Effective communication with the patient
about the role of antibiotics in acute bronchitis is essential. The discussion should address possible
misconceptions about the effectiveness of antibiotic therapy and the expectation of an antibiotic prescription.
Box 2.22 provides a useful template for these discussions and outlines the approach to managing acute
bronchitis with symptomatic therapy and patient education.
A graphic to support shared decision making discussions has been created by the Australian Commission on
Safety and Quality in Health Care and is available here.
Approach to managing a patient with acute bronchitis (Box 2.22)
Printable box
To manage a patient presenting with acute bronchitis:
Exclude important differential diagnoses and other causes of cough. A routine chest X-ray is not
indicated for acute bronchitis. If pneumonia is suspected, consider chest X-ray to confirm the
diagnosis (see Pneumonia diagnosis). Consider performing nucleic acid amplification testing (NAAT)
(eg polymerase chain reaction [PCR]) to detect respiratory viruses and Bordetella pertussis. Let the
patient know that exclusion of more serious causes, such as pneumonia, is good news.
Reassure the patient that acute bronchitis is a self-limiting condition, caused by a virus in over 90% of
cases. The severity of symptoms can range from mild to severe; severe symptoms do not indicate a
bacterial cause nor the need for antibiotic therapy.
Ask about the patient or carer’s expectations for management of acute bronchitis.
Explain to the patient that antibiotics are of no benefit for viral illnesses and are associated with
harms. A decision aid is available to communicate the harms and benefits of antibiotic therapy [NB1].
this are not fully understood, it can cause problems ranging from yeast infections (eg thrush) through
to more serious infections (eg Clostridium difficile). Antibiotics can also cause bacteria in the body to
become resistant to antibiotics so that future infections are harder to treat. Multidrug-resistant bacteria
(known as ‘superbugs’) can be spread between people, affecting other family members and the
community.
Set realistic expectations of the time for symptoms to improve. Explain that the cough lasts on
average for 2 to 3 weeks and 90% of patients have cough resolution by 4 weeks. Occasionally, the
cough may persist for up to 8 weeks. Acknowledge that this is frustrating.
Provide the patient information on symptom management [NB2]. For pain or fever, paracetamol and
nonsteroidal anti-inflammatory drugs (NSAIDs) can be used (for dosages, see here for adults or here
for children). Drug and nondrug interventions (eg measures to reduce further irritation to the larynx)
can also be considered for cough, see Cough for further information.
Ask about the preferences, values and concerns of the patient, and answer any remaining questions.
Ask the patient to return for reassessment if symptoms take longer than 3 weeks to resolve, or earlier
if fever persists, symptoms worsen or new symptoms occur. If the cough persists for more than 8
weeks, investigate causes of chronic cough (see Table 9.29).
NB1: A graphic to support shared decision making discussions has been created by the Australian Commission on Safety and Quality in
Health Care and is available here.
NB2: Patient information on symptom management has been created by NPS MedicineWise and is available here for adults or here for
children; alternatively, see the NPS MedicineWise website.
Note 2: Smith SM, Fahey T, Smucny J, Becker LA. Antibiotics for acute bronchitis. Cochrane Database Syst Rev 2017;(6):CD000245. [URL]
Key references
Definition and aetiology of acute bronchitis
Kinkade S, Long NA. Acute bronchitis. Am Fam Physician 2016;94(7):560–5.
Llor C, Moragas A, Bayona C, Morros R, Pera H, Plana-Ripoll O, et al. Efficacy of anti-inflammatory or antibiotic
treatment in patients with non-complicated acute bronchitis and discoloured sputum: randomised placebo
controlled trial. BMJ 2013;347:f5762.
Macfarlane J, Holmes W, Gard P, Macfarlane R, Rose D, Weston V, et al. Prospective study of the incidence,
aetiology and outcome of adult lower respiratory tract illness in the community. Thorax 2001;56(2):109–14.
Royal Australian College of General Practitioners. Tests, treatments and procedures clinicians and consumers
should question. Recommendation 7: Choosing Wisely Australia. Sydney: NPS MedicineWise; Last reviewed 22
April 2015. http://www.choosingwisely.org.au/recommendations/racgp
Assessment of acute bronchitis
Braman SS. Chronic cough due to acute bronchitis: ACCP evidence-based clinical practice guidelines. Chest
2006;129(1 Suppl):95S–103S.
Cao AM, Choy JP, Mohanakrishnan LN, Bain RF, van Driel ML. Chest radiographs for acute lower respiratory
tract infections. Cochrane Database Syst Rev 2013;(12):CD009119.
Gibson PG, Chang AB, Glasgow NJ, Holmes PW, Katelaris P, Kemp AS, et al. CICADA: Cough in Children and
Adults: Diagnosis and Assessment. Australian cough guidelines summary statement. Med J Aust
2010;192(5):265–71.
Gordon J, Miller G, Pan Y. Ordering chest X-rays in Australian general practice. Aust Fam Physician
2015;44(8):537–9.
Harris AM, Hicks LA, Qaseem A. Appropriate antibiotic use for acute respiratory tract infection in adults: Advice
for high-value care from the american college of physicians and the centers for disease control and prevention.
Annals of Internal Medicine 2016;164(6):425–34.
Macfarlane J, Holmes W, Gard P, Macfarlane R, Rose D, Weston V, et al. Prospective study of the incidence,
aetiology and outcome of adult lower respiratory tract illness in the community. Thorax 2001;56(2):109–14.
Moore M, Stuart B, Little P, Smith S, Thompson MJ, Knox K, et al. Predictors of pneumonia in lower respiratory
tract infections: 3C prospective cough complication cohort study. Eur Respir J 2017;50(5).
Smith SM, Fahey T, Smucny J, Becker LA. Antibiotics for acute bronchitis. Cochrane Database Syst Rev 2017;
(6):CD000245.
Thompson M, Vodicka TA, Blair PS, Buckley DI, Heneghan C, Hay AD, et al. Duration of symptoms of respiratory
tract infections in children: systematic review. BMJ 2013;347:f7027.
Management of acute bronchitis
Cao AM, Choy JP, Mohanakrishnan LN, Bain RF, van Driel ML. Chest radiographs for acute lower respiratory
tract infections. Cochrane Database Syst Rev 2013;(12):CD009119.
Gordon J, Miller G, Pan Y. Ordering chest X-rays in Australian general practice. Aust Fam Physician
2015;44(8):537–9.
Hickner J. 6 steps to take when a patient insists on that antibiotic. J Fam Pract 2016;65(12):862.
Moore M, Stuart B, Little P, Smith S, Thompson MJ, Knox K, et al. Predictors of pneumonia in lower respiratory
tract infections: 3C prospective cough complication cohort study. Eur Respir J 2017;50(5).
NPS MedicineWise. Childhood RTI Fact Sheet: What every parent should know Sydney: NPS MedicineWise;
2017. https://www.nps.org.au/medical-info/clinical-topics/reducing-antibiotic-resistance#resources
NPS MedicineWise. Respiratory tract infection action plan. Sydney: NPS MedicineWise; 2016.
https://www.nps.org.au/medical-info/clinical-topics/reducing-antibiotic-resistance#resources
Smith SM, Fahey T, Smucny J, Becker LA. Antibiotics for acute bronchitis. Cochrane Database Syst Rev 2017;
(6):CD000245.
Thompson M, Vodicka TA, Blair PS, Buckley DI, Heneghan C, Hay AD, et al. Duration of symptoms of respiratory
tract infections in children: systematic review. BMJ 2013;347:f7027.
Wark P. Bronchitis (acute). BMJ Clin Evid 2011;2011.
Protracted bacterial bronchitis in children
Protracted bacterial bronchitis in children
Protracted bacterial bronchitis (PBB), also called persistent bacterial bronchitis, is an infective cause of
chronic wet cough lasting longer than 4 weeks in children.
Protracted bacterial bronchitis causes a wet cough lasting longer than 4 weeks in children.
Protracted bacterial bronchitis is caused by lower airways infection with nontypeable Haemophilus
influenzae, Streptococcus pneumoniae or Moraxella catarrhalis. Protracted bacterial bronchitis typically
occurs in children younger than 5 years of age and requires an extended course of antibiotic treatment.
Children with recurrent episodes of protracted bacterial bronchitis (eg more than 3 per year) may have an
increased risk of developing chronic suppurative lung disease; further research is needed to confirm whether
a causal relationship exists.
Diagnosis of protracted bacterial bronchitis can be challenging because there are many causes of chronic
cough in children. Treating children who do not have protracted bacterial bronchitis with an extended course
of antibiotics exposes them to unnecessary harms including diarrhoea and rash. Antibiotics disrupt the
balance of bacteria in the body (the microbiome) and cause bacteria in the body to become resistant to
antibiotics so that future infections are harder to treat. Therefore, a thorough history and clinical examination
are essential to exclude other causes of cough before considering antibiotic therapy for protracted bacterial
bronchitis. Protracted bacterial bronchitis causes a chronic wet cough (see Box 2.23 for clinical features). If
the child has a dry cough, this excludes the diagnosis of protracted bacterial bronchitis. If the diagnosis is
uncertain, seek expert advice from a paediatrician.
If the child has a dry cough, this excludes the diagnosis of protracted bacterial bronchitis.
Clinical features of protracted bacterial bronchitis in children (Box 2.23)
In a child with protracted bacterial bronchitis (PBB):
the cough is present for longer than 4 weeks

the cough is an isolated symptom and the child is otherwise well
the cough is wet or moist in nature, with a ‘rattly’ sound often present on chest examination
the cough is present day and night; it worsens when changing posture
coughing episodes can cause shortness of breath but shortness of breath is not present at other times.
Exclude, when possible, other causes of chronic cough before considering antibiotic therapy for protracted bacterial
bronchitis.
In a child who has had a cough for longer than 4 weeks, consider other causes, particularly:
asthma—consider if wheeze, shortness of breath and night cough are present. See Asthma in children:
general information and diagnosis
environmental exposure to cigarette smoke—smoke is a significant trigger for cough. Parent or carer
smoking cessation reduces cough in children
postviral cough—following an acute viral respiratory tract infection, such as acute rhinosinusitis or
acute bronchitis, cough may last up to 8 weeks
upper airway cough syndrome (previously called postnasal drip)—consider if the child has acute
rhinitis (see Rhinitis and rhinosinusitis)
retained inhaled foreign body—if the cough was sudden in onset, particularly if cough started while
the child was eating or playing with small objects
infections including pertussis (whooping cough), lung abscess or tuberculosis
congenital airway abnormalities (eg tracheomalacia, vascular ring)
chronic lung disease (eg bronchiectasis)—consider if clubbing of the fingers, chest wall deformity or
abnormal growth or development are observed.
See Cough for an overview of diagnosis and general management, and the Cough in Children and Adults
Diagnosis and Assessment (CICADA) guidelines [Note 1] for detailed advice on diagnosis and assessment.
Antibiotic therapy for protracted bacterial bronchitis in children should ideally be prescribed in consultation with a
paediatrician.
Antibiotic therapy should be prescribed if protracted bacterial bronchitis is considered the most likely
diagnosis after excluding (where possible) other causes of chronic cough, ideally in consultation with a
paediatrician. For protracted bacterial bronchitis in children, use:
amoxicillin+clavulanate (child 2 months or older) 22.5+3.2 mg/kg up to 875+125 mg

orally, 12-hourly for 2 weeks [Note 2].
cefuroxime (child 3 months or older) 15 mg/kg up to 500 mg orally, 12-hourly for 2

weeks [Note 3].
trimethoprim+sulfamethoxazole (child 1 month or older) 5+25 mg/kg up to 160+800

mg orally, 12-hourly for 2 weeks.
Duration of therapy and patient follow-up: if symptoms improve, this confirms the diagnosis of protracted
bacterial bronchitis—continue antibiotic therapy for the full 2-week course because symptoms often return if
the course is shortened. If the cough does not resolve within 2 weeks, extend antibiotic therapy for a further 2
weeks (4 weeks total duration of therapy). If the cough does not resolve after 4 weeks of antibiotic treatment,
or if the child has frequent recurrences of cough, refer the child to a paediatrician or paediatric respiratory
specialist to exclude other causes of chronic cough such as bronchiectasis.
Note 1: Gibson PG, Chang AB, Glasgow NJ, Holmes PW, Katelaris P, Kemp AS, et al. CICADA: Cough in
Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement. Med J
Aust 2010;192(5):265-71. [URL]
Key references
Chang AB, Oppenheimer JJ, Weinberger M, Rubin BK, Irwin RS. Children with chronic wet or productive cough--
treatment and investigations: A systematic review. Chest 2016;149(1):120–42.
Chang AB, Redding GJ, Everard ML. Chronic wet cough: Protracted bronchitis, chronic suppurative lung disease
and bronchiectasis. Pediatr Pulmonol 2008;43(6):519–31.
Chang AB, Upham JW, Masters IB, Redding GR, Gibson PG, Marchant JM, et al. Protracted bacterial bronchitis:
The last decade and the road ahead. Pediatr Pulmonol 2016;51(3):225–42.
Di Filippo P, Scaparrotta A, Petrosino MI, Attanasi M, Di Pillo S, Chiarelli F, et al. An underestimated cause of
chronic cough: The protracted bacterial bronchitis. Ann Thorac Med 2018;13(1):7–13.
Gibson PG, Chang AB, Glasgow NJ, Holmes PW, Katelaris P, Kemp AS, et al. CICADA: Cough in Children and
Adults: Diagnosis and Assessment. Australian cough guidelines summary statement. Med J Aust
2010;192(5):265–71.
Marchant J, Masters IB, Champion A, Petsky H, Chang AB. Randomised controlled trial of amoxycillin
clavulanate in children with chronic wet cough. Thorax 2012;67(8):689–93.
Marchant JM, Gibson PG, Grissell TV, Timmins NL, Masters IB, Chang AB. Prospective assessment of
protracted bacterial bronchitis: airway inflammation and innate immune activation. Pediatr Pulmonol
2008;43(11):1092–9.
Marchant JM, Petsky HL, Morris PS, Chang AB. Antibiotics for prolonged wet cough in children. Cochrane
Wurzel DF, Marchant JM, Chang AB. Drug treatments of childhood coughs. Aust Prescr 2014;37(4):115–9.
https://www.nps.org.au/australian-prescriber/articles/drug-treatments-of-childhood-coughs
Wurzel DF, Marchant JM, Yerkovich ST, Upham JW, Petsky HL, Smith-Vaughan H, et al. Protracted bacterial
bronchitis in children: Natural history and risk factors for bronchiectasis. Chest 2016;150(5):1101–8.
Antibiotic management of COPD
This topic focuses on the antibiotic management of exacerbations of chronic obstructive pulmonary disease
(COPD). The harms and benefits of long-term antibiotic therapy for patients with severe COPD and frequent
exacerbations are also discussed. For information about the diagnosis and nonantibiotic management of COPD, see
Chronic obstructive pulmonary disease.
If a patient with COPD has a chest X-ray confirming pneumonia, see the applicable type of pneumonia:

Is the COPD exacerbation caused by infection?

Exacerbations of chronic obstructive pulmonary disease (COPD) can be triggered by viral or bacterial infection, or
by noninfective causes (eg environmental pollutants, psychosocial stressors, heart failure and pulmonary
embolism). For management of noninfective COPD exacerbations, see Acute exacerbations of COPD.
Respiratory viruses commonly trigger exacerbations of COPD, with viruses identified up to 64% of patients with
exacerbations. Common viruses identified include influenza A, rhinovirus and respiratory syncytial virus (RSV).
Consider performing nose and throat swabs for nucleic acid amplification testing (NAAT) (eg polymerase chain
reaction [PCR]) for influenza and other respiratory viruses. If influenza is confirmed, see Influenza for
management.
A bacterial cause of the COPD exacerbation is more likely if the patient has the clinical features listed in Box 2.24.
Clinical features suggestive of a bacterial infection in exacerbations of COPD (Box 2.24)
A bacterial cause of the COPD exacerbation is more likely if the patient has all three of the following clinical
features:
increased sputum volume

sputum purulence or a change in sputum colour
fever.
The clinical features of pneumonia overlap with those of an exacerbation of COPD. Consider pneumonia in
patients with tachypnoea at rest, tachycardia, rigors, and crepitations (crackles) on auscultation that do not clear
with coughing; a chest X-ray is indicated to confirm the diagnosis. See Pneumonia diagnosis.
Sputum culture is not routinely recommended for exacerbations of COPD.
Sputum culture is not routinely recommended for exacerbations of COPD. Although bacteria are identified by
culture in around 50% of cases, many patients with COPD are persistently colonised with Haemophilus influenzae,
Moraxella catarrhalis or Streptococcus pneumoniae, and a positive sputum culture result is not necessarily
indicative of infection.
Gram-negative bacteria, such as Enterobacteriaceae, are sometimes identified by sputum culture in patients with
COPD. These are likely to be colonising organisms, reflecting the high levels of antibiotic use and the frequency of
hospitalisation in these patients. The pathogenicity of Enterobacteriaceae in exacerbations of COPD is uncertain.
Antibiotic therapy for exacerbations of COPD

The role of antibiotic therapy for exacerbations of COPD
Do not use antibiotic therapy unless the patient has clinical features suggestive of bacterial infection (see Box
2.24).
The benefit of antibiotic therapy in exacerbations of chronic obstructive pulmonary disease (COPD) is related to
disease severity—see Box 2.25. For assessment of severity and indicators for hospital admission, see Assessing
severity.
Benefit of antibiotic therapy for exacerbations of COPD (Box 2.25)
The benefit of antibiotic therapy in exacerbations of COPD is related to disease severity [NB1].
For patients managed in the community with less severe exacerbations, treatment with antibiotics does not
consistently improve outcomes. Low quality evidence shows that treatment with currently used antibiotics
results in a small reduction in the rate of treatment failure. For every 100 patients treated with antibiotics,
only 8 patients will be better by 4 weeks because they took antibiotics. Antibiotics can be safely withheld
in most cases.
For patients managed in hospital with a severe exacerbation but not in intensive care, treatment with
antibiotics does not consistently improve outcomes. Moderate quality evidence shows that currently used
antibiotics do not result in a reduction in the rate of treatment failure.
For patients managed in the intensive care unit, antibiotics significantly reduce the rate of treatment
failure and reduce mortality.
NB1: For assessment of severity and indicators for hospital admission, see Assessing severity.
Consider withholding antibiotics for patients managed in the community.
Many patients have an expectation of treatment with antibiotics. Effective communication with the patient or carer
about the role of antibiotics in exacerbations of COPD is essential. The discussion should address misconceptions
about the effectiveness of antibiotic therapy and the expectation of an antibiotic prescription. Shared decision
making, which involves a discussion of the evidence for the potential benefits and harms of therapy, provides a
useful template for these discussions.
Shared decision making for antibiotic treatment in exacerbations of COPD in the

community
available evidence and the patient’s or carer’s values and preferences.
Patients who had taken part in shared decision making discussions had a more accurate understanding of the
benefits and harms of the available treatment approaches, and were more likely to choose conservative
management. Further, short-term trial data demonstrated that shared decision making reduced antibiotic
prescribing in primary care.
The steps for shared decision making when deciding whether antibiotic treatment will be used for exacerbations of
COPD in the community are outlined in Box 2.26. A graphic to support shared decision making discussions is
available here.
Shared decision making for antibiotic treatment in exacerbations of COPD in the community
(Box 2.26)
Printable box
Ask about the patient or carer’s expectations for management of exacerbations of COPD.
Explain that the duration of a COPD exacerbation is related to the severity of underlying COPD. For
patients with mild COPD, symptoms of the exacerbation can last 7 to 10 days. In patients with more
severe COPD, symptoms can persist for weeks.
Explain that inhaled bronchodilators and corticosteroids are the standard treatment for exacerbations of
COPD. Additional treatment with antibiotics should only be considered if all three of the following
clinical features of a bacterial infection are present:
increased sputum volume
sputum purulence or a change in sputum colour
fever.
Discuss the limited benefits of antibiotic therapy for nonsevere exacerbations of COPD, even when a
bacterial cause is likely.
For patients managed in the community with less severe exacerbations, antibiotics result in a very
small reduction in the rate of treatment failure. For every 100 patients treated with antibiotics, only 8
patients will be better by 4 weeks because they took antibiotics.
this are not fully understood, it can cause problems ranging from yeast infections (eg thrush)
through to more serious infections (eg Clostridium difficile infection).
Antibiotics can cause bacteria in the body to become resistant to antibiotics so that future infections
are harder to treat. Multidrug-resistant bacteria (known as ‘superbugs’) can be spread between
people, affecting other family members and the community.
questions.
Make a joint decision about whether to add antibiotics to standard care (inhaled bronchodilators and,
where necessary, oral corticosteroids) [NB1]; if a decision is made to use antibiotic therapy, see Antibiotic
regimens for exacerbations of COPD for treatment recommendations.
Discuss criteria for patient follow-up and reassessment.
NB1: A graphic to support shared decision making discussions is available here.
Antibiotic regimens for exacerbations of COPD
Do not use antibiotic therapy unless the patient has clinical features suggestive of bacterial infection (see Box
2.24). For patients managed in the community, engage in shared decision making with the patient or carer to
decide whether to use antibiotic therapy. If antibiotics are indicated, use oral antibiotic therapy for all patients,
including hospitalised patients.
If antibiotics are indicated for exacerbations of COPD, use oral antibiotic therapy for all patients, including hospitalised patients.
In exacerbations of COPD, antibiotic therapy aims to hasten recovery rather than eradicate the colonising organism
because most patients have persistent airways colonisation. Therefore, lower doses of amoxicillin and doxycycline
are used for treating exacerbations of COPD than are used in community-acquired pneumonia.
Avoid amoxicillin+clavulanate for initial antibiotic therapy of exacerbations of COPD.
Other antibiotics such as amoxicillin+clavulanate, macrolides and cephalosporins are not recommended for initial
therapy because they are not more effective than amoxicillin or doxycycline, and they expose the patient to harms
from unnecessary broader-spectrum treatment. Amoxicillin+clavulanate is often prescribed instead of amoxicillin
because of a preference for twice-daily dosing; however, amoxicillin can also be given twice daily for
exacerbations of COPD.
For patients with an exacerbation of COPD who have clinical features of bacterial infection (see Box 2.24), if
antibiotic therapy is indicated, use:
1 amoxicillin 500 mg orally, 8-hourly for 5 days
OR
1 amoxicillin 1 g orally, 12-hourly for 5 days
OR
1 doxycycline 100 mg orally, daily for 5 days.
Lack of response to initial antibiotic therapy rarely requires a change to broader-spectrum therapy. Ensure the
patient is receiving appropriate inhaled bronchodilator and, where necessary, oral corticosteroid therapy. Viral and
noninfective causes of COPD exacerbations are common. Consider other diagnoses such as pneumonia,
influenza or heart failure.
The role of long-term antibiotic therapy in COPD

For patients with severe chronic obstructive pulmonary disease (COPD) and recurrent exacerbations requiring
hospitalisation despite maximal preventive therapy (including long-acting bronchodilators and when appropriate,
inhaled corticosteroids), long-term low-dose oral macrolides may reduce the frequency of exacerbations. There are
many potential significant adverse effects of long-term, low-dose macrolide therapy, including cardiac toxicity,
ototoxicity, diarrhoea, and the development of antibiotic resistance (which affects both the individual and the
community). Referral to a respiratory physician and exclusion of nontuberculous mycobacterial infection are
recommended before starting long-term, low-dose macrolide therapy.
If long-term macrolide therapy is started, review the benefit of therapy after 6 to 12 months. The benefit of
ongoing therapy should be reconsidered after each exacerbation.
Key references
Is the COPD exacerbation caused by infection?
Biancardi E, Fennell M, Rawlinson W, Thomas PS. Viruses are frequently present as the infecting agent in acute
exacerbations of chronic obstructive pulmonary disease in patients presenting to hospital. Intern Med J
2016;46(10):1160–5.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and
prevention of chronic obstructive pulmonary disease (2017 Report). Fontana, WI: GOLD; 2017.
http://goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd/.
Sethi S. Bacteria in exacerbations of chronic obstructive pulmonary disease: phenomenon or epiphenomenon? Proc
Am Thorac Soc 2004;1(2):109–14.
Yang IA, Dabscheck E, George J, Jenkins S, McDonald CF, McDonald V, et al. The COPD-X Plan: Australian and New
Zealand Guidelines for the management of chronic obstructive pulmonary disease [Version 2.50]. Brisbane, QLD: Lung
Foundation Australia; 2017. http://copdx.org.au/copd-x-plan/
Antibiotic therapy for exacerbations of COPD
Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of
chronic obstructive pulmonary disease. Ann Intern Med 1987;106(2):196–204.
(11):CD010907.
El Moussaoui R, Roede BM, Speelman P, Bresser P, Prins JM, Bossuyt PM. Short-course antibiotic treatment in acute
exacerbations of chronic bronchitis and COPD: a meta-analysis of double-blind studies. Thorax 2008;63(5):415–22.
Fanning M, McKean M, Seymour K, Pillans P, Scott I. Adherence to guideline-based antibiotic treatment for acute
exacerbations of chronic obstructive pulmonary disease in an Australian tertiary hospital. Intern Med J 2014;44(9):903–
10.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and
prevention of chronic obstructive pulmonary disease (2017 Report). Fontana, WI: GOLD; 2017.
http://goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd/.
Med J Aust 2014;201(9):513–4.
van Velzen P, Ter Riet G, Bresser P, Baars JJ, van den Berg BTJ, van den Berg JWK, et al. Doxycycline for outpatient-
treated acute exacerbations of COPD: a randomised double-blind placebo-controlled trial. Lancet Respir Med
2017;5(6):492–99.
Vollenweider DJ, Frei A, Steurer-Stey CA, Garcia-Aymerich J, Puhan MA. Antibiotics for exacerbations of chronic
obstructive pulmonary disease. Cochrane Database Syst Rev 2018;10:CD010257.
10.1002/14651858.CD010257.pub2.30371937 .
Vollenweider DJ, Jarrett H, Steurer-Stey CA, Garcia-Aymerich J, Puhan MA. Antibiotics for exacerbations of chronic
obstructive pulmonary disease. Cochrane Database Syst Rev 2012;(12):CD010257.
Yang IA, Dabscheck E, George J, Jenkins S, McDonald CF, McDonald V, et al. The COPD-X Plan: Australian and New
Zealand Guidelines for the management of chronic obstructive pulmonary disease [Version 2.50]. Brisbane, QLD: Lung
Foundation Australia; 2017. http://copdx.org.au/copd-x-plan/
The role of long-term antibiotic therapy in COPD
Ni W, Shao X, Cai X, Wei C, Cui J, Wang R, et al. Prophylactic use of macrolide antibiotics for the prevention of
chronic obstructive pulmonary disease exacerbation: a meta-analysis. PLoS One 2015;10(3):e0121257.
Influenza
Background information on influenza
Influenza is caused by influenza A and B viruses. These viruses cause minor or major epidemics of seasonal
influenza in most years, usually during the winter months.
Novel strains of influenza virus have the potential to cause pandemics, due to lack of immunity in the population
or increased virulence of the strain. Take a detailed travel history from patients with an influenza-like illness,
because international travel is an important vehicle for the rapid spread of these viruses. The management of novel
strains of influenza virus depends on local epidemiology and the characteristics of the strain.
The influenza virus is spread through droplets and contact with fomites (virus-contaminated objects), so infection
control precautions (eg hand hygiene, patient isolation, use of personal protective equipment) are essential,
particularly in hospitals.
Diagnosis of influenza
The most useful tests for diagnosis of influenza are rapid specific tests, such as nucleic acid amplification tests (eg
polymerase chain reaction [PCR]), performed on nose or throat swab samples. Use infection control precautions
when collecting samples from patients with suspected influenza. Clinical features alone may be adequate for
diagnosis during an influenza epidemic, when the probability of influenza is high.
Do not rule out influenza in vaccinated patients, because nonvaccine-related strains may be responsible, and,
especially in the elderly, seroconversion can be suboptimal.
Treatment of influenza for individual benefit

Treatment of influenza with a neuraminidase inhibitor, such as oseltamivir or zanamivir, has been associated with
fewer complications, hospital admissions and deaths due to influenza in systematic reviews of observational
studies. These studies included people at high risk of severe influenza or mortality due to influenza. By contrast,
systematic reviews of randomised controlled trials did not demonstrate such benefits; however, these studies
largely recruited healthy, low-risk adults and were underpowered to detect important outcomes such as
hospitalisation and mortality.
In otherwise healthy adults who have a low risk of complications, treatment with a neuraminidase inhibitor
reduces duration of influenza symptoms by less than 1 day on average, when treatment is started within 48 hours
of symptom onset. Such limited benefit must be balanced against the potential adverse effects of antiviral
treatment, including nausea, vomiting, headaches and neuropsychiatric events.
Antiviral therapy for influenza

Regardless of the duration of symptoms, offer treatment to patients:
with established complications

who need to be admitted to hospital for management of influenza (see also Additional considerations in
severe influenza)
with moderate-severity or high-severity community-acquired pneumonia, during the influenza season.
Consider treatment for individuals at higher risk of poor outcomes from influenza (see Box 2.27), despite
equivocal data to support benefit. Antiviral therapy is recommended for pregnant women after discussion of the
benefits and harms of therapy, because of the higher risk of poor outcomes from influenza in pregnancy (for
information on Australian categorisation of drugs in pregnancy, see Pregnancy and breastfeeding). Use of
antivirals outside of the higher-risk groups listed in Box 2.27 is not recommended, except to prevent disease
transmission in some circumstances (see Treatment of infuenza to prevent disease transmission).
If treatment for influenza is indicated, use:
1 oseltamivir orally, 12-hourly for 5 days

adult: 75 mg
child younger than 1 year: 3 mg/kg
child 1 year or older and less than 15 kg: 30 mg
child 1 year or older and 15 to 23 kg: 45 mg
child 1 year or older and more than 40 kg: 75 mg
OR
1 zanamivir (adult and child 5 years or older) 10 mg by inhalation using the device
provided, 12-hourly for 5 days.
Guidelines on the choice of neuraminidase inhibitors vary depending on local epidemiology and the resistance
profile of the circulating strain of influenza. Circumstances can change rapidly, so consult official surveillance data
for current information (see Australian Influenza Surveillance Report and Activity Updates [URL]). Epidemics can
be caused by strains resistant to neuraminidase inhibitors (usually oseltamivir). Resistance to a neuraminidase
inhibitor has also emerged during therapy.
Individuals at higher risk of poor outcomes from influenza (Box 2.27) [NB1]
The following groups of individuals are at higher risk of poor outcomes from influenza (eg complications, severe
influenza, hospitalisation, death):
adults aged 65 years or older

pregnant women
people with the following conditions:
heart disease
Down syndrome
obesity (body mass index [BMI] 30 kg/m2 or more)
chronic respiratory conditions
severe neurological conditions
immune compromise
other chronic illnesses
Aboriginal and Torres Strait Islander people of any age
children aged 5 years or younger
residents of aged-care facilities or long-term residential facilities
homeless people.
NB1: Higher-risk groups vary depending on the strain of influenza.
Additional considerations in severe influenza

Severe influenza can be defined as cases that require ventilatory or haemodynamic support. Although the World
Health Organization continues to recommend a higher dose of oseltamivir (150 mg orally, 12-hourly) for patients
with severe influenza, randomised controlled trials did not demonstrate clinical or virological benefit with double-
dose regimens. Furthermore, pharmacokinetic studies suggest that an oseltamivir dose of 75 mg orally, 12-hourly
provides adequate drug exposure in severe influenza, including in patients receiving renal replacement therapy,
extracorporeal membrane oxygenation (ECMO), or in patients who are obese.
A longer duration of neuraminidase inhibitor therapy can be considered in patients with severe influenza or who
are immunocompromised, despite the lack of clinical evidence.
Intravenous zanamivir and peramivir have been used in Australia for ventilated patients with severe influenza,
despite limited data to support their use.
Corticosteroids are not recommended as part of therapy for severe influenza.
Treatment of influenza to prevent disease transmission

Treatment with neuraminidase inhibitors may reduce the risk of viral shedding and disease transmission. Consider
treatment for patients with influenza who:
are in hospital or are residents of an aged-care facility

have household contacts that are at higher risk of poor outcomes from influenza (see Box 2.27).
The treatment regimens to prevent disease transmission are the same as those for Treatment of influenza for
individual benefit.
Prevention of influenza
Introduction
Vaccination or postexposure prophylaxis can be used to prevent acquisition of influenza for individual benefit or to
prevent disease transmission. Prevention of influenza is particularly important for individuals at higher risk of poor
outcomes from influenza (see Box 2.27) and in healthcare settings.
Postexposure prophylaxis for influenza

Neuraminidase inhibitors can be used for postexposure prophylaxis of influenza when vaccination is
contraindicated, or when the circulating strain is not covered by the annual vaccine. Start postexposure prophylaxis
as soon as possible after exposure, within 48 hours.
Consider postexposure prophylaxis for individuals at higher risk of poor outcomes from influenza (see Box 2.27).
Additionally, postexposure prophylaxis is appropriate for some people (eg patients in hospital, healthcare workers)
to prevent transmission after unprotected exposure to influenza. It can also be used to manage influenza outbreaks
in institutions (eg hospitals, aged-care facilities).
If postexposure prophylaxis for influenza is indicated, use:
1 oseltamivir orally, daily for 10 days
adult: 75 mg
child 1 year or older and less than 15 kg: 30 mg
child 1 year or older and more than 40 kg: 75 mg
OR
1 zanamivir (adult and child 5 years or older) 10 mg by inhalation using the device
provided, daily for 10 days.
Check the resistance profile of the circulating strain of influenza when choosing treatment. For children younger
than 1 year, seek expert advice.
For information about primary prophylaxis of influenza in immunocompromised patients in a high-risk unit (eg
haematopoietic stem cell transplant [HSCT] unit), see Influenza virus prophylaxis in immunocompromised adults
without HIV infection.
Influenza vaccination
In Australia, annual influenza vaccination is recommended for individuals at higher risk of poor outcomes from
influenza (see Box 2.27) and for some other patient groups. For more information, see the Australian
Immunisation Handbook [URL].
Key references
Treatment of influenza for individual benefit
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Lung abscess
Presentations of lung abscess
Lung abscesses are usually identified on chest X-ray imaging. For patients with suspected lung abscess, consider
differential diagnoses. Peripheral lung abscesses should be differentiated from loculated parapneumonic effusions
or empyema (see Investigations for lung abscess). In patients with a solitary cavitary pulmonary lesion, differential
diagnoses include:
consolidation surrounding pre-existing bullae in patients with emphysema

tumours
vasculitis
tuberculosis.
Lung abscess can be:
caused by aspiration of oral bacteria. Treatment is stratified by infection severity and, for severe infections,
the setting in which the infection was acquired. See:
Nonsevere lung abscess due to aspiration of oral bacteria
Community-acquired severe lung abscess due to aspiration of oral bacteria
Hospital-acquired severe lung abscess due to aspiration of oral bacteria
a metastatic complication of bacteraemia, particularly Staphylococcus aureus bacteraemia (see Lung abscess
due to Staphylococcus aureus) or septic jugular thrombophlebitis
a complication of pneumonia. Treatment choice depends on whether a pathogen is identified (see below).
Lung abscess due to aspiration of oral bacteria is more common in patients with periodontal disease. There may be
a history of aspiration or an aspiration event (see Table 2.57). Lung abscess due to aspiration of oral bacteria is
usually polymicrobial, and pathogens include anaerobic bacteria and microaerophilic streptococci. Malodorous
sputum or severe halitosis suggests the involvement of anaerobic bacteria.
Patients with lung abscess complicating necrotising or cavitary pneumonia may have infection with S. aureus,
Klebsiella pneumoniae or Nocardia species. Use directed therapy if S. aureus, K. pneumoniae or Nocardia
species is identified. For lung abscess complicating pneumonia when the pathogen is not known, manage the
patient as for lung abscess due to aspiration of oral bacteria, because pneumonia is usually caused by aspiration of
bacteria from the oropharynx.
When lung abscess is a metastatic complication of bacteraemia, multiple abscesses are often present, as are other
metastatic infections (eg right-sided endocarditis). Lung abscess due to S. aureus bacteraemia is often seen in
people with a history of injecting drugs. Septic jugular thrombophlebitis (Lemierre syndrome) can result in lung
abscess formation due to haematogenous spread of anaerobic bacteria (eg Fusobacterium necrophorum).
In children, lung abscess associated with staphylococcal pneumonia or S. aureus bacteraemia is more common
than lung abscess due to aspiration of oral bacteria.
Investigations for lung abscess

Patients requiring hospital assessment or admission because of lung abscess may require the following
investigations:
blood culture—if haematogenous spread from Staphylococcus aureus bacteraemia or septic jugular
thrombophlebitis is suspected, or the patient has sepsis or septic shock, collect three sets of blood samples
for culture before starting antibiotic therapy.
sputum Gram stain and culture—collect a sputum sample for Gram stain and culture before starting
antibiotic therapy. Ensure a good quality sample (eg presence of polymorphs, but few or no squamous
epithelial cells on microscopy) is collected.
pleural ultrasound—if loculated parapneumonic effusion is a differential diagnosis, perform a pleural
ultrasound. This test is usually superior to computed tomography (CT) in determining loculation.
CT of the chest—if the diagnosis is uncertain, perform CT of the chest to distinguish between a peripheral
lung abscess and empyema.
echocardiogram—if bacteraemia is suspected in an adult, perform a transthoracic echocardiogram (TTE) or
transoesophageal echocardiogram (TOE) to exclude endocarditis (see Assessment and monitoring of patients
with Staphylococcus aureus bacteraemia).
bronchoscopy—if an obstructing tumour or aspirated foreign body (eg tooth, peanut) is suspected, perform
bronchoscopy. In immunocompromised patients, bronchoscopy may be indicated to obtain samples for
extensive microbiological testing, because infection with unusual pathogens is possible (see Approach to
pneumonia in immunocompromised patients).
Nonsevere lung abscess due to aspiration of oral bacteria

A lung abscess can be classified as nonsevere if:
there is no evidence of bacteraemia or Staphylococcus aureus infection

the patient does not have sepsis or septic shock (for definitions, see here for adults or here for children).
Oral therapy is recommended for patients with nonsevere lung abscess who do not have systemic features of
infection (eg tachypnoea, hypoxaemia) or chest wall pain. Patients with systemic features of infection or chest wall
pain need hospital admission and, unless an antibiotic with good bioavailability is available, initial intravenous
therapy.
For patients with nonsevere lung abscess due to aspiration of oral bacteria (including patients with lung abscess
complicating pneumonia), who do not have systemic features of infection or chest wall pain, use:
amoxicillin 1 g (child: 25 mg/kg up to 1 g) orally or enterally, 8-hourly; see below for

advice on modification and duration of therapy
PLUS
below for advice on modification and duration of therapy.
therapy), use:

875+125 mg) orally or enterally, 12-hourly; see below for advice on modification and
duration of therapy [Note 1] [Note 2].
For patients with penicillin hypersensitivity who do not have systemic features of infection or chest wall pain,
use:
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally or enterally, 8-hourly; see
For patients with nonsevere lung abscess due to aspiration of oral bacteria (including patients with lung abscess
complicating pneumonia) with systemic features of infection or chest wall pain, use:
advice on modifying therapy and intravenous to oral switch
PLUS EITHER
below for advice on modification and duration of therapy
OR if oral or enteral metronidazole is not tolerated
below for advice on modifying therapy and intravenous to oral switch.
For patients with penicillin hypersensitivity who have systemic features of infection or chest wall pain, and can
tolerate oral or enteral therapy, use:
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally or enterally, 8-hourly; see
For patients with penicillin hypersensitivity who have systemic features of infection or chest wall pain, and
cannot tolerate oral or enteral therapy, use:
for advice on modifying therapy and intravenous to oral switch
OR
modifying therapy and intravenous to oral switch.
Modifying therapy: modify therapy based on the results of culture and susceptibility testing. If an anaerobic
pathogen is identified by culture, the infection is often polymicrobial—seek expert advice on adjusting therapy.
Intravenous to oral switch: if intravenous therapy is used initially, switch to oral or enteral therapy once the
patient has improved (see Box 2.35 for guidance on when to switch to oral therapy); if a pathogen has not been
identified, use the regimens recommended for patients who do not have systemic features of infection or chest wall
pain (see dosage above).
Duration of therapy: the total duration of therapy is usually 3 to 4 weeks (intravenous + oral). For large abscesses
with persistent fluid, a longer duration of therapy may be required—seek expert advice. Consider monitoring
serum C-reactive protein (CRP) for the response to therapy.
If the patient is not improving with antibiotic therapy, review the diagnosis and antibiotic choice. If lung abscess
remains the likely diagnosis, seek expert advice from a respiratory physician or thoracic surgeon on the
appropriateness of surgery or percutaneous drainage. These interventions are not routinely performed because of
the potential for bronchopleural fistula formation when an intercostal catheter is inserted into the abscess;
antibiotic therapy alone is often sufficient.
Note 1: Consider giving additional amoxicillin (eg 25 mg/kg up to 1 g orally or enterally, at midday) when
prescribing amoxicillin+clavulanate for patients with a large lung abscess, or lung abscess due to Streptococcus
pneumoniae.
Community-acquired severe lung abscess due to aspiration of oral

bacteria
A lung abscess is considered to be severe if the patient has sepsis or septic shock (for definitions, see here for
adults or here for children). Start antibiotic therapy within 1 hour of the patient presenting to medical care or, for a
ward-based patient, developing sepsis or septic shock; antibiotics should be given immediately after appropriate
If severe lung abscess occurs in a patient who has been in hospital for longer than 48 hours, treat as for Hospital-
acquired severe lung abscess due to aspiration of oral bacteria.
When treating a patient with severe community-acquired lung abscess due to aspiration of oral bacteria (including
patients with lung abscess complicating pneumonia), consider both the recommendations in this topic and the
management advice in the Community-acquired pneumonia in adults or Community-acquired pneumonia in
children topic. Additional treatment may be needed for:
influenza (see here for adults or here for children)

Staphylococcus aureus (see here for adults or here for children)
Pseudomonas aeruginosa (see here for adults or here for children).
Atypical pathogens are unlikely to cause lung abscess so the addition of azithromycin is not required.
For patients with severe community-acquired lung abscess due to aspiration of oral bacteria use:
1 amoxicillin+clavulanate intravenously; see below for advice on modifying therapy and

intravenous to oral switch
adult: 1+0.2 g 6-hourly [Note 3]
child 3 months or older: 25+5 mg/kg up to 1+0.2 g 6-hourly [Note 4] [Note 5]
1 metronidazole 500 mg (child: 12.5 mg/kg up to 500 mg) intravenously, 12-hourly; see
below for advice on modifying therapy and intravenous to oral switch
PLUS EITHER
patients with septic shock or requiring intensive care support, use ceftriaxone 1 g
(child 1 month or older: 50 mg/kg up to 1 g) intravenously, 12-hourly. See below for
OR

septic shock or requiring intensive care support, use cefotaxime 2 g (child: 50 mg/kg
up to 2 g) intravenously, 6-hourly. See below for advice on modifying therapy and
If the source of the lung abscess is unclear and the patient has septic shock, add gentamicin and vancomycin to
the above regimens while awaiting blood culture results:

principles of use [Note 6]. See below for advice on modifying therapy and intravenous to
oral switch
PLUS

advice on modifying therapy and intravenous to oral switch.
For patients with severe community-acquired lung abscess due to aspiration of oral bacteria who have immediate
nonsevere or delayed nonsevere hypersensitivity to penicillins, use the ceftriaxone or cefotaxime-based regimen,
with or without gentamicin plus vancomycin, as above.
meropenem 1 g (child: 20 mg/kg up to 1 g) intravenously, 8-hourly [Note 11]; see below

PLUS if the patient has septic shock

Modifying therapy: modify therapy based on the results of culture and susceptibility testing. If Gram-positive
cocci in clusters are identified by Gram stain of a blood sample, see Staphylococcus aureus bacteraemia. If an
anaerobic pathogen is identified by culture, the infection is often polymicrobial. If the anaerobe is identified in a
blood sample, see Lung abscess due to septic jugular thrombophlebitis for ongoing treatment. If the anaerobe is
identified in a respiratory tract sample, seek expert advice on adjusting therapy.
Intravenous to oral switch: once the patient has improved, switch to oral or enteral therapy (see Box 2.35 for
guidance on when to switch to oral therapy). Use:
amoxicillin 1 g (child: 25 mg/kg up to 1 g) orally or enterally, 8-hourly; see also advice on

modification and duration of therapy
PLUS
also advice on modification and duration of therapy.
therapy), use:

875+125 mg) orally or enterally, 12-hourly; see also advice on modification and duration
12-hourly; see also advice on modification and duration of therapy [Note 14]
PLUS
severe or delayed severe hypersensitivity to penicillins, choosing a safe and effective regimen is complex. Review
the results of culture and susceptibility testing. Treatment options may include clindamycin with or without
ciprofloxacin—seek expert advice.
the potential for bronchopleural fistula formation when an intercostal catheter is inserted into the abscess;
intravenous amoxicillin+clavulanate. A reasonable alternative regimen for adults with lung abscess is 2+0.2 g
intravenously, 8-hourly.
intravenous amoxicillin+clavulanate. For children who weigh 40 kg or more who have a lung abscess, a
reasonable alternative regimen is 2+0.2 g intravenously, 8-hourly.
calculate the dose.
function.
Note 9: If the patient is obese, use adjusted body weight (see Box 2.46) to calculate the dose.
treatment options.
pneumoniae.
Hospital-acquired severe lung abscess due to aspiration of oral bacteria

A lung abscess is considered to be severe if the patient has sepsis or septic shock (for definitions, see here for
adults or here for children). Start antibiotic therapy within 1 hour of the patient presenting to medical care or, for a
ward-based patient, developing sepsis or septic shock; antibiotics should be given immediately after appropriate
If severe lung abscess occurs in a patient who is not in hospital, or has been in hospital for less than 48 hours, see
Community-acquired severe lung abscess due to aspiration of oral bacteria.
When treating a patient with severe hospital-acquired lung abscess due to aspiration of oral bacteria (including
patients with lung abscess complicating pneumonia), consider both the recommendations in this topic and the
management advice in the Hospital-acquired pneumonia or Ventilator-associated pneumonia topic. Additional
treatment may be needed for:
Staphylococcus aureus (see here for hospital-acquired pneumonia or here for ventilator-associated
pneumonia)
Gram-negative bacteria (see here for hospital-acquired pneumonia or here for ventilator-associated
pneumonia).
For patients with severe hospital-acquired lung abscess due to aspiration of oral bacteria, use:

hourly; see below for advice on modifying therapy and intravenous to oral switch.
For patients with septic shock, add gentamicin plus vancomycin to the empirical regimen until blood culture
results are available:

principles of use [Note 15]. See below for advice on modifying therapy and intravenous to
oral switch
PLUS

For patients with severe hospital-acquired lung abscess due to aspiration of oral bacteria who have immediate
nonsevere or delayed nonsevere hypersensitivity to penicillins, replace piperacillin+tazobactam with cefepime
plus metronidazole. For patients with septic shock, add gentamicin plus vancomycin (see dosage above) to
cefepime plus metronidazole. Use:
cefepime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly; see below for advice on
modifying therapy and intravenous to oral switch
PLUS
below for advice on modifying therapy and intravenous to oral switch.
meropenem 1 g (child: 20 mg/kg up to 1 g) intravenously, 8-hourly [Note 20]; see below

PLUS if the patient has septic shock

Modifying therapy: modify therapy based on the results of culture and susceptibility testing. If Gram-positive
cocci in clusters are identified by Gram stain of a blood sample, see Staphylococcus aureus bacteraemia. If an
anaerobic pathogen is identified by culture, the infection is often polymicrobial. If the anaerobe is identified in a
blood sample, see Lung abscess due to septic jugular thrombophlebitis for ongoing treatment. If the anaerobe is
identified in a respiratory tract sample, seek expert advice on adjusting therapy.
Intravenous to oral switch: once the patient has improved, switch to oral or enteral therapy (see Box 2.35 for

12-hourly; see also advice on modification and duration of therapy [Note 23]
PLUS
severe or delayed severe hypersensitivity to penicillins, choosing a safe and effective regimen is complex. Review
the results of culture and susceptibility testing. Treatment options may include clindamycin with or without
ciprofloxacin—seek expert advice.
Duration of therapy: the total duration of therapy (intravenous + oral) is usually 3 to 4 weeks. For large abscesses
the potential for bronchopleural fistula formation when an intercostal catheter is inserted into the lung abscess;
calculate the dose.
function.
Note 18: If the patient is obese, use adjusted body weight (see Box 2.46) to calculate the dose.
treatment options.
pneumoniae.
Lung abscess due to septic jugular thrombophlebitis

Lung abscess can be a complication of septic jugular thrombophlebitis (Lemierre syndrome). The abscess develops
because of haematogenous spread of anaerobic bacteria (eg Fusobacterium necrophorum), but the infection is
usually polymicrobial. Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]) can also cause
septic jugular thrombophlebitis.
For patients with lung abscess associated with septic jugular thrombophlebitis, seek expert advice for nonantibiotic
management. In addition to antibiotic therapy, surgical drainage and debridement is often needed—early surgical
consultation is recommended. The role of anticoagulation is controversial. If echocardiography confirms
endocarditis, see Approach to managing infective endocarditis and seek expert advice for treatment choice.
For patients with sepsis or septic shock (for definitions, see here for adults or here for children), start antibiotic
therapy within 1 hour of the patient presenting to medical care or, for a ward-based patient, developing sepsis or
septic shock; antibiotics should be given immediately after appropriate samples are taken for culture. For
nonantibiotic management of sepsis or septic shock, see Early intervention for sepsis or septic shock.
For initial management of patients with septic jugular thrombophlebitis, including patients with associated lung
abscess, while awaiting the results of culture and susceptibility testing, use:
1 amoxicillin+clavulanate intravenously; see below for advice on modifying therapy and

intravenous to oral switch
adult: 1+0.2 g 8-hourly. If the patient has an abscess, or has septic shock or requires
intensive care support, use a dose of 1+0.2 g 6-hourly [Note 24]
child 3 months or older: 25+5 mg/kg up to 1+0.2 g 8-hourly. If the child has an abscess, or
has septic shock or requires intensive care support, use a dose of 25+5 mg/kg up to 1+0.2
g 6-hourly [Note 25] [Note 26]
1 metronidazole 500 mg (child: 12.5 mg/kg up to 500 mg) intravenously, 12-hourly; see
below for advice on modifying therapy and intravenous to oral switch
PLUS EITHER

patients with septic shock or requiring intensive care support, use ceftriaxone 1 g
(child 1 month or older: 50 mg/kg up to 1 g) intravenously, 12-hourly. See below for
OR
septic shock or requiring intensive care support, use cefotaxime 2 g (child: 50 mg/kg
up to 2 g) intravenously, 6-hourly. See below for advice on modifying therapy and
If the patient has septic shock, add to the above regimens:

For initial therapy for patients with septic jugular thrombophlebitis (including patients with associated lung
abscess) who have immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use the ceftriaxone
or cefotaxime-based regimen, with or without vancomycin, as above.
For initial therapy for patients with immediate severe or delayed severe hypersensitivity to penicillins who have
septic jugular thrombophlebitis (including patients with associated lung abscess) but do not have septic shock, use:
OR
For initial therapy for patients with immediate severe or delayed severe hypersensitivity to penicillins who have
septic jugular thrombophlebitis (including patients with associated lung abscess) and have septic shock, use:
meropenem 1 g (child: 20 mg/kg up to 1 g) intravenously, 8-hourly; see below for advice

on modifying therapy and intravenous to oral switch [Note 27]
PLUS

Modifying therapy: modify therapy as soon as additional information is available (eg results of Gram stain,
culture and susceptibility testing). If Gram-positive cocci in clusters are identified by Gram stain of a blood
sample, see Staphylococcus aureus bacteraemia. If S. aureus is not identified, stop vancomycin.
If an anaerobic pathogen (eg F. necrophorum) is identified by blood culture, the infection is often polymicrobial.
Suitable regimens for ongoing therapy for patients with septic jugular thrombophlebitis (including patients with
associated lung abscess) due to anaerobic pathogens include the amoxicillin+clavulanate, ceftriaxone or
cefotaxime plus metronidazole, clindamycin, or lincomycin regimens above.
Intravenous to oral switch: once the patient has improved, switch to oral (or enteral) therapy (see Box 2.35 for
amoxicillin 1 g (child: 25 mg/kg up to 1 g) orally or enterally, 8-hourly; see also advice on

modification and duration of therapy
PLUS
therapy), use:

For patients with septic jugular thrombophlebitis (including patients with associated lung abscess) who are
hypersensitive to penicillins, use:
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally or enterally, 8-hourly; see also
advice on modification and duration of therapy.
intravenous amoxicillin+clavulanate. For adults with an abscess, or with septic shock or requiring intensive care
support, a reasonable alternative regimen is 2+0.2 g intravenously, 8-hourly.
intravenous amoxicillin+clavulanate. For children who weigh 40 kg or more who have an abscess, or have septic
shock or require intensive care support, a reasonable alternative regimen is 2+0.2 g intravenously, 8-hourly.
prescribing amoxicillin+clavulanate for patients with a large lung abscess.
Lung abscess due to Staphylococcus aureus

Staphylococcus aureus lung abscess can be a complication of staphylococcal pneumonia or S. aureus bacteraemia.
If S. aureus is confirmed or strongly suspected as the cause of lung abscess, assess the likely source of infection. If
the patient has a recent history of pneumonia, initial management as for staphylococcal pneumonia is
recommended while awaiting the results of blood culture. In people with a history of injecting drugs or an
intravascular device in situ, initial management as for Staphylococcus aureus bacteraemia is recommended.
If Gram-positive cocci in clusters are identified by Gram stain of a blood sample, see Staphylococcus aureus
bacteraemia for management and duration of therapy.
Duration of therapy for lung abscess due to staphylococcal pneumonia: the total duration of therapy is usually
3 to 4 weeks (intravenous + oral). For large abscesses with persistent fluid, a longer duration of therapy may be
required—seek expert advice. Consider monitoring serum C-reactive protein (CRP) for the response to therapy.
Lung abscess due to Klebsiella pneumoniae

For treatment of lung abscess due to Klebsiella pneumoniae, see Nonmultidrug-resistant Enterobacteriaceae
pneumonia. However, extend the treatment duration (as below).
Lung abscess due to nocardiosis

For treatment of lung abscess due to Nocardia species, see Nocardiosis.
Key references
Chan PC, Huang LM, Wu PS, Chang PY, Yang TT, Lu CY, et al. Clinical management and outcome of childhood lung
abscess: a 16-year experience. J Microbiol Immunol Infect 2005;38(3):183–8.
Jariwala RH, Srialluri S, Huang MZ, Boppana SB. Methicillin-resistant Staphylococcus aureus as a cause of Lemierre's
syndrome. Pediatr Infect Dis J 2017;36(4):429–31.
Kuhajda I, Zarogoulidis K, Tsirgogianni K, Tsavlis D, Kioumis I, Kosmidis C, et al. Lung abscess-etiology, diagnostic
and treatment options. Ann Transl Med 2015;3(13):183.
Dis 2016;16(8):e139–52.
Tan TQ, Seilheimer DK, Kaplan SL. Pediatric lung abscess: clinical management and outcome. Pediatr Infect Dis J
1995;14(1):51–5.
Yazbeck MF, Dahdel M, Kalra A, Browne AS, Pratter MR. Lung abscess: update on microbiology and management.
Am J Ther 2014;21(3):217–21.
Tuberculosis
Introduction to tuberculosis
Tuberculosis (TB) is uncommon in Australia. It should be considered in high-risk patient groups (eg people from
high-prevalence countries), and anyone with an undiagnosed febrile or wasting illness, or a persistent cough.
Primary Mycobacterium tuberculosis infection is usually contained by the immune system (see Latent
tuberculosis), but it may produce active disease in the form of a primary tuberculous pleural effusion, or spread to
produce miliary (disseminated) or central nervous system TB. At least 90% of individuals infected with M.
tuberculosis do not develop active disease.
Postprimary disease, caused by reactivation of latent TB, usually occurs within 5 years of initial infection, and
most commonly produces pulmonary TB.
TB can produce a wide range of clinical syndromes in addition to the classic upper lobe cavitary pulmonary
infection. Risk factors for extrapulmonary TB include childhood, HIV infection and immune compromise.
Investigations for tuberculosis

Initial investigations for suspected pulmonary tuberculosis (TB) include chest X-ray and sputum microscopy
with acid-fast (Ziehl-Neelsen) stain. Sputum culture and susceptibility testing are used to confirm the diagnosis
and check for drug resistance.
Children younger than 10 years old with pulmonary TB are rarely able to produce a sputum sample, so early
morning gastric aspirates or induced sputum are often used for culture and diagnosis.
Rapid molecular testing (eg nucleic acid amplification testing [eg polymerase chain reaction (PCR)]) for
rifampicin resistance is recommended if there is a risk of multidrug-resistant TB (MDR-TB) (see Drug resistance
in tuberculosis), and should be performed on all smear-positive sputum samples regardless of risk of multidrug-
resistant TB.
The diagnosis of extrapulmonary TB is challenging and requires investigations and sampling directed at the
likely affected organ system. It is important to notify radiologists and microbiology laboratory staff that TB is
being considered.
Approach to managing tuberculosis

Key requirements when managing patients with TB
Management of patients with tuberculosis (TB) requires:
close consultation with specialists who have appropriate training and experience
reference to local policies and guidelines
prompt notification of cases to the local public health authority [Note 1]
contact tracing, performed by trained professionals liaising closely with treating physicians.
For more information on the management of TB, refer to the National Tuberculosis Advisory Committee (NTAC)
Tuberculosis Information Portal [URL], which includes links to the state and territory TB websites.
are available here.
Before starting therapy
Before starting therapy for TB:
document the patient’s weight

assess liver function (perform liver biochemistry, discuss alcohol consumption and review hepatotoxic
medications)
assess kidney function
assess visual acuity and colour vision
perform full blood count
perform HIV testing
perform viral hepatitis (B and C) serology.
Discuss contraception with women of childbearing age, including the potential for drug interactions between
tuberculosis therapy and oral contraceptives.
Institute infection control measures for patients with pulmonary TB.
Infection control for pulmonary tuberculosis
Infection control is particularly important for pulmonary TB because it is the predominant infectious form of TB.
Patients with TB caused by fully drug-susceptible bacteria may be noninfectious after 2 weeks of daily treatment
with standard short-course therapy, but this should not be assumed. Assess whether the patient is likely to be
infectious beyond 2 weeks on a case-by-case basis. In particular, precautions against airborne transmission may be
required for longer than 2 weeks in patients:
with extensive cavitation

with confirmed or likely drug-resistant TB
who are smear-positive
who do not improve after 2 weeks of therapy.
Children younger than 10 years of age are usually considered noninfectious. Extrapulmonary TB is not an
infection risk in the absence of lung disease.
Treatment adherence and directly observed therapy (DOT)

Patient-centred case management helps patients to adhere to drug therapy, which is key to the successful treatment
of TB. Strict adherence is essential to:
achieve a satisfactory treatment outcome

reduce the risk of transmission
reduce the risk of relapse
prevent the emergence of drug resistance.
Prolonged treatment durations, complex drug regimens, and adverse effects associated with TB therapy often have
a significant impact on patient adherence. Adherence is improved by comprehensive patient and family education
using verbal and written information, close follow-up, and provision of directly observed therapy (DOT) if
appropriate.
In directly observed therapy, trained healthcare professionals supervise administration of TB medication. Directly
observed therapy is indicated for patients likely to be nonadherent; it may be required in the early stages of
treatment or throughout treatment. Assess the need for directly observed therapy on a case-by-case basis. Directly
observed therapy should be used for children with TB when the ability of caregivers to administer medication is
assessed to be unreliable. Directly observed therapy is also recommended for patients with drug-resistant TB, and
when intermittent (three-times-weekly) therapy is used.
Some patients require directly observed therapy in the initial stage of treatment only—in the absence of adverse
drug effects, the need for directly observed therapy can diminish as patients become familiar with their drug
regimen. Continue directly observed therapy for as long as there is concern about adherence.
Regardless of whether directly observed therapy is used, it is important that the treating team maintains close
contact with the patient to monitor adherence and identify adverse effects early.
Drug resistance in tuberculosis
Multidrug regimens are necessary in all patients with TB to cover the possibility of pre-existing drug resistance
and to prevent the emergence of resistant bacteria.
Isoniazid resistance is present in 10% of Mycobacterium tuberculosis isolates in Australia, predominantly in

patients born overseas and in those who have previously been treated for TB. For patients with isoniazid-
monoresistant TB, seek advice on treatment from the local TB authority—standard short-course therapy is not
appropriate in these patients.
Standard short-course therapy is not appropriate for patients with isoniazid-monoresistant TB.
Multidrug-resistant TB (MDR-TB), defined as TB resistant to at least isoniazid and rifampicin, is uncommon in
Australia (about 1 to 3% of isolates) but is common in many other parts of the world. It should be suspected in:
people from countries with high rates of multidrug-resistant TB

patients in whom treatment has failed
patients who do not respond to treatment (either clinically or bacteriologically) within 3 months
contacts of patients with multidrug-resistant TB.
Rapid molecular testing (eg nucleic acid amplification testing [eg polymerase chain reaction (PCR)]) for
rifampicin resistance is recommended if there is a risk of multidrug-resistant TB. If rifampicin resistance is
detected, ensure that laboratory staff perform second-line drug susceptibility testing and, if indicated, rapid
molecular testing for second-line drug resistance.
For more information about drug-resistant TB, see the World Health Organization website.
Standard short-course therapy for tuberculosis

Overview of standard short-course therapy for tuberculosis
Modern regimens for fully drug-susceptible tuberculosis (TB) have an initial cure rate of over 98% and a five-year
relapse rate of under 1%.
Standard short-course therapy requires 2 months of treatment with isoniazid, rifampicin, ethambutol and
pyrazinamide (the ‘intensive phase’), followed by a further 4 months of treatment with isoniazid and rifampicin
(the ‘continuation phase’) [Note 2]. Quinolones (eg moxifloxacin) are not part of standard short-course therapy and
should not be used for fully drug-susceptible TB, except in patients with tuberculous meningitis and those with
kidney or liver impairment.
Standard short-course therapy is only suitable if:
the bacteria are susceptible to isoniazid, rifampicin and pyrazinamide (for drug-resistant infection, see
Treatment of drug-resistant tuberculosis)
the patient tolerates and adheres to the regimen
tuberculous meningitis or other central nervous system TB, and complicated musculoskeletal TB, have been
excluded
extensive cavitation is not present on the initial chest X-ray.
Use of daily and intermittent drug regimens:
For pulmonary TB, use the daily regimen for at least the first 2 months of therapy [Note 3]. The intermittent
(three-times-weekly) regimen can be used in the continuation phase on the advice of a TB specialist, but
only after the patient demonstrates a clear clinical response to 2 months of daily therapy.
Whenever it is used, intermittent therapy is generally restricted to adults, and should only be considered if
directly observed therapy (DOT) is available.
For extrapulmonary TB, it may be reasonable to start intermittent therapy earlier in the treatment course (ie
during the intensive phase) in selected patients with paucibacillary disease (eg TB lymphadenopathy).
Use the daily regimen for the entire treatment course in HIV-infected patients, multidrug-resistant TB, or
when there is no smear conversion after 2 months of treatment.
Monitor response to treatment, and extend the duration of therapy if the response is not satisfactory. Monitor the
patient’s weight and adjust drug doses if necessary. For more information, see Monitoring tuberculosis therapy.
Additional information on management of tuberculosis is covered in the following sections:
Corticosteroid use in tuberculosis

Treatment of tuberculous meningitis
Specific considerations in extrapulmonary tuberculosis
Tuberculosis management in special patient groups.
Note 2: Ethambutol should be discontinued once susceptibility to isoniazid and rifampicin is confirmed, even if
this is before 2 months of therapy have elapsed; continue ethambutol if susceptibility results are not available at
2 months.
Note 3: Intermittent therapy (twice or thrice weekly therapy) is no longer endorsed by the World Health
Organization due to higher failure rates compared with daily therapy, particularly when intermittent therapy is
used in the intensive phase.
Daily treatment regimen
Compared with adults, higher mg/kg doses of some tuberculosis drugs are needed in children to achieve effective
serum concentrations.
For the daily regimen, use:
isoniazid (adults and children) 10 mg/kg up to 300 mg orally, daily for 6 months [Note 4]
PLUS
rifampicin 10 mg/kg up to 600 mg (child younger than 14 years and more than 50 kg: 600
mg; child younger than 14 years and less than 50 kg: 15 mg/kg up to 450 mg) orally, daily
for 6 months
PLUS
ethambutol 15 mg/kg up to 1200 mg (child younger than 14 years: 20 mg/kg up to 1200

mg) orally, daily for 2 months [Note 5]
PLUS
pyrazinamide 25 mg/kg up to 2 g (child younger than 14 years: 35 mg/kg up to 2 g) orally,

daily for 2 months [Note 6] [Note 7].
The tables of practical doses for tuberculosis therapy for adults and children show daily doses that have been
calculated based on weight, then rounded to a practical dose for the drug preparations available in Australia. Box
2.28 shows tuberculosis drug preparations available in Australia. Oral liquid formulations of isoniazid, ethambutol
and pyrazinamide are not commercially available; for formulation options for children or people with swallowing
difficulties, see the Don’t Rush to Crush Handbook, published by the Society of Hospital Pharmacists of Australia
[URL].
Intravenous formulations of isoniazid [Note 8] and rifampicin are available and should be used in critically ill
patients when oral therapy is not possible.
Pyridoxine is no longer recommended routinely for all patients taking isoniazid, but should be used in patients at
risk of peripheral neuropathy (eg pregnant women, people with HIV infection, diabetes, malnutrition, chronic
kidney disease, a history of hazardous alcohol use, or advanced age). Children on isoniazid therapy should receive
pyridoxine if they are exclusively breastfed, have HIV infection or are malnourished. Children being breastfed by
a mother who is taking isoniazid do not routinely require pyridoxine.
Note 4: In patients who are at risk of peripheral neuropathy, administer pyridoxine (adult: 25 mg; child: 6.25 to
12.5 mg) orally, with each dose of isoniazid.
Note 5: Discontinue ethambutol once susceptibility to isoniazid and rifampicin is confirmed, even if this is
before 2 months of therapy have elapsed; continue ethambutol if susceptibility results are not available at 2
months.
Note 6: Pyrazinamide should only be discontinued after at least 2 months of treatment have elapsed AND
susceptibility to isoniazid and rifampicin is confirmed.
Note 7: Pyrazinamide is not marketed in Australia but is available via the Special Access Scheme.
Note 8: Isoniazid injection is not marketed in Australia but is available via the Special Access Scheme.
Intermittent (three-times-weekly) treatment regimen
For discussion about intermittent therapy and when it may be used, see Overview of standard short-course therapy
for tuberculosis.
If a switch to intermittent therapy is appropriate for an adult with TB, continue therapy with the following
regimen:
isoniazid 10 mg/kg up to 900 mg orally, 3 times weekly to complete a total of 6 months’

therapy (daily + intermittent therapy) [Note 9]
PLUS
rifampicin 10 mg/kg up to 600 mg orally, 3 times weekly to complete a total of 6 months’

therapy (daily + intermittent therapy)
PLUS (if required—see [Note 10])
ethambutol 30 mg/kg up to 2400 mg orally, 3 times weekly
PLUS (if required—see [Note 11])
pyrazinamide 35 mg/kg up to 3 g orally, 3 times weekly [Note 12].
Table 2.61 shows three-times-weekly doses for adults that have been calculated based on weight, then rounded to a
practical dose for the drug preparations available in Australia.
Note 9: In adults who are at risk of peripheral neuropathy, administer pyridoxine 25 mg orally, with each dose of
isoniazid.
Note 10: Discontinue ethambutol once susceptibility to isoniazid and rifampicin is confirmed, even if this is
before 2 months of therapy have elapsed; continue ethambutol if susceptibility results are not available at 2
months.
Note 11: Pyrazinamide should only be discontinued after at least 2 months of treatment have elapsed AND
susceptibility to isoniazid and rifampicin is confirmed.
Note 12: Pyrazinamide is not marketed in Australia but is available via the Special Access Scheme.
Practical doses for tuberculosis therapy
Practical doses for tuberculosis therapy—Daily oral regimen: Adults (Table 2.59)
Drug Adult dose Recommended daily dose (mg) by patient weight [NB1]
30 kg 40 kg 50 kg 60 kg 70 kg 80 kg or
more
isoniazid [NB2] 10 mg/kg up to 300 mg 300 300 300 300 300 300
rifampicin 10 mg/kg up to 600 mg 300 450 600 600 600 600
ethambutol
15 mg/kg up to 1200 mg 400 800 800 1200 1200 1200
[NB3]
pyrazinamide 25 mg/kg up to 2000 mg 750 1000 1500 1500 2000 2000
NB1: Doses have been calculated based on weight and rounded to a practical dose for the preparations available in Australia (see Box 2.28). For duration
of therapy, see Standard short-course therapy.
NB2: In adults who are at risk of peripheral neuropathy, administer pyridoxine 25 mg orally with each dose of isoniazid.
NB3: Ethambutol doses are rounded to the nearest 400 mg tablet; if tablets are halved, doses can be rounded to the nearest 200 mg.
Practical doses for tuberculosis therapy—Daily oral regimen: Children younger than 14 years
(Table 2.60)
Drug Child dose Recommended daily dose (mg) by patient weight [NB1]
5 kg 10 kg 15 kg 20 kg 25 kg 30 kg 35 40 50
kg kg kg
isoniazid 10 mg/kg up to 300
50 100 150 200 250 300 300 300 300
[NB2] mg
less than 50 kg: 15
mg/kg up to 450 mg
rifampicin 80 150 220 300 400 450 450 450 600
50 kg or more: 600
mg
20 mg/kg up to
ethambutol 100 200 300 400 500 600 700 800 1000
1200 mg
35 mg/kg up to
pyrazinamide 175 350 500 750 750 1000 1250 1500 1750
2000 mg
NB1: Doses have been calculated based on weight and rounded to a practical dose for the preparations available in Australia (see Box 2.28). Liquid
formulations are usually preferred for younger children, while older children can often swallow capsules or tablets. Oral liquid formulations of isoniazid,
ethambutol and pyrazinamide are not commercially available; for formulation options for children, see the Don’t Rush to Crush Handbook published by
the Society of Hospital Pharmacists of Australia [URL]. For duration of therapy, see Standard short-course therapy.
NB2: In children who are at risk of peripheral neuropathy, administer pyridoxine 6.25 to 12.5 mg orally with each dose of isoniazid.
Practical doses for tuberculosis therapy—Intermittent oral regimen (three-times-weekly): Adults

(Table 2.61)
Drug Adult dose Recommended three-times-weekly dose (mg) by patient weight

[NB1]
30 kg 40 kg 50 kg 60 kg 70 kg 80 kg 90
kg
10 mg/kg up to 900
isoniazid [NB2] 300 400 500 600 700 800 900
mg
10 mg/kg up to 600
rifampicin 300 450 600 600 600 600 600
mg
30 mg/kg up to
ethambutol [NB3] 800 1200 1600 2000 2000 2400 2400
2400 mg
35 mg/kg up to
pyrazinamide 1000 1500 1750 2000 2500 3000 3000
3000 mg
NB1: Doses have been calculated based on weight and rounded to a practical dose for the preparations available in Australia (see Box 2.28). For duration
of therapy, see Standard short-course therapy.
NB2: In adults at risk of peripheral neuropathy, administer pyridoxine 25 mg orally with each dose of isoniazid.
NB3: Ethambutol doses are rounded to the nearest 400 mg tablet; if tablets are halved, doses can be rounded to the nearest 200 mg.
Tuberculosis drug preparations available in Australia (Box 2.28)
isoniazid
100 mg scored tablets

300 mg tablets available via the Special Access Scheme
an oral liquid formulation is not commercially available; for formulation options for children or people
with swallowing difficulties, see the Don’t Rush to Crush Handbook [NB1]
500 mg injection available via the Special Access Scheme
rifampicin
150 mg and 300 mg capsules

600 mg tablets
20 mg/mL syrup
600 mg injection
ethambutol
400 mg tablets
100 mg tablets available via the Special Access Scheme
pyrazinamide
500 mg scored tablets available via the Special Access Scheme

NB1: The Don’t Rush to Crush Handbook is published by the Society of Hospital Pharmacists of Australia [URL].
Treatment of tuberculous meningitis (TB meningitis)

The treatment of tuberculous meningitis (TB meningitis) is complicated—seek expert advice.
Emerging pharmacokinetic evidence suggests that many first-line tuberculosis drugs do not sufficiently penetrate
the cerebrospinal fluid (CSF), with inadequate concentrations reached in brain tissue compared with the lung.
Consequently, there is uncertainty about the appropriateness of standard drug dosage regimens for TB meningitis.
In particular, many specialists replace ethambutol with an alternative drug that has better CSF penetration, such as
ethionamide or moxifloxacin. Pharmacokinetic studies have also shown relatively poor CSF penetration of
rifampicin, so higher doses (eg 20 mg/kg) should be considered when used to treat TB meningitis. The use of
intravenous rifampicin in the first weeks of treatment increased survival in a small pilot study [Note 13].
Treatment with corticosteroids is recommended in the first 6 to 8 weeks of treatment of TB meningitis—see

Corticosteroid use in tuberculosis.
Treatment for TB meningitis is continued for 12 months.
Note 13: Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, et al. Intensified regimen
containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2
trial. Lancet Infect Dis 2013;13(1):27-35. [URL]

Extrapulmonary tuberculosis (TB) is not an infection risk in the absence of lung disease.
Many forms of extrapulmonary TB (eg lymph node, pleural, genitourinary, musculoskeletal) can be treated with
standard short-course therapy, but expert advice is required.
Clinical trials to evaluate duration of therapy in extrapulmonary TB are lacking. Current guidelines suggest the
standard duration of short-course therapy (ie 6 months) is sufficient for most forms of extrapulmonary TB
including miliary TB, and in those with HIV co-infection. An exception is TB meningitis, when treatment is
extended to 12 months. Courses longer than 6 months may also be required in complicated musculoskeletal
disease (eg Pott’s disease). Consider extending the duration of treatment in patients with TB that is slow to
respond, regardless of the site of infection.
Adjunctive surgical management (eg for relief of ureteric obstruction or spinal cord compression) is sometimes
required.
Lymph nodes infected with TB (tuberculosis lymphadenitis) can increase in size or form sinuses during and after
treatment—this response is an immunological reaction to dead bacilli and does not indicate treatment failure.
Treatment of drug-resistant tuberculosis

For discussion about risk groups and testing for drug-resistant tuberculosis (TB), see Drug resistance in
tuberculosis.
Treatment of drug-resistant TB must be under the supervision of an expert. Second-line drugs are necessary and
treatment duration is usually extended to 18 to 24 months. Directly observed therapy is recommended to minimise
the development of further drug resistance, particularly extensively drug-resistant TB (XDR-TB), defined as
multidrug-resistant TB (MDR-TB) with additional resistance to quinolones and second-line parenteral drugs.
Treatment regimens for multidrug-resistant TB usually include an aminoglycoside—amikacin is preferred but

kanamycin and capreomycin have also been used.

Corticosteroids may have beneficial effects in patients with tuberculosis (TB) by suppressing harmful reactive
immune responses such as immune reconstitution inflammatory syndrome, which can lead to compressive oedema.
Use corticosteroids as part of tuberculosis treatment in severely ill patients with extensive TB (eg those requiring
intensive care support or those with respiratory failure or hypotension), and in the first 6 to 8 weeks of treatment of
tuberculous meningitis and pericarditis.
Rifampicin increases the metabolism of (endogenous and exogenous) corticosteroids, reducing their activity. The
corticosteroid dosages below are recommended when the patient is receiving rifampicin; for patients not receiving
rifampicin, lower corticosteroid dosages will be required.
Patients not taking a rifampicin-containing regimen need lower corticosteroid doses than those shown below.
If oral corticosteroid therapy is suitable, a typical regimen for adults on a rifampicin-containing regimen is:
prednis(ol)one 60 mg orally, daily for 2 to 3 weeks, then taper the dose gradually over 4 to
6 weeks according to clinical response.
For children on a rifampicin-containing regimen, a typical oral regimen is:
prednis(ol)one 2 to 4 mg/kg up to 60 mg orally, daily for 4 weeks, then taper the dose
gradually over 1 to 2 weeks according to clinical response.
Use the higher end of the dose range for children who are severely ill.
For critically ill adults and children who require intravenous corticosteroids, a suggested regimen for those on a
rifampicin-containing regimen is:
dexamethasone 0.4 mg/kg intravenously, daily for 7 days, then

dexamethasone 0.1 mg/kg intravenously, daily for 7 days
FOLLOWED BY
dexamethasone 4 mg (child: 0.08 mg/kg) orally, daily; decreasing by 1 mg (child: 0.02

mg/kg) every 7 days [Note 14].
Note 14: An equivalent dose of prednis(ol)one can be used instead; prednis(ol)one 5 mg is equivalent to
dexamethasone 0.75 mg.
Tuberculosis management in special patient groups

Introduction
For information on tuberculosis (TB) in adults with HIV infection, see here.
Tuberculosis in women who are pregnant or breastfeeding

Untreated TB is a greater hazard to a pregnant woman and her fetus than potential adverse effects of treatment.
Treat TB in pregnant women with standard short-course therapy—these first-line TB drugs are considered safe in
pregnancy, with low risk of teratogenicity.
All infants born to mothers with smear-positive pulmonary disease require preventive treatment from birth (see
Neonates born to a mother with tuberculosis), and close monitoring.
Do not discourage breastfeeding in women receiving TB treatment; however, the mother should wear a mask while
breastfeeding. The concentrations of TB drugs in breast milk are very low, so do not provide effective treatment
for active or latent TB in a breastfed infant.
The mother does not need to be separated from the infant, but consider having the infant sleep in a separate room
at night until the mother is smear-negative.
Neonates born to a mother with tuberculosis

A neonate born to a mother with TB should be evaluated for congenital TB; management of congenital TB is not
covered in these guidelines—seek expert advice.
If there is no clinical suspicion of congenital TB, obtain a first gastric aspirate (of three) from the infant and start
presumptive therapy for latent TB promptly. Use:
1 isoniazid 10 mg/kg orally, daily for 6 months [Note 15] [Note 16]
OR A COMBINATION OF
1 isoniazid 10 mg/kg orally, daily for 3 months [Note 15] [Note 16]
PLUS
rifampicin 15 mg/kg orally, daily for 3 months.
In infants at lower risk of acquiring TB who have been started on a 6-month course of isoniazid monotherapy, a
tuberculin skin test (TST) can be performed at 3 months of age and, if negative, isoniazid can be stopped after 3
months.
If the tuberculin skin test is negative after completion of presumptive therapy, vaccinate the infant with Bacille
Calmette-Guérin (BCG) vaccine (however, if the mother is HIV positive, exclude HIV infection in the infant
before giving BCG). Seek expert advice.
Note 15: An oral liquid formulation of isoniazid is not commercially available; for formulation options, see the
Don’t Rush to Crush Handbook, published by the Society of Hospital Pharmacists of Australia [URL].
Note 16: Children on isoniazid therapy should receive pyridoxine 6.25 to 12.5 mg daily if they are exclusively
breastfed, have HIV infection or are malnourished.
Tuberculosis in children
Children with TB often acquired the infection from an adult. Children are particularly susceptible to invasive
disease (miliary [disseminated] TB and tuberculous meningitis), especially if they have not received Bacille
Calmette-Guérin (BCG) vaccination. Children are usually not infectious.
Standard short-course therapy is appropriate for children with TB. Compared to adults, higher mg/kg doses of
some tuberculosis drugs are needed in children to achieve effective serum concentrations. Adverse effects are rare
in children.
Monitoring tuberculosis therapy

A number of tests are recommended before starting treatment for tuberculosis (TB)—see Before starting therapy.
If tuberculosis therapy is not being administered under supervision (eg directly observed therapy), check adherence
with the patient, and by other measures such as pill counting, and urine testing if available [Note 17]. If possible,
collect a sputum sample for culture on a monthly basis until it is culture-negative; thereafter, collect a sputum
sample for culture when clinically indicated, and at the end of treatment.
Ask patients who are taking ethambutol about visual adverse effects at each visit. Check visual acuity and colour
vision before starting treatment and then at monthly intervals, especially if therapy is continued for longer than 2
months. Checking for visual adverse effects is particularly important in people with kidney impairment because
ethambutol accumulates (due to decreased clearance). If signs of ocular toxicity develop, discontinue ethambutol
immediately and refer to an ophthalmologist.
Educate patients about the risk and symptoms of hepatitis and monitor liver function (eg in adults, at baseline, 2, 4
and 8 weeks, then monthly or second monthly while on treatment). Liver function monitoring is particularly
important for older patients, and patients with abnormal baseline liver biochemistry, pre-existing liver disease,
chronic viral hepatitis or a history of hazardous alcohol consumption. Minor elevation of serum transaminases is
common and usually does not require discontinuation of therapy. Withdraw all drugs immediately if clinical
jaundice develops or if the patient has elevated serum transaminases (five times the upper limit of normal if
asymptomatic, or three times the upper limit of normal if symptomatic [eg nausea, vomiting]).
TB therapy can be reintroduced once the alanine aminotransferase (ALT) concentration has returned to below 2
times the upper limit of normal, or, in patients with elevated baseline ALT (from pre-existing liver disease), drugs
are restarted when the ALT returns to near-baseline levels. There are two approaches to reintroduce TB therapy
when all drugs have been stopped due to drug-related liver injury. One is to reintroduce rifampicin plus
ethambutol, followed by isoniazid a week later, and pyrazinamide a week after that, while monitoring liver
function. Alternatively, depending on the degree of liver injury and the presence of other risk factors for liver
disease, it may be reasonable to reintroduce all three drugs simultaneously, at the full doses. Both approaches carry
a risk of recurrence of hepatotoxicity of approximately 12%.
Note 17: Urine is orange for at least 6 (possibly for longer than 12) hours after a dose of rifampicin.
Latent tuberculosis
Introduction
People with Mycobacterium tuberculosis infection without active disease have latent tuberculosis (TB). Latent TB
can be identified by a positive tuberculin skin test (TST) or a TB-specific interferon gamma release assay (IGRA).
Interpretation of the tuberculin skin test and interferon gamma release assay is complex and requires a detailed
patient history and careful patient assessment—seek expert advice. Individuals with positive tests should be
clinically assessed for evidence of active TB. Consider HIV testing in patients with latent TB.
Exclude active tuberculosis in all patients infected with Mycobacterium tuberculosis.
Treatment of latent TB reduces the incidence of progression to active disease. Once active disease has been
excluded, consider treatment of latent TB in:
patients with HIV infection

recent converters from a negative to positive tuberculin skin test (TST) or TB-specific interferon gamma
release assay (IGRA) (within last 2 years)
close contacts of a patient with smear-positive pulmonary TB
people younger than 35 years (even if no known TB contact)
healthcare workers
patients who are immunocompromised or are receiving (or expected to receive) immunosuppressive drugs—
seek expert advice. See also Additional considerations in immunocompromised patients.
In pregnant women, the timing of treatment of latent TB is complex and needs to be weighed against the increased
risk of drug-induced hepatotoxicity in pregnancy. Treatment can often be deferred until the postpartum period.
Seek expert advice.
Treatment of latent tuberculosis
International guidelines recommend a number of regimens for latent TB that are likely to be equivalent in efficacy.
The choice of regimen for a patient should be based on: age-related risk of hepatotoxicity from isoniazid, potential
for drug interactions with rifamycins (eg rifampicin interacts with the oral contraceptive pill), duration of therapy,
likelihood of drug resistance and drug availability. Regimens include:
1 isoniazid (adult and child) 10 mg/kg up to 300 mg orally, daily for 9 months [Note 18]
[Note 19] [Note 20]
OR
1 rifampicin 10 mg/kg up to 600 mg (child younger than 14 years and more than 50 kg: 600
for 4 months
OR
1 rifampicin 10 mg/kg up to 600 mg (child younger than 14 years and more than 50 kg: 600
for 3 months
PLUS
isoniazid (adult and child) 10 mg/kg up to 300 mg orally, daily for 3 months [Note
19] [Note 20]
OR
1 rifapentine orally, weekly for 3 months [Note 21]:
adult and child 12 years or older and more than 50 kg: 900 mg
adult and child 12 years or older and 32.1 to 50 kg: 750 mg
child age 2 to 11 years: 10 to 14 kg: 300 mg; 14.1 to 25 kg: 450 mg; 25.1 to 32 kg: 600
mg; 32.1 to 50 kg: 750 mg; more than 50 kg: 900 mg
PLUS
isoniazid 15 mg/kg up to 900 mg (child age 2 to 11 years: 25 mg/kg up to 900 mg)

orally, weekly for 3 months [Note 19] [Note 20] [Note 22].
Monitor liver function for patients being treated for latent TB; for example, at 2 and 4 weeks after starting therapy,
or more frequently if there are risk factors for or pre-existing liver disease (see Monitoring tuberculosis therapy).
Educate patients about the symptoms of hepatitis.
People who have been treated for latent TB can acquire TB again (eg migrants who return to visit family and
friends in countries where TB is endemic).
Note 18: A 6-month course of isoniazid is used in some centres.
Note 19: An oral liquid formulation of isoniazid is not commercially available; for formulation options for
Note 20: In patients who are at risk of peripheral neuropathy, administer pyridoxine (adult: 25 mg; child: 6.25 to
12.5 mg) orally, with each dose of isoniazid.
Note 21: Rifapentine is not marketed in Australia at the time of writing, but is available via the Special Access
Scheme.
Note 22: Isoniazid 300 mg tablets are not marketed in Australia, but are available via the Special Access
Scheme.
Additional considerations in immunocompromised patients

Immune compromise is a risk factor for reactivation of TB. If latent TB is diagnosed in an immunocompromised
patient, treatment is recommended.
The benefits of treating latent TB are likely to extend to those in whom immunosuppressive therapy is being
planned; for example, patients being considered for organ or haematopoietic stem cell transplant or who will be
starting immunomodulatory therapy for connective tissue disease.
Consider the following when assessing and managing latent TB in immunocompromised patients (or those
expected to start immunosuppressive therapy):
Diagnosis is complicated because investigations such as a tuberculin skin test (TST) or TB-specific
interferon gamma release assay (IGRA) often produce false-negative results in immunocompromised
patients.
Active TB may be more difficult to rule out in these patients given the higher rates of extrapulmonary
infection.
Timing of therapy—if completion of treatment for latent TB is required before listing for organ or
haematopoietic stem cell transplant, consider one of the shorter duration regimens (see Treatment of latent
tuberculosis). However, in many cases completion of treatment before starting immunosuppressive therapy
is not required or not possible. If immunosuppressive therapy can be delayed, one approach is to start
treatment for latent TB a month before starting immunosuppressive therapy; this allows time to monitor for
adverse effects of TB therapy (eg hepatotoxicity), and, should an adverse effect occur, makes it easier to
identify the causative drug.
Consider potential drug interactions, particularly with rifampicin and calcineurin inhibitors (ciclosporin,
tacrolimus).
Active TB may develop despite treatment of latent TB—consider the possibility of active TB in an
immunocompromised patient with fever of unclear origin.
People treated for latent TB can acquire TB again—for example, migrants who return to countries where
TB is endemic to visit family and friends.
Complications of BCG vaccine

Bacille Calmette-Guérin (BCG) is a live vaccine against tuberculosis (TB) that is indicated for some patients at an
increased risk of TB (see the Australian Immunisation Handbook [URL] for further information).
Reactions to BCG vaccine are usually self-limiting and treatment is not required. Lymph node enlargement or a
marked local pustular reaction after BCG vaccination is normal. Consider percutaneous aspiration if lymph nodes
are fluctuant and seem about to discharge. Surgery is rarely indicated. In the absence of well-conducted trials, the
management of BCG-related lymphadenitis is based on expert opinion and local experience.
In patients with BCG lymphadenitis, there have been cases of Mycobacterium bovis being positive on molecular
testing for rpo mutations, and being falsely diagnosed as multidrug-resistant TB (MDR-TB). Discuss the
interpretation of results with laboratory staff in the setting of suspected M. bovis infection.
BCG vaccination can precipitate a disseminated infection in immunocompromised patients, and following its use
for the treatment of bladder cancer. Disseminated infection following BCG vaccination can also occur in patients
without obvious immune compromise who have a genetic susceptibility, but this is rare. Seek expert advice.
Local abscess formation caused by poor vaccination technique, or sinus formation from suppurating lymph nodes,
will heal without treatment.
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Sharma SK, Singla R, Sarda P, Mohan A, Makharia G, Jayaswal A, et al. Safety of 3 different reintroduction regimens
of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. Clin Infect Dis
2010;50(6):833–9.
Tweed CD, Wills GH, Crook AM, Dawson R, Diacon AH, Louw CE, et al. Liver toxicity associated with tuberculosis
chemotherapy in the REMoxTB study. BMC Med 2018;16(1):46.
Latent tuberculosis
Bliven-Sizemore EE, Sterling TR, Shang N, Benator D, Schwartzman K, Reves R, et al. Three months of weekly
rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI. Int J Tuberc Lung Dis
2015;19(9):1039–44, i-v.
Centers for Disease Control and Prevention (CDC). Recommendations for use of an isoniazid-rifapentine regimen with
direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep
2011;60(48):1650–3.
Diallo T, Adjobimey M, Ruslami R, Trajman A, Sow O, Obeng Baah J, et al. Safety and side effects of rifampin versus
isoniazid in children. N Engl J Med 2018;379(5):454–63.
Getahun H, Matteelli A, Abubakar I, Aziz MA, Baddeley A, Barreira D, et al. Management of latent Mycobacterium
tuberculosis infection: WHO guidelines for low tuberculosis burden countries. Eur Respir J 2015;46(6):1563–76.
Menzies D, Adjobimey M, Ruslami R, Trajman A, Sow O, Kim H, et al. Four months of rifampin or nine months of
isoniazid for latent tuberculosis in adults. N Engl J Med 2018;379(5):440–53.
Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, et al. Three months of rifapentine and
isoniazid for latent tuberculosis infection. N Engl J Med 2011;365(23):2155–66.
World Health Organization (WHO). Latent tuberculosis infection: Updated and consolidated guidelines for
programmatic management. Geneva: WHO; 2018. http://www.who.int/tb/publications/2018/latent-tuberculosis-
infection/en/
Complications of BCG vaccine
Hesseling AC, Schaaf HS, Victor T, Beyers N, Marais BJ, Cotton MF, et al. Resistant Mycobacterium bovis Bacillus
Calmette-Guerin disease: implications for management of Bacillus Calmette-Guerin Disease in human
immunodeficiency virus-infected children. Pediatr Infect Dis J 2004;23(5):476–9.
Hong DN, Huyen MN, Lan NT, Duong NH, Ngo VV, Ngoc DT, et al. Rifampin-resistant Mycobacterium bovis BCG-
induced disease in HIV-infected infant, Vietnam. Emerg Infect Dis 2013;19(7):1168–70.
Rheumatic fever
Introduction to acute rheumatic fever
Acute rheumatic fever results from an inflammatory immune response to infection with particular ‘rheumatogenic’
strains of Streptococcus pyogenes (group A streptococcus); approximately 3 to 5% of any population have an
inherent susceptibility to acute rheumatic fever. Acute rheumatic fever occurs most frequently in children aged 5 to
14 years, although recurrent episodes may continue into the fourth decade of life. The Australian Aboriginal and
Torres Strait Islander population has among the highest reported rate of acute rheumatic fever of any ethnic group
in the world, with an annual incidence of 250 to 300 per 100 000 children. Maori and Pacific Islander people and
immigrants from countries where acute rheumatic fever remains common may also be at high risk of acute
rheumatic fever. Acute rheumatic fever is rare in other Australians.
Acute rheumatic fever is the most common cause of acquired heart disease in children and young adults
worldwide; resultant rheumatic heart disease peaks in the third and fourth decades of life.
For detailed information on the diagnosis, management and prevention of acute rheumatic fever and rheumatic
heart disease in Australia, see The Australian Guideline for Prevention, Diagnosis and Management of Acute
Rheumatic Fever and Rheumatic Heart Disease [URL].
Diagnosis of acute rheumatic fever

Diagnosis of acute rheumatic fever is complex; detailed guidance is available from RHDAustralia [Note 1]. An
overview is included here.
In the absence of a specific diagnostic test, the diagnosis of acute rheumatic fever is based on a set of clinical
manifestations. The diagnostic value of these criteria may vary between ethnic, geographic and socioeconomic
groups, so the Australian guideline considers the clinical manifestations in the context of an individual’s risk of
developing acute rheumatic fever (see Table 2.62). A diagnosis of acute rheumatic fever is defined as:
initial episode—two major, or one major plus two minor, manifestations (see Table 2.62) plus evidence of
preceding S. pyogenes infection
recurrent episode—two major, or one major plus one minor, or three minor, manifestations (see Table 2.62)
plus evidence of preceding S. pyogenes infection.
Consider alternative diagnoses (eg gonococcal arthritis), even in patients who meet the diagnostic criteria for acute
rheumatic fever.
Do not discount the possibility of acute rheumatic fever in patients who do not meet the diagnostic criteria. The
Australian guideline includes the concept of ‘probable acute rheumatic fever’, which describes presentations in
which acute rheumatic fever (either an initial or recurrent episode) is considered the most likely diagnosis but the
above criteria are not met because the patient falls short by one major (or, for a recurrent episode, one minor)
criterion or streptococcal serology is not available. A further group of patients is categorised as having ‘possible
acute rheumatic fever’ if the diagnosis of ‘probable acute rheumatic fever’ is not made, differential diagnoses are
excluded, and the diagnosis of acute rheumatic fever remains possible because some manifestations are present.
Patients with ‘probable acute rheumatic fever’ are managed as though acute rheumatic fever has been confirmed,
whereas patients with ‘possible acute rheumatic fever’ are given 12 months of prophylaxis and then reassessed for
evidence suggesting a diagnosis of acute rheumatic fever (see Prevention of recurrent rheumatic fever for
recommendations for prophylaxis).
Major and minor manifestations for the diagnosis of acute rheumatic fever (Table 2.62)
‘High-risk’ individual [NB1] All other individuals

Major manifestations
carditis (including subclinical echocardiograph
carditis (excluding subclinical echocardiograph
changes)
changes)
polyarthritis, aseptic monoarthritis, or
polyarthritis
polyarthralgia
chorea
chorea
erythema marginatum
erythema marginatum
subcutaneous nodules
subcutaneous nodules
Minor manifestations
monoarthralgia polyarthralgia or aseptic monoarthritis
fever of 38°C or higher fever of 38.5°C or higher
ESR 30 mm/hour or more, or CRP 30 mg/L or ESR 60 mm/hour or more, or CRP 30 mg/L or
more more
prolonged PR interval on ECG prolonged PR interval on ECG
CRP = C-reactive protein; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate

NB1: Aboriginal and Torres Strait Islander Australians living in rural or remote settings are known to be at high risk. Aboriginal and Torres Strait
Islander people living in urban settings, Maori and Pacific Islander people and, potentially, immigrants from developing countries may also be at high
risk.
Adapted from: RHDAustralia (ARF/RHD writing group), National Heart Foundation of Australia, Cardiac Society of Australia and New Zealand.
Australian guideline for prevention, diagnosis and management of acute rheumatic fever and rheumatic heart disease. 2nd ed. 2012. [URL]
Note 1: To access the RHDAustralia ‘Guidelines and Diagnosis Calculator App’, see [URL]. For the
RHDAustralia ‘ARF Diagnosis Flowchart’, see [URL].
Management of suspected acute rheumatic fever

Unless heart failure is present, there is no urgent need to start specific therapy other than analgesia until the
diagnosis is confirmed. Arthritis due to acute rheumatic fever can present with severe pain; for management of
acute pain, see Acute pain.
As the migratory polyarthritis, arthralgia and fever in acute rheumatic fever are very responsive to nonsteroidal
anti-inflammatory drugs (NSAIDs), including aspirin, avoid this class of drugs in the evaluation phase to ensure
these important diagnostic features are not masked.
Management of confirmed acute rheumatic fever

For treatment of acute rheumatic fever, use:
benzathine benzylpenicillin intramuscularly, as a single dose [Note 2]

child 16 kg to less than 20 kg: 0.9 million units (1.7 mL).
Benzathine benzylpenicillin is long acting and the drug of choice for acute rheumatic fever. Do not confuse
If adherence and adequate supervision are assured, a 10-day course of oral penicillin may be used instead. Use:
phenoxymethylpenicillin 500 mg (child: 15 mg/kg up to 500 mg) orally, 12-hourly for 10

days.
Use:
cefalexin 1 g (child: 25 mg/kg up to 1 g) orally, 12-hourly for 10 days.
For arthritis or severe arthralgia, use:
1 aspirin (adult and child) 50 to 60 mg/kg orally, daily in 4 or 5 divided doses until
symptoms resolve. If needed, increase to 80 to 100 mg/kg (up to 8 g in adults) orally,
daily in 4 or 5 divided doses; when symptoms improve, decrease the dose to 50 to 60
mg/kg daily
OR
2 naproxen (adult and child) 5 to 10 mg/kg up to 625 mg orally, twice daily.
Stop NSAID therapy once the patient has been symptom free for 1 to 2 weeks, provided inflammatory markers
have substantially normalised. The typical duration of NSAID therapy is 6 weeks.
Although there are no data to support the use of ibuprofen in acute rheumatic fever, it has been used successfully
(at a dose of 30 mg/kg up to 1600 mg orally, daily in 3 divided doses) and is available as a suspension. The
potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high risk
of harms (see Principles of NSAID use for musculoskeletal conditions in adults and Practical prescribing
considerations for rheumatological diseases in children and adolescents for more information).
In children, influenza vaccination is advised because of the rare association between virus-induced Reye syndrome
and aspirin therapy. Consider stopping aspirin in patients with an acute viral illness.
For the management of chorea associated with acute rheumatic fever, see Sydenham chorea.
Heart failure complicating rheumatic carditis requires urgent management. See The Australian Guideline for
Prevention, Diagnosis and Management of Acute Rheumatic Fever and Rheumatic Heart Disease [URL] for
recommendations.
Patients with acute rheumatic fever should receive antibiotic prophylaxis against S. pyogenes infection, see
Prevention of recurrent rheumatic fever below.
Note 2: All benzathine benzylpenicillin preparations (benzathine benzylpenicillin 900 mg/2.3 mL [equivalent to
1.2 million units]; benzathine benzylpenicillin tetrahydrate 1 200 000 units/2.3 mL [equivalent to 1016.6 mg
benzathine benzylpenicillin tetrahydrate]; benzathine benzylpenicillin tetrahydrate 600,000 units/1.17 mL
[equivalent to 517 mg benzathine benzylpenicillin tetrahydrate]) contain the same concentration of benzathine
benzylpenicillin.
Prevention of recurrent rheumatic fever

Patients with acute rheumatic fever or rheumatic heart disease should receive antibiotic prophylaxis against
Streptococcus pyogenes (group A streptococcus) infection to prevent recurrence of acute rheumatic fever and
development or progression of rheumatic heart disease. Use:
1 benzathine benzylpenicillin (adult and child 20 kg or more: 1.2 million units [2.3 mL];
child less than 20 kg: 0.6 million units [1.2 mL]) intramuscularly [Note 4], every 21 or 28
days. See below for advice on frequency of administration and duration of prophylaxis
OR (for patients refusing or unable to have intramuscular benzathine benzylpenicillin)
2 phenoxymethylpenicillin (all ages) 250 mg orally, 12-hourly. See below for advice on
duration of prophylaxis.
Benzathine benzylpenicillin is long acting and the drug of choice for prophylaxis of recurrent rheumatic fever. Do
not confuse benzathine benzylpenicillin with benzylpenicillin, which is short acting.
Intramuscular benzathine benzylpenicillin is preferred, especially in remote areas, because it is more effective and
patient adherence is more likely than with other antibiotic regimens. For strategies to reduce pain associated with
intramuscular benzathine benzylpenicillin and other measures to improve patient adherence to prophylaxis, see
The Australian Guideline for Prevention, Diagnosis and Management of Acute Rheumatic Fever and Rheumatic
Heart Disease [URL].
Administration of benzathine benzylpenicillin every 28 days is the standard prophylaxis recommended for most
patients. Administration every 21 days is recommended for patients who have had a confirmed breakthrough of
acute rheumatic fever despite adherence to benzathine benzylpenicillin given every 28 days, and for selected
patients with moderate or severe carditis or a history of cardiac valve surgery (provided adherence to the more
frequent injections is likely).
antimicrobial hypersensitivity).
1 erythromycin (base) 250 mg (adult or child over 20 kg) orally, 12-hourly [Note 5]. See
below for advice on duration of prophylaxis
OR
1 erythromycin (ethyl succinate) 400 mg (child 1 month or older: 20 mg/kg up to 400 mg)
orally, 12-hourly. See below for advice on duration of prophylaxis.
The duration of antibiotic prophylaxis depends on patient factors such as social circumstances, clinical features,
and the likelihood of ongoing exposure to S. pyogenes and further episodes of acute rheumatic fever. The
minimum duration is:
10 years after the most recent episode of acute rheumatic fever, or until 21 years of age (whichever is longer)
for patients without moderate or severe rheumatic heart disease [Note 6]
until 35 years of age for patients with moderate rheumatic heart disease [Note 6]
until 40 years of age or lifelong for patients with severe rheumatic heart disease [Note 6] and those who
require or have had cardiac valve surgery for rheumatic heart disease.
The decision to stop antibiotic prophylaxis should be based on clinical and echocardiographic assessment, and be
made in conjunction with a physician who has expertise in rheumatic fever. Lifelong prophylaxis is preferable for
patients who have had cardiac valve surgery.
Some patients with rheumatic heart disease may be at higher risk of developing infective endocarditis—see
Prevention of infective endocarditis.
Note 4: All benzathine benzylpenicillin preparations (benzathine benzylpenicillin 900 mg/2.3 mL [equivalent to
1.2 million units]; benzathine benzylpenicillin tetrahydrate 1 200 000 units/2.3 mL [equivalent to 1016.6 mg
benzathine benzylpenicillin tetrahydrate]; benzathine benzylpenicillin tetrahydrate 600,000 units/1.17 mL
[equivalent to 517 mg benzathine benzylpenicillin tetrahydrate]) contain the same concentration of benzathine
benzylpenicillin.
Note 5: An oral liquid formulation of erythromycin base is not commercially available. If an oral liquid
formulation of erythromycin is required, use the liquid formulation of erythromycin ethyl succinate.
Note 6: For definitions of moderate and severe rheumatic heart disease, see The Australian Guideline for
Prevention, Diagnosis and Management of Acute Rheumatic Fever and Rheumatic Heart Disease [URL].
Key references
Acute rheumatic fever
Gewitz MH, Baltimore RS, Tani LY, Sable CA, Shulman ST, Carapetis J, et al. Revision of the Jones Criteria for the
diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American
Heart Association. Circulation 2015;131(20):1806–18.
Hashkes PJ, Tauber T, Somekh E, Brik R, Barash J, Mukamel M, et al. Naproxen as an alternative to aspirin for the
treatment of arthritis of rheumatic fever: a randomized trial. J Pediatr 2003;143(3):399–401.
RHDAustralia (ARF/RHD writing group), National Heart Foundation of Australia, Cardiac Society of Australia and New
Zealand. The Australian guideline for prevention, diagnosis and management of acute rheumatic fever and rheumatic
heart disease (2nd edition). Darwin: Menzies School of Health Research; 2012.
http://www.rhdaustralia.org.au/resources/arf-rhd-guideline
Uziel Y, Hashkes PJ, Kassem E, Padeh S, Goldman R, Wolach B. The use of naproxen in the treatment of children
with rheumatic fever. J Pediatr 2000;137(2):269–71.
Prevention of recurrent rheumatic fever
https://www.safetyandquality.gov.au/antimicrobial-use-and-resistance-in-australia/
RHDAustralia (ARF/RHD writing group), National Heart Foundation of Australia, Cardiac Society of Australia and New
Zealand. The Australian guideline for prevention, diagnosis and management of acute rheumatic fever and rheumatic
heart disease (2nd edition). Darwin: Menzies School of Health Research; 2012.
http://www.rhdaustralia.org.au/resources/arf-rhd-guideline
Rickettsial infections
Rickettsial infections
Rickettsial infections usually present as a nonspecific febrile illness, often with a characteristic generalised rash.
Fever may be preceded by localised tender lymphadenopathy, with an eschar at the site of the tick or mite bite. A
small proportion of cases develop severe complications such as pneumonitis, encephalitis or septic shock.
Diagnosis is usually based on serology, but nucleic acid amplification testing (eg polymerase chain reaction
[PCR]) of eschar swab or biopsy samples can be used to identify the species.
To treat Australian rickettsial infections (Queensland tick typhus [Rickettsia australis], Flinders Island spotted
fever [Rickettsia honei], Australian spotted fever [Rickettsia honei subspecies marmionii], Rickettsia gravesii,
scrub typhus [Orientia tsutsugamushi] or murine typhus [Rickettsia typhi]) and imported rickettsial infections that
occasionally occur in Australia (such as Mediterranean spotted fever [Rickettsia conorii]), use:
1 doxycycline 100 mg (child: 2.2 mg/kg up to 100 mg) orally, 12-hourly for 7 days
OR
2 azithromycin 500 mg (child: 10 mg/kg up to 500 mg) orally on the first day, then 250 mg
(child: 5 mg/kg up to 250 mg) orally, daily for a further 4 days.
Doxycycline is recommended to treat rickettsial infections in children of all ages because it is the most effective
treatment. The risk of dental adverse effects in young children is minimal, particularly when a single short course
of doxycycline is used.
Intravenous doxycycline can be used for severe disease if available, but therapy must not be delayed—start oral
therapy if the intravenous preparation is not immediately available. Seek expert advice.
Key references
Aung AK, Spelman DW, Murray RJ, Graves S. Rickettsial infections in Southeast Asia: implications for local populace
and febrile returned travelers. Am J Trop Med Hyg 2014;91(3):451–60.
Biggs HM, Behravesh CB, Bradley KK, Dahlgren FS, Drexler NA, Dumler JS, et al. Diagnosis and management of
tickborne rickettsial diseases: Rocky mountain spotted fever and other spotted fever group rickettsioses, ehrlichioses,
and anaplasmosis - United States. MMWR Recomm Rep 2016;65(2):1–44.
Boast A, Curtis N, Gwee A. Question 1: Teething issues: can doxycycline be safely used in young children? Arch Dis
Child 2016;101(8):772–4.
Chanta C, Phloenchaiwanit P. Randomized controlled trial of azithromycin versus doxycycline or chloramphenicol for
treatment of uncomplicated pediatric scrub typhus. J Med Assoc Thai 2015;98(8):756–60.
Cross R, Ling C, Day NP, McGready R, Paris DH. Revisiting doxycycline in pregnancy and early childhood--time to
rebuild its reputation? Expert Opin Drug Saf 2016;15(3):367–82.
Jang MO, Jang HC, Kim UJ, Ahn JH, Kang SJ, Jung SI, et al. Outcome of intravenous azithromycin therapy in patients
with complicated scrub typhus compared with that of doxycycline therapy using propensity-matched analysis.
McGready R, Prakash JA, Benjamin SJ, Watthanaworawit W, Anantatat T, Tanganuchitcharnchai A, et al. Pregnancy
outcome in relation to treatment of murine typhus and scrub typhus infection: a fever cohort and a case series analysis.
PLoS Negl Trop Dis 2014;8(11):e3327.
Regan JJ, Traeger MS, Humpherys D, Mahoney DL, Martinez M, Emerson GL, et al. Risk factors for fatal outcome
from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011. Clin Infect Dis 2015;60(11):1659–66.
Stewart A, Armstrong M, Graves S, Hajkowicz K. Rickettsia australis and Queensland tick typhus: A Rickettsial spotted
fever group infection in Australia. Am J Trop Med Hyg 2017;97(1):24–9.
Todd SR, Dahlgren FS, Traeger MS, Beltran-Aguilar ED, Marianos DW, Hamilton C, et al. No visible dental staining in
children treated with doxycycline for suspected Rocky Mountain Spotted Fever. J Pediatr 2015;166(5):1246–51.
Principles of managing sepsis and septic shock
Early recognition of sepsis or septic shock in adults
Sepsis and septic shock are characterised by life-threatening organ dysfunction caused by an abnormal response to
infection. Septic shock is a subset of sepsis associated with profound circulatory, cellular and metabolic
abnormalities. The risk of mortality is high for both conditions, but is increased in septic shock compared to sepsis.
Prompt recognition and treatment of these syndromes is vital, because appropriate resuscitation, organ support and
rapid initiation of antibiotic therapy reduces mortality. See Early intervention for sepsis or septic shock.
Life-threatening organ dysfunction in response to infection is necessary for a diagnosis of sepsis. See Box 2.29 for
signs of life-threatening organ dysfunction in adults.
An adult should be considered to have septic shock if they have sepsis and, despite adequate fluid resuscitation
(see Early intervention for sepsis or septic shock), either of the following features [Note 1]:
inability to maintain a mean arterial pressure of 65 mmHg (or a systolic blood pressure of 90 mmHg)
without vasopressors
blood lactate concentration more than 2 mmol/L.
The Antibiotic Expert Groups recommend that all patients with suspected infection are assessed clinically for
indications of life-threatening organ dysfunction. If any of these are present, rapid implementation of sepsis care,
including prompt administration of antibiotics, is vital to optimise survival.
Clinically assess all patients with suspected infection for life-threatening organ dysfunction. If present, rapid implementation of
sepsis care is vital.
Signs of life-threatening organ dysfunction in adults (Box 2.29)
Life-threatening organ dysfunction is indicated by the following features, and these are associated with a
significant risk of deterioration or death:
impaired consciousness
tachypnoea (respiratory rate 22 breaths/minute or more) or hypoxaemia
hypotension (systolic blood pressure less than 90 mmHg)
Life-threatening organ dysfunction is also indicated by the following features:
poor peripheral perfusion or mottled skin

acute oliguria or elevated serum creatinine (above baseline)
low platelet count
elevated serum bilirubin (above baseline).
NB1: Blood lactate can be measured with arterial or venous blood gas analysis. Venous blood gas analysis is acceptable for quick lactate
assessment.
Recognising a patient with sepsis can be challenging. Patients with suspected infection but without signs of life-
threatening organ dysfunction require close monitoring in case of deterioration. The signs of sepsis may be subtle,
especially in elderly patients. Signs may include hypo- or hyperthermia, tachycardia, reduced urine output or, in
older adults, functional decline. Also consider whether the patient is at increased risk of sepsis (eg has underlying
malignancy, is immunosuppressed, is elderly, has had recent surgery or another invasive procedure) or has
symptoms associated with a serious infection (eg headache and neck stiffness may indicate meningitis). An
emergency department physician or other senior medical staff should be involved to ensure appropriate, timely
initiation of antibiotic therapy, source control and fluid therapy.
Various risk stratification tools can be used to predict a patient’s risk of mortality but their use should be deferred
until after initiation of time-critical interventions (eg resuscitation, organ support, antibiotics) [Note 2].
Note 1: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) require the patient
to have both features for a diagnosis of septic shock. However, because the risk of mortality remains high in
patients who have only one feature, the consensus of the Antibiotic Expert Groups is that patients with either
feature should be considered to have septic shock. See: Singer M, Deutschman CS, Seymour CW, Shankar-Hari
M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock
(Sepsis-3). JAMA 2016;315(8):801-10. [URL]
Note 2: In 2016, the Third International Consensus Group (Sepsis-3) published an updated definition of sepsis,
which includes the quick sepsis-related organ failure assessment (qSOFA) tool to identify patients with at least a
10% chance of dying from this sepsis episode—see: Singer M, Deutschman CS, Seymour CW, Shankar-Hari M,
Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-
3). JAMA 2016;315(8):801-10 [URL]. In older adults, risk stratification tools that incorporate age and comorbid
illness burden—such as Mortality in Emergency Department Sepsis (MEDS)—have better predictive value in
the emergency department for mortality than tools relying on physiological derangement alone.
Early recognition of sepsis or septic shock in neonates, infants and

children
At the time of writing, definitions of sepsis and septic shock for neonates, infants and children have not been
updated; however, it is likely that the updated definitions will focus on infection-related, life-threatening organ
dysfunction, similar to the new adult definitions. In neonates and younger children, the signs of sepsis may be
subtle and may differ from the signs of sepsis in adults.
The risk of mortality is high for both sepsis and septic shock, but is increased in septic shock compared to sepsis.
Prompt recognition and treatment of these syndromes is vital, because appropriate resuscitation and organ support,
together with rapid initiation of antibiotic therapy, reduces mortality. See Early intervention for sepsis or septic
shock for prehospital management of sepsis or septic shock and the general principles of resuscitation; however,
note that the lactate and blood pressure targets are not applicable to children. For specific advice on resuscitation of
neonates, infants or children with sepsis, refer to local protocols or seek expert advice.
Consider meningitis in neonates and infants presenting with nonspecific signs of sepsis, because classical signs are
often absent.
In neonates, clinical features of sepsis or septic shock may be nonspecific and include signs that are not typical of
sepsis in older patients (eg apnoea, temperature instability, feeding intolerance). Consider sepsis in neonates when
their clinical state is causing significant concern to family or clinical staff. Multiple Australian and international
resources provide guidance on recognising and managing neonatal sepsis; this information is not covered in these
guidelines.
Because the signs of sepsis in neonates may be nonspecific, it is usual to give antibiotics initially for suspected
sepsis (eg neonates born to mothers with confirmed intra-amniotic infection). Antibiotic therapy is then modified
or stopped based on clinical progress, microbiology (eg blood culture results) and other laboratory investigations
(eg full blood count, C-reactive protein). If infection is confirmed, seek expert advice.
In infants and children, standard observations (eg respiratory rate, blood pressure) and signs of life-threatening
organ dysfunction vary according to the patient’s age; age-appropriate standard observation charts are available in
most jurisdictions. Clinical features can be nonspecific and include signs that are not typical of sepsis in older
patients (eg gasping, grunting, increased irritability or lethargy, inability to feed or eat). Consider sepsis in infants
and children when their clinical state is causing significant concern to family or clinical staff. Detailed information
on recognising and managing sepsis in infants and children is not covered in these guidelines. Age-appropriate
sepsis management pathways are available in some jurisdictions.
Early intervention for sepsis or septic shock

General approach
Patients with sepsis or septic shock require urgent intervention, including immediate resuscitation and prompt
administration of antibiotics. They should be managed in a closely monitored, high-acuity area, such as an
emergency department resuscitation area, high-dependency unit, or intensive care unit.
In these guidelines, the antibiotic regimens for treating sepsis or septic shock are categorised according to whether
the source of infection is known or the pathogen has been identified. Antibiotic regimens are included for:
prehospital management if arrival at a hospital is likely to be delayed by 1 hour or more, or

meningococcaemia is suspected on clinical grounds
empirical therapy when the source of infection is not apparent
empirical therapy when the source of infection is apparent
directed therapy when the pathogen has been identified.
Consult local protocols or other references for comprehensive advice on nonantibiotic management of patients
with sepsis or septic shock; these guidelines include limited advice on resuscitation.
Prehospital management
Transfer patients with suspected sepsis or septic shock to hospital urgently.
If arrival at a hospital is likely to be delayed by 1 hour or more (such as in regional, rural or remote areas), start
resuscitation, take blood samples for culture, and administer an immediate dose of antibiotic. Antibiotic choice
should be based on local protocols, if available. In the absence of local protocols, use:
ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously or

intramuscularly [Note 3] .
If ceftriaxone is not available, seek expert advice. Benzylpenicillin may be a suitable, and readily available,
alternative.
Ceftriaxone can be used in patients hypersensitive to penicillins but not in those with a history of severe delayed
hypersensitivity (eg a severe cutanenous adverse reaction)—see Management of patients reporting hypersensitivity
to penicillins. Closely observe patients with immediate hypersensitivity to penicillins who are treated with
ceftriaxone because there is a small chance of cross-reactivity with cephalosporins. For patients with severe
delayed hypersensitivity to penicillins, seek expert advice.
For neonates, use:
1 cefotaxime 50 mg/kg intravenously or intramuscularly
OR
1 benzylpenicillin 90 mg/kg intravenously or intramuscularly.
Urgent administration of empirical antibiotics is required once the patient is admitted to hospital, even if
antibiotics were given before admission.
If meningococcaemia is suspected on clinical grounds (eg fever plus purpuric rash, sepsis plus meningeal
symptoms, unexplained septic shock in young adults), immediate antibiotics are required because meningococcal
sepsis may be rapidly fatal (see Prehospital management of suspected meningitis).
Resuscitation
Begin initial resuscitation with rapid assessment of the patient’s clinical state.
In patients with sepsis or septic shock, start therapy within 1 hour of presentation to medical care or, for ward-
based patients, development of sepsis or septic shock. Initial therapy includes:
measuring blood lactate concentration [Note 4] [Note 5]. If initial lactate concentration is more than 2
mmol/L, measure again within 2 to 4 hours
obtaining blood samples for culture [Note 4]. Collect two sets (ie four bottles) from adults; a single smaller
volume sample is appropriate for neonates and young children
collecting other relevant samples as soon as possible, but not if doing so will delay antibiotic
administration. Samples taken after antibiotic therapy has started can still be useful
administering broad-spectrum antibiotics [Note 6] (see Choice of empirical antibiotic regimen for sepsis or
septic shock for antibiotic choice). Prompt administration of antibiotics is essential in septic shock
beginning rapid administration of intravenous fluids to manage hypotension or a blood lactate
concentration more than 2 mmol/L. If the patient is hypotensive during or after fluid resuscitation, give a
vasopressor to maintain a mean arterial blood pressure of at least 65 mmHg [Note 7].
If a source of infection is identified, rapid specific treatment is essential (eg drainage of an abscess, removal of a
vascular access device). Such management should be in consultation with appropriate specialist teams, because a
timely multidisciplinary approach to sepsis management is associated with improved outcomes.
It is important to establish whether an advance care plan is in place and whether therapy for sepsis and septic
shock is consistent with the expressed goals of the patient.
Note 4: If intravenous access cannot be promptly established, collect blood samples by the intraosseous route.
Note 5: Blood lactate can be measured with arterial or venous blood gas analysis. Venous blood gas analysis is
acceptable for quick lactate assessment.
Note 6: If intravenous access cannot be promptly established, administer the initial antibiotic dose(s) by the
intraosseous route.
Note 7: Some patients, particularly older persons or those with pre-existing hypertension, require a higher mean
arterial blood pressure for adequate systemic perfusion.
Management of patients at risk of sepsis

Closely monitor patients with suspected infection who are at risk of sepsis but do not have sepsis or septic shock,
in case of deterioration. See here for definitions in adults or here for definitions in neonates, infants and children.
Collect blood samples, as well as appropriate samples from sites considered to be a potential source of infection.
Depending on the clinical scenario, it may be appropriate to start antibiotic therapy while awaiting the results of
testing; antibiotic choice is guided by the suspected source of infection.
Key references
ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, et al. Goal-directed
resuscitation for patients with early septic shock. N Engl J Med 2014;371(16):1496–1506 .
Burston J, Adhikari S, Hayen A, Doolan H, Kelly ML, Fu K, et al. A Role for Antimicrobial Stewardship in Clinical
Sepsis Pathways: a Prospective Interventional Study. Infect Control Hosp Epidemiol 2017;38(9):1032–8.
Churpek MM, Snyder A, Han X, Sokol S, Pettit N, Howell MD, et al. Quick sepsis-related organ failure assessment,
systemic inflammatory response syndrome, and early warning scores for detecting clinical deterioration in infected
patients outside the intensive care unit. Am J Respir Crit Care Med 2017;195(7):906–911 .
Ferrer R, Martin-Loeches I, Phillips G, Osborn TM, Townsend S, Dellinger RP, et al. Empiric antibiotic treatment
reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance
improvement program. Crit Care Med 2014;42(8):1749–1755 .
Freund Y, Lemachatti N, Krastinova E, Van Laer M, Claessens YE, Avondo A, et al. Prognostic accuracy of Sepsis-3
criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department.
JAMA 2017;317(3):301–308 .
Henning DJ, Puskarich MA, Self WH, Howell MD, Donnino MW, Yealy DM, et al. An emergency department validation
of the SEP-3 sepsis and septic shock definitions and comparison with 1992 consensus definitions. Ann Emerg Med
2017;70(4):544–552.e5 .
Johnston ANB, Park J, Doi SA, Sharman V, Clark J, Robinson J, et al. Effect of immediate administration of antibiotics
in patients with sepsis in tertiary care: A systematic review and meta-analysis. Clin Ther 2017;39(1):190–202.e6
.
Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of
effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med
2006;34(6):1589–1596 .
Macdonald SP, Arendts G, Fatovich DM, Brown SG. Comparison of PIRO, SOFA, and MEDS scores for predicting
mortality in emergency department patients with severe sepsis and septic shock. Acad Emerg Med 2014;21(11):1257–
63.
Moskowitz A, Patel PV, Grossestreuer AV, Chase M, Shapiro NI, Berg K, et al. Quick sequential organ failure
assessment and systemic inflammatory response syndrome criteria as predictors of critical care intervention among
patients with suspected infection. Crit Care Med 2017;45(11):1813–1819 .
Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed
resuscitation for septic shock. N Engl J Med 2015;372(14):1301–1311 .
National Institute for Health and Care Excellence (NICE). Sepsis: recognition, diagnosis and early management
[NG51]. London: NICE; 2016. https://www.nice.org.uk/guidance/ng51.
PRISM Investigators, Rowan KM, Angus DC, Bailey M, Barnato AE, Bellomo R, et al. Early, goal-directed therapy for
septic shock - A patient-level meta-analysis. N Engl J Med 2017;376(23):2223–2234 .
Raith EP, Udy AA, Bailey M, McGloughlin S, MacIsaac C, Bellomo R, et al. Prognostic accuracy of the SOFA score,
SIRS criteria, and qSOFA score for in-hospital mortality among adults with suspected infection admitted to the intensive
care unit. JAMA 2017;317(3):290–300 .
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International
Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med 2017;45(3):486–552.
Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, et al. Time to treatment and mortality
during mandated emergency care for sepsis. N Engl J Med 2017;376(23):2235–2244 .
Shane AL, Sanchez PJ, Stoll BJ. Neonatal sepsis. Lancet 2017;390(10104):1770–80.
Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al. Developing a new definition and
assessing new clinical criteria for septic shock: For the Third International Consensus Definitions for Sepsis and Septic
Shock (Sepsis-3). JAMA 2016;315(8):775–787 .
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International
Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315(8):801–10.
Williams JM, Greenslade JH, McKenzie JV, Chu K, Brown AFT, Lipman J. Systemic inflammatory response syndrome,
quick sequential organ function assessment, and organ dysfunction: Insights from a prospective database of ED
patients with infection. Chest 2017;151(3):586–596 .
Empirical regimens for sepsis or septic shock
Choice of empirical antibiotic regimen for sepsis or septic shock
General approach
Broad-spectrum therapy targeting the most likely pathogens is used initially for sepsis or septic shock (see here),
until additional information is available (eg source of infection, Gram stain, results of culture and susceptibility
testing).
Source of infection is not apparent

The choice of empirical regimen for sepsis or septic shock when the source of infection is not apparent is
influenced by:
the patient’s age—these guidelines include empirical regimens for neonates (if the infection is early onset, or
late onset and acquired in the community), young infants, children 2 months or older and adults; the
common pathogens causing sepsis or septic shock are different for each of these age groups
whether the infection was acquired in the community or in hospital, or is associated with healthcare
contact or overseas travel—in adults, the most common cause of community-acquired sepsis or septic
shock without an identifiable source is Escherichia coli. Other important causes are Staphylococcus aureus,
Streptococcus pneumoniae and Neisseria meningitidis. Infection with drug-resistant organisms (eg
methicillin-resistant S. aureus [MRSA], multidrug-resistant Enterobacteriaceae, Pseudomonas aeruginosa)
is more common if the infection was acquired in hospital, or is associated with healthcare contact (eg
outpatient dialysis or chemotherapy) or overseas travel. Furthermore, organisms that are rare in community-
acquired sepsis (eg Candida species) may cause hospital-acquired or healthcare-associated infections.
Appropriate regimens are recommended throughout these guidelines
results of recent culture and susceptibility testing (relevant to the presentation). If these results suggest that
likely pathogens are not susceptible to the empirical regimen, modified regimens are needed—seek expert
advice
whether infection with a multidrug-resistant Gram-negative bacterium is likely (see Box 2.30)—
alternative regimens are recommended throughout these guidelines
whether infection with methicillin-resistant S. aureus (MRSA) is likely (see Box 2.31)—alternative
regimens are recommended throughout these guidelines
whether local microbiology and antimicrobial susceptibility is known; this is particularly important for
infections acquired from healthcare contact, in hospital or overseas—refer to local protocols and seek expert
advice
whether the patient is neutropenic or immunocompromised. Patients with neutropenia are at increased risk
of infection with P. aeruginosa—see Febrile neutropenia for antibiotic choice. For patients who are
immunocompromised but not neutropenic, the empirical antibiotic regimens in this topic may be
appropriate; however, evaluate the appropriateness of the empirical regimen based on the patient’s
susceptibility to infection, the underlying disease and comorbidities, and other patient factors
whether toxic shock syndrome is suspected—a lincosamide and intravenous immunoglobulin (IVIg) should
be added to the empirical regimen (see Streptococcus pyogenes bloodstream infections, including toxic
shock syndrome for clinical presentation, and lincosamide and IVIg dosing).
The choice of empirical antibiotics in neonates with sepsis or septic shock depends on the caregiving environment
and whether infection occurs within 72 hours of birth.
Sepsis or septic shock that occurs within 72 hours of birth is considered to be early onset. The causative
organisms are most commonly acquired from the mother (eg Streptococcus agalactiae [group B
streptococcus], E. coli, herpes simplex virus [HSV], Listeria monocytogenes).
Sepsis or septic shock that occurs more than 72 hours after birth is considered to be late onset. The
causative organisms may be acquired from the mother or the caregiving environment (eg S. agalactiae, E.
coli and other Gram-negative bacteria, HSV, S. aureus, coagulase-negative staphylococci, L.
monocytogenes).
If the sick neonate is preterm, or develops sepsis more than 72 hours after birth but before discharge from
hospital (eg preterm neonates treated in an intensive care unit), management is complex—seek expert
advice, and consult local protocols (for antibiotic choice) or a neonatal formulary (for dosing).
Table 2.81 lists the empirical regimens included in these guidelines for sepsis or septic shock when the source of
infection is not apparent. The appropriate regimen may also be influenced by results of recent culture and
susceptibility testing; local microbiology and antimicrobial susceptibility; whether the patient is neutropenic or
immunocompromised; and whether toxic shock syndrome is suspected—see above for antibiotic choice.
Empirical antibiotic regimens for sepsis or septic shock, source not apparent (Table 2.81) [NB1]
Patient age Antibiotic regimen based on infection onset (location and timing)
community-acquired
adults
hospital-acquired
community-acquired
children 2 months or older
hospital-acquired—consult local protocols, or seek clinical microbiology or
infectious diseases advice
community-acquired
infants 1 month to younger than 2
months hospital-acquired—consult local protocols, or seek clinical microbiology or
early-onset (within 72 hours of birth)
late-onset (more than 72 hours after birth) in neonates admitted from the
community
term neonates
late-onset (more than 72 hours after birth) in neonates who have been in
hospital since birth—consult local protocols, or seek clinical microbiology or
preterm neonates consult local protocols, or seek expert advice
NB1: The appropriate regimen may also be influenced by results of recent culture and susceptibility testing; local microbiology and antimicrobial
susceptibility; whether the patient is neutropenic or immunocompromised; and whether toxic shock syndrome is suspected—see here for antibiotic
choice.
Source of infection is apparent
When the source of sepsis or septic shock is apparent (eg sepsis or septic shock that develops in a patient with
pneumonia), antibiotic choice is guided by the usual susceptibility of pathogens associated with the source. For
treatment recommendations for common sources of sepsis, see:
respiratory sources:
community-acquired pneumonia in adults
community-acquired pneumonia in children
hospital-acquired pneumonia
urinary tract sources:
in adults
in children
biliary or gastrointestinal tract source
skin sources:
cellulitis
diabetic foot infection, including for sepsis associated with a chronic ulcer (eg decubitus or ischaemic
ulcer)
necrotising skin or soft tissue infections, including for sepsis associated with a water-immersed wound
surgical site infection
meningitis
intravascular device source
bone or joint sources
endocarditis
female genital tract sources:
intra-amniotic infection (chorioamnionitis)
postpartum endometritis
neck or oropharyngeal sources (see Lung abscess due to septic jugular thrombophlebitis).
In patients with hospital-acquired infection, the spectrum of pathogens and their susceptibility can be difficult to
predict. Local protocols, or clinical microbiology or infectious diseases advice, should guide antibiotic choice.
These guidelines include limited advice on antimicrobial therapy for neonatal sepsis or septic shock when the
source of infection is apparent—seek expert advice.
Multidrug-resistant Gram-negative bacteria

The incidence of infections caused by multidrug-resistant Gram-negative bacteria is increasing. Gram-negative
bacteria that have strains with acquired resistance to multiple antibiotics include E. coli, Klebsiella species,
Acinetobacter baumannii and P. aeruginosa.
Multidrug-resistance in Gram-negative bacteria is often mediated by extended-spectrum beta-lactamase (ESBL)

enzymes. ESBL enzymes confer resistance to penicillins and cephalosporins. ESBL-producing bacteria may also
be resistant to aminoglycosides and quinolones. Outcomes are inferior when piperacillin+tazobactam, rather than
meropenem, is used to treat infection caused by ESBL-producing bacteria—see Enterobacteriaceae (including
E. coli and K. pneumoniae) sepsis or septic shock.
In some cases, carbapenem-resistant strains should be considered—seek expert advice.
Risk factors for infection with a multidrug-resistant Gram-negative bacterium are described in Box 2.30.
Risk factors for infection with a multidrug-resistant Gram-negative bacterium (Box 2.30)
A patient with one or more of the risk factors below is at increased risk of infection with a multidrug-resistant
Gram-negative bacterium (such as an ESBL-producing bacterium). However, patients at increased risk will not
necessarily be infected or colonised with a resistant bacterium.
Consider whether to modify empirical therapy for the individual patient, taking into account the severity of
infection. Culture results are particularly important to guide ongoing therapy.
Risk factors for infection with a multidrug-resistant Gram-negative bacterium include:
recent stay in hospital or a long-term care facility (eg within 12 months) in a country with a high
prevalence of multidrug-resistant Gram-negative bacteria [NB1] [NB2] or an Australian facility with
a known outbreak [NB2]
recent overseas travel (eg within 6 months) to an area with a high prevalence of multidrug-resistant Gram-
negative bacteria, particularly if associated with antibiotic use or medical care [NB2]
previous colonisation or infection with a multidrug-resistant Gram-negative bacterium, particularly if
recent or associated with the current episode of care
frequent stays, or a current prolonged stay, in a hospital with a high prevalence of multidrug-resistant
Gram-negative bacteria, particularly if associated with antibiotic exposure
residence in an aged-care facility with a high prevalence of multidrug-resistant Gram-negative bacteria,
particularly if the patient has had multiple courses of antibiotics.
Local policies should address the role of routine rectal screening in patients with risk factors for multidrug-
resistant Gram-negative bacteria.
ESBL = extended-spectrum beta-lactamase
NB1: This risk factor is associated with the highest risk of infection with a multidrug-resistant Gram-negative bacterium.
NB2: This risk factor also applies in neonates born to mothers with this risk factor.
Methicillin-resistant Staphylococcus aureus
Risk factors for infection with methicillin-resistant Staphylococcus aureus are described in Box 2.31.
Risk factors for infection with methicillin-resistant Staphylococcus aureus (Box 2.31)
A patient with one or more of the risk factors below is at increased risk of methicillin-resistant Staphylococcus
aureus (MRSA) infection. However, patients at increased risk will not necessarily be colonised or infected with
MRSA.
Consider whether to modify empirical therapy on an individual patient basis, taking into account the severity of
infection.
Risk factors for infection with MRSA include:
residence in an area with a high prevalence of MRSA (eg Northern Territory; remote communities in
northern Queensland; regions north of metropolitan Perth in Western Australia, especially the Kimberly
and Pilbara)
previous colonisation or infection with MRSA, particularly if recent or associated with the current episode
of care [NB1]
frequent stays, or a current prolonged stay, in a hospital with a high prevalence of MRSA, particularly if
associated with antibiotic exposure or recent surgery
residence in an aged-care facility with a high prevalence of MRSA, particularly if the patient has had
multiple courses of antibiotics.
If modifying empirical therapy based on the presence of risk factors, consider local MRSA epidemiology and
susceptibility patterns (particularly of community-associated MRSA).
NB1: This risk factor also applies in neonates exposed to caregivers colonised or infected with MRSA.
Empirical regimens for adults with community-acquired sepsis or septic

shock, source not apparent
additional information is available (eg source of infection; results of Gram stain, culture and susceptibility testing).
Evaluate appropriateness of antimicrobial therapy daily, with consideration given to the patient’s clinical status and
the principles of antimicrobial stewardship.
The empirical regimens are intended for initial therapy only (up to 48 hours)—modify as soon as additional information is
available.
For advice on recognising sepsis and septic shock and early intervention, see Principles of managing sepsis and
septic shock.
Modified empirical regimens are included below for patients:
hypersensitive to penicillins
at risk of infection with a multidrug-resistant Gram-negative bacterium (see Box 2.30 for risk factors)
in tropical regions of Australia [Note 1] where infection with Burkholderia pseudomallei is possible.
The following empirical regimens may also need to be modified according to local epidemiology, if known.
For adults with community-acquired sepsis or septic shock without an apparent source of infection, use:

PLUS
PLUS if the patient has septic shock or is at increased risk of MRSA infection

vancomycin use for subsequent dosing and principles of use
PLUS if Neisseria meningitidis infection is suspected [Note 5]
OR
Gentamicin continues to be recommended for empirical treatment for community-acquired sepsis and septic shock
because the rates of gentamicin resistance in community-associated Gram-negative pathogens are low. The balance
of benefits and harms favours its use in life-threatening infection.

PLUS
PLUS if the patient has septic shock or is at increased risk of MRSA infection

PLUS if N. meningitidis infection is suspected [Note 5]
OR
chain cross-reactivity (see Cross-reactivity between beta lactams). Seek expert advice. If the above regimen is not
suitable, use the regimen below for patients with delayed severe hypersensitivity to penicillins.

PLUS

PLUS if N. meningitidis infection is suspected [Note 5]
ciprofloxacin 400 mg intravenously, 8-hourly.
For patients at risk of infection with a multidrug-resistant Gram-negative bacterium (for risk factors, see Box
2.30), consider replacing the above regimens with:
meropenem 1 g intravenously, 8-hourly [Note 6] [Note 7] [Note 8]
PLUS

vancomycin use for subsequent dosing and principles of use.
If infection with carbapenemase-producing Enterobacteriaceae is suspected, seek expert advice.
In tropical regions of Australia [Note 1] where infection with B. pseudomallei is possible, for patients with sepsis
who do not require intensive care support and do not have risk factors for B. pseudomallei infection (see Box
2.17), a modified regimen is not required. Select the appropriate regimen from those above (either a gentamicin- or
meropenem-based regimen).
In tropical regions of Australia [Note 1] where infection with B. pseudomallei is possible, for patients with sepsis
who do not require intensive care support but have risk factors for B. pseudomallei infection (see Box 2.17),
consider replacing the above regimens with:
piperacillin+tazobactam 4+0.5 g intravenously, 6-hourly
PLUS if the patient is at increased risk of MRSA infection

Do not use piperacillin+tazobactam in patients hypersensitive to penicillins. Meropenem (see dosage above) may
be a suitable alternative if the patient is treated in a supervised setting—seek expert advice.
In tropical regions of Australia [Note 1] where infection with B. pseudomallei is possible, for patients with septic
shock or requiring intensive care support, consider using the regimen recommended for patients at risk of
infection with a multidrug-resistant Gram-negative bacterium.
calculate the dose.
function.
Note 5: Typical features of N. meningitidis infection include fever, meningitis symptoms and a nonblanching,
purpuric rash. Leg pain, cold extremities and abnormal skin colour may also occur. Increasingly, N. meningitidis
infection has an atypical presentation—gastrointestinal symptoms may predominate, as well as other nonspecific
features. Purpuric rash and meningitis symptoms may be absent.
treatment options.
At room temperature, meropenem is not stable in solution for 24 hours. If continuous infusion is used,
administer the 24-hour dose as 3 × 8-hour infusions.
Note 8: A higher dosage of meropenem (2 g intravenously, 8-hourly) is required if neurological infection is

suspected.
Empirical regimens for adults with hospital-acquired sepsis or septic

shock, source not apparent
septic shock.
The choice of antibiotics for hospital-acquired sepsis or septic shock is complex. Regimens based on local
protocols, or clinical microbiology or infectious diseases advice improve outcomes, because survival is increased
when appropriate antibiotics are given early. This is particularly important for patients in the intensive care unit.
The choice of empirical antibiotics for hospital-acquired sepsis or septic shock is complex and should be based on local
protocols, or clinical microbiology or infectious diseases advice.
In the absence of local protocols and immediately available clinical microbiology or infectious diseases advice,
and when the source of infection is not apparent to guide antibiotic choice, the following empirical regimens can
be used initially. However, seek advice and modify therapy as soon possible.
Evaluate appropriateness of antimicrobial therapy daily, with consideration given to newly available information
(eg source of infection, Gram stain, results of culture and susceptibility testing), the patient’s clinical status, and
The empirical regimens are intended for initial therapy when local protocols, or clinical microbiology or infectious diseases
advice, is not available.
Modified empirical regimens are included below for patients at increased risk of infection with:
a multidrug-resistant Gram-negative bacterium (see Box 2.30 for risk factors)

methicillin-resistant Staphylococcus aureus (MRSA) (see Box 2.31 for risk factors).
For adults with hospital-acquired sepsis or septic shock without an apparent source of infection, in the absence of
local protocols or advice, use initially:
piperacillin+tazobactam 4+0.5 g intravenously, 6-hourly [Note 9]
PLUS if the patient has septic shock or suspected line-related sepsis, or if the hospital has a significant rate of
nosocomial MRSA infection

If the patient is at risk of infection with a multidrug-resistant Gram-negative bacterium (for risk factors, see
Box 2.30), consider replacing piperacillin+tazobactam with:
meropenem 1 g intravenously, 8-hourly [Note 10] [Note 11] [Note 12].
Systematic reviews suggest that adding an aminoglycoside to the empirical regimen for hospital-acquired sepsis or
septic shock is associated with increased toxicity without additional clinical benefit. However, for patients with
septic shock in whom the margin for error is small, adding an aminoglycoside may be prudent in case of resistance
to monotherapy. This practice is most useful if local microbiological data show a significant proportion of Gram-
negative organisms are aminoglycoside-susceptible.
Candidaemia is an important cause of hospital-acquired sepsis, particularly in immunocompromised or critically

ill patients. Strong evidence to inform a recommendation about who should receive empirical antifungal therapy is
lacking, but therapy should be considered in high-risk patients. See also Candida species sepsis (candidaemia).
treatment options.
At room temperature, meropenem is not stable in solution for 24 hours. If continuous infusion is used, administer
the 24-hour dose as 3 × 8-hour infusions.
Note 12: A higher dosage of meropenem (2 g intravenously, 8-hourly) is required if neurological infection is
suspected.
Empirical regimens for early-onset sepsis or septic shock in neonates,

source not apparent
Seek expert advice for the management of neonates with confirmed sepsis or microbiologically proven infection.
There is a risk of resistant pathogens in neonates born to mothers with certain risk factors for infection with a
multidrug-resistant Gram-negative bacterium (see Box 2.30) or methicillin-resistant Staphylococcus aureus
(MRSA) (see Box 2.31).
Evaluate appropriateness of antimicrobial therapy daily, with consideration given to the neonate’s clinical status
and the principles of antimicrobial stewardship.
available.
septic shock.
The following recommendations apply to term neonates (gestational age 37 weeks or older) with early-onset sepsis
or septic shock (sepsis or septic shock occurring within 72 hours of birth). They also apply to term neonates born
to mothers with confirmed intra-amniotic infection, if empirical therapy is indicated. Antimicrobial choice depends
on illness severity, and whether meningitis has been excluded or encephalitis is suspected. Although amoxicillin
and ampicillin have traditionally been preferred to benzylpenicillin because of a theoretical advantage for sepsis
caused by Gram-negative pathogens (such as Escherichia coli), no difference has been observed in clinical
outcomes. Benzylpenicillin is preferred for its narrower spectrum of activity.
For empirical therapy for term neonates with early-onset sepsis or septic shock who are not severely unwell, or are
severely unwell but do not have meningitis (ie excluded by lumbar puncture), use:
gentamicin 5 mg/kg intravenously over 3 to 5 minutes, for the first dose; see Principles of
aminoglycoside use for subsequent dosing and principles of use [Note 13]
PLUS
benzylpenicillin 60 mg/kg intravenously, 12-hourly.
For empirical therapy for term neonates with early-onset sepsis or septic shock who are severely unwell and may
have meningitis (ie not excluded by lumbar puncture), use:
cefotaxime 50 mg/kg intravenously, 8-hourly
PLUS
benzylpenicillin 90 mg/kg intravenously, 8-hourly.
If herpes simplex encephalitis is suspected (see Figure 2.5), add aciclovir to the above regimens. Use:
If herpes simplex encephalitis is confirmed, see Neonatal herpes simplex infection for subsequent management.
If intravenous or intraosseous access cannot be rapidly established (eg within 15 minutes), the initial dose of
antimicrobial therapy can be administered intramuscularly. For term neonates with early-onset sepsis or septic
shock who are not severely unwell, or are severely unwell but do not have meningitis (ie excluded by lumbar
puncture), use:
gentamicin 5 mg/kg intramuscularly, as a single dose while establishing intravenous or

intraosseous access; see Principles of aminoglycoside use for principles of use [Note 13]
PLUS
benzylpenicillin 60 mg/kg intramuscularly, as a single dose while establishing intravenous

or intraosseous access.
For term neonates with early-onset sepsis or septic shock who are severely unwell and may have meningitis (ie
not excluded by lumbar puncture), use:
cefotaxime 50 mg/kg intramuscularly, as a single dose while establishing intravenous or

intraosseous access
PLUS
benzylpenicillin 90 mg/kg intramuscularly, as a single dose while establishing intravenous

or intraosseous access.
Aciclovir cannot be administered intramuscularly. If herpes simplex encephalitis is suspected (see Figure 2.5), seek
expert advice.
Establish intravenous or intraosseous access before the next scheduled antimicrobial dose. Some antimicrobials are
not suitable for intramuscular administration, and there are few data on absorption and distribution of
intramuscular antimicrobials in sepsis or septic shock.
Empirical regimens for late-onset sepsis or septic shock in neonates who

have been in hospital since birth, source not apparent
septic shock.
Management of late-onset sepsis or septic shock in neonates who have been in hospital since birth is beyond the
scope of these guidelines—antibiotic choice should be based on local protocols, or clinical microbiology or
infectious diseases advice.
Empirical regimens for late-onset sepsis or septic shock in neonates

admitted from the community, source not apparent
Seek expert advice for the management of neonates with confirmed sepsis or microbiologically proven infection.
There is a risk of resistant pathogens in neonates born to mothers with certain risk factors for infection with a
multidrug-resistant Gram-negative bacterium (see Box 2.30) or methicillin-resistant Staphylococcus aureus
(MRSA) (see Box 2.31).
Evaluate appropriateness of antimicrobial therapy daily, with consideration given to the neonate’s clinical status
and the principles of antimicrobial stewardship.
available.
septic shock.
The following recommendations apply to term neonates (gestational age 37 weeks or older) who present to
hospital from the community with late-onset sepsis or septic shock (sepsis or septic shock occurring more than 72
hours after birth). Antimicrobial choice depends on illness severity, and whether meningitis has been excluded or
encephalitis is suspected.
Modified empirical regimens are included below for neonates:
in whom herpes simplex encephalitis is suspected (see Figure 2.5)

at increased risk of MRSA infection (eg exposed to a caregiver colonised with MRSA; see also Box 2.31).
The following regimens may also need to be modified according to local epidemiology, if known.
For empirical therapy for term neonates with late-onset community-acquired sepsis or septic shock who are not
severely unwell, or who are severely unwell but do not have meningitis (ie excluded by lumbar puncture), use:
gentamicin 5 mg/kg intravenously over 3 to 5 minutes, for the first dose; see Principles of
aminoglycoside use for subsequent dosing and principles of use [Note 14]
PLUS EITHER
1 amoxicillin 50 mg/kg intravenously
neonates 7 days or younger: 12-hourly

neonates older than 7 days: 8-hourly
OR
1 ampicillin 50 mg/kg intravenously

neonates older than 7 days: 8-hourly.
For empirical therapy for term neonates with late-onset community-acquired sepsis or septic shock who are
severely unwell and may have meningitis (ie not excluded by lumbar puncture), use:
cefotaxime 50 mg/kg intravenously

PLUS EITHER
1 amoxicillin 100 mg/kg intravenously

OR
1 ampicillin 100 mg/kg intravenously

neonates older than 7 days: 8-hourly.
If herpes simplex encephalitis is suspected (see Figure 2.5), add aciclovir to the above regimens. Use:
If herpes simplex encephalitis is confirmed, see Neonatal herpes simplex infection for subsequent management.
For neonates at increased risk of MRSA infection (eg exposed to a caregiver colonised with MRSA; see also Box
2.31), add vancomycin to the above regimens. Use:
vancomycin intravenously. See Principles of vancomycin use for principles of use

neonates 7 days or younger: 15 mg/kg 12-hourly. Consider a 20 mg/kg loading dose for
neonates with septic shock or requiring intensive care support
neonates older than 7 days and younger than 45 weeks postmenstrual age [Note 15]: 15
mg/kg 8-hourly. Consider a 20 mg/kg loading dose for neonates with septic shock or
requiring intensive care support
neonates older than 7 days and 45 weeks postmenstrual age or older [Note 15]: 15 mg/kg
6-hourly. Consider a 20 mg/kg loading dose for neonates with septic shock or requiring
antimicrobial therapy can be administered intramuscularly. For neonates who are not severely unwell, or are
severely unwell but do not have meningitis (ie excluded by lumbar puncture), use:
gentamicin 5 mg/kg intramuscularly, as a single dose while establishing intravenous or

PLUS EITHER
1 amoxicillin 50 mg/kg intramuscularly, as a single dose while establishing intravenous or

intraosseous access
OR
1 ampicillin 50 mg/kg intramuscularly, as a single dose while establishing intravenous or

intraosseous access.
For neonates who are severely unwell and may have meningitis (ie not excluded by lumbar puncture), use:
cefotaxime 50 mg/kg intramuscularly, as a single dose while establishing intravenous or

intraosseous access
PLUS EITHER

intraosseous access
OR

For neonates at increased risk of MRSA infection (eg exposed to a caregiver colonised with MRSA; see also Box
2.31), add teicoplanin to the above regimens. Use:
teicoplanin 16 mg/kg up to 80 mg intramuscularly, as a single dose while establishing

intravenous or intraosseous access.
Aciclovir cannot be administered intramuscularly. If herpes simplex encephalitis is suspected (see Figure 2.5), seek
expert advice.
Note 15: Postmenstrual age = gestational age plus postnatal age.
Empirical regimens for community-acquired sepsis or septic shock in

infants 1 month to younger than 2 months, source not apparent
Evaluate appropriateness of antimicrobial therapy daily, with consideration given to the infant’s clinical status and
available.
septic shock.
Modified empirical regimens are included below for infants:
in whom herpes simplex encephalitis is suspected

at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (eg exposed to a caregiver
colonised with MRSA; see also Box 2.31).
For infants 1 month to younger than 2 months with community-acquired sepsis or septic shock without an
apparent source of infection, who may have meningitis (ie not excluded by lumbar puncture), as a two-drug
regimen, use:
1 cefotaxime 50 mg/kg intravenously, 6-hourly
OR
1 ceftriaxone 50 mg/kg intravenously, 12-hourly
PLUS EITHER
1 amoxicillin 50 mg/kg intravenously, 6-hourly
OR
1 ampicillin 50 mg/kg intravenously, 6-hourly.

For infants 1 month to younger than 2 months with community-acquired sepsis or septic shock without an
apparent source of infection, who do not have meningitis (ie excluded by lumbar puncture), use:
gentamicin 7.5 mg/kg intravenously over 3 to 5 minutes, for the first dose; see Principles
of aminoglycoside use for subsequent dosing and principles of use [Note 16]
PLUS EITHER
1 amoxicillin 50 mg/kg intravenously, 6-hourly
OR
1 ampicillin 50 mg/kg intravenously, 6-hourly.
If herpes simplex encephalitis is suspected, add aciclovir to the above regimens. Use:
aciclovir 500 mg/m2 intravenously, 8-hourly [Note 17] [Note 18].
If herpes simplex encephalitis is confirmed, seek expert advice. See also Herpes simplex encephalitis for
subsequent management.
For infants at increased risk of MRSA infection (eg exposed to a caregiver colonised with MRSA; see also Box
2.31), add vancomycin to the above regimens. Use:
use. Consider a 25 to 30 mg/kg loading dose.
antimicrobial therapy can be administered intramuscularly. For infants 1 month to younger than 2 months who may
have meningitis (ie not excluded by lumbar puncture), as a two-drug regimen, use:
1 cefotaxime 50 mg/kg intramuscularly, as a single dose while establishing intravenous or

intraosseous access [Note 19]
OR
1 ceftriaxone 50 mg/kg intramuscularly, as a single dose while establishing intravenous or

intraosseous access [Note 20]
PLUS EITHER

intraosseous access
OR

For infants 1 month to younger than 2 months who do not have meningitis (ie excluded by lumbar puncture), use:
gentamicin 7.5 mg/kg intramuscularly, as a single dose while establishing intravenous or

PLUS EITHER

intraosseous access
OR

For infants at increased risk of MRSA infection (eg exposed to a caregiver colonised with MRSA; see also Box
2.31), add teicoplanin to the above regimens. Use:
teicoplanin 10 mg/kg intramuscularly, as a single dose while establishing intravenous or

Aciclovir cannot be administered intramuscularly. If herpes simplex encephalitis is suspected, seek expert advice.
Note 18: A dose of 500 mg/m2 is approximately equal to 20 mg/kg for children 1 month to younger than 2
months.
Note 19: Intramuscular injection of cefotaxime is painful; consider reconstituting with lidocaine 0.5%.
Empirical regimens for hospital-acquired sepsis or septic shock in

infants 1 month to younger than 2 months, source not apparent
septic shock.
Management of hospital-acquired sepsis or septic shock in infants 1 month to younger than 2 months is beyond the
scope of these guidelines. Regimens based on local protocols, or clinical microbiology or infectious diseases
advice, improve outcomes, because survival is increased when appropriate antibiotics are given early. This is
particularly important for infants in the intensive care unit.
Empirical regimens for community-acquired sepsis or septic shock in

children 2 months or older, source not apparent
Evaluate appropriateness of antimicrobial therapy daily, with consideration given to the child’s clinical status and
available.
septic shock.
Modified empirical regimens are included below for children:
at risk of infection with a multidrug-resistant Gram-negative bacterium (see Box 2.30 for risk factors)
in tropical regions of Australia [Note 21] where infection with Burkholderia pseudomallei is possible
hypersensitive to penicillins
in whom meningitis is suspected
in whom herpes simplex encephalitis is suspected
at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31).
A two or three-drug regimen is recommended to ensure adequate treatment of bacteria not susceptible to
cefotaxime and ceftriaxone (eg some strains of Streptococcus pneumoniae, MRSA, some strains of Gram-negative
bacteria).
For children 2 months or older with community-acquired sepsis or septic shock without an apparent source of
infection (whether or not meningitis has been excluded), use:

PLUS EITHER
1 cefotaxime 50 mg/kg up to 2 g intravenously, 6-hourly [Note 25]
OR
1 ceftriaxone 50 mg/kg up to 2 g intravenously, 12-hourly
PLUS with either of the above regimens if the child has septic shock or is at increased risk of MRSA infection (se
Box 2.31)
Prioritise administration of gentamicin and either cefotaxime or ceftriaxone, because vancomycin requires slow
infusion.
For children with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, the above regimens
are suitable.
For children with immediate severe or delayed severe hypersensitivity to penicillins, replace cefotaxime or
ceftriaxone in the above regimen with ciprofloxacin. Use:
ciprofloxacin 10 mg/kg up to 400 mg intravenously, 8-hourly [Note 26].
For children at risk of infection with a multidrug-resistant Gram-negative bacterium (for risk factors, see Box
2.30), consider replacing the above regimens with:
meropenem 20 mg/kg up to 1 g intravenously, 8-hourly [Note 27] [Note 28]
PLUS if the child has septic shock or is at increased risk of MRSA infection
In tropical regions of Australia [Note 21] where infection with B. pseudomallei is possible, for children with
sepsis who do not require intensive care support and do not have risk factors for B. pseudomallei infection (see
Box 2.17), a modified empirical regimen is not required. Select the appropriate regimen from those above (either a
gentamicin- or meropenem-based regimen).
In tropical regions of Australia [Note 21] where infection with B. pseudomallei is possible, for children with
sepsis who do not require intensive care support but have risk factors for B. pseudomallei infection (see Box
2.17), consider replacing the gentamicin-based regimen with:
piperacillin+tazobactam 100+12.5 mg/kg up to 4+0.5 g intravenously, 6-hourly
PLUS if the patient is at increased risk of MRSA infection
use.
In tropical regions of Australia [Note 21] where infection with B. pseudomallei is possible, for patients with
septic shock or requiring intensive care support, consider replacing the above regimens with:
meropenem 25 mg/kg up to 1 g intravenously, 8-hourly [Note 27] [Note 28]
PLUS
If meningitis is suspected, add to the above regimens:
dexamethasone 0.15 mg/kg up to 10 mg intravenously, started before or with the first dose
of antibiotic, then 6-hourly [Note 29]. See Meningitis for the duration of therapy.
If herpes simplex encephalitis is suspected, add to the above regimens:
aciclovir (child 12 years or younger: 500 mg/m2; child older than 12 years: 10 mg/kg)
intravenously, 8-hourly [Note 30] [Note 31].
If herpes simplex encephalitis is confirmed, seek expert advice. See also Herpes simplex encephalitis for
subsequent management.
antimicrobial therapy can be administered intramuscularly. Use:
gentamicin intramuscularly, as a single dose while establishing intravenous or intraosseous

access; see Principles of aminoglycoside use for principles of use [Note 22]
child 2 months to younger than 10 years: 7.5 mg/kg up to 320 mg [Note 23] [Note 24]
child 10 years or older with septic shock or requiring intensive care support: 7 mg/kg
[Note 24]
mg/kg up to 560 mg [Note 24]
PLUS EITHER
1 cefotaxime 50 mg/kg up to 2 g intramuscularly, as a single dose while establishing

intravenous or intraosseous access [Note 32]
OR
1 ceftriaxone 50 mg/kg up to 2 g intramuscularly, as a single dose while establishing

intravenous or intraosseous access [Note 33]
PLUS with either of the above regimens if the child has septic shock or is at increased risk of MRSA infection (se
Box 2.31)
teicoplanin 10 mg/kg up to 400 mg intramuscularly, as a single dose while establishing

intravenous or intraosseous access.
Aciclovir cannot be administered intramuscularly. If herpes simplex encephalitis is suspected, seek expert advice.
Note 25: If meningitis has been excluded, the frequency of cefotaxime dosing can be reduced to 8-hourly.
effect on cartilage development; however, there are few data from human trials to support this finding.
Ciprofloxacin can be used in children when it is the drug of choice.
treatment options.
Note 29: If dexamethasone is not available, hydrocortisone (4 mg/kg up to 200 mg intravenously) may be used
for the initial dose.
Note 32: Intramuscular injection of cefotaxime is painful; consider reconstituting with lidocaine 0.5%. Split
large intramuscular doses into two injections.
Empirical regimens for hospital-acquired sepsis or septic shock in

children 2 months or older, source not apparent
septic shock.
Management of hospital-acquired sepsis or septic shock in children 2 months or older is beyond the scope of these
guidelines. Regimens based on local protocols, or clinical microbiology or infectious diseases advice, improve
outcomes, because survival is increased when appropriate antibiotics are given early. This is particularly important
for children in the intensive care unit.
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Directed therapy for bloodstream infections,
including sepsis and septic shock
Modifying empirical therapy for bloodstream infections when the
pathogen is identified
Modify antimicrobial therapy for sepsis or septic shock as soon as additional information is available (eg source of
infection, Gram stain, results of culture and susceptibility testing). If the pathogen has been identified and is
consistent with the source of infection, de-escalate treatment according to the following pathogen-specific
recommendations. However, in some cases (eg intra-abdominal sepsis associated with a perforated viscus) it is
appropriate to continue empirical therapy targeted to the source of infection. Occasionally, an organism identified
by culture (eg a coagulase-negative staphylococci) is a contaminant. A clinical microbiologist or infectious
diseases physician can assist with modifying therapy based on microbiological results and clinical progress.
Pathogen-specific regimens are included for:
Candida species sepsis (candidaemia)

Enterobacteriaceae (including E. coli and K. pneumoniae) sepsis or septic shock
Neisseria meningitidis (meningococcal) sepsis
Pseudomonas aeruginosa sepsis or septic shock
Salmonella typhi and paratyphi A, B and C bacteraemia (typhoid and paratyphoid fever)
Staphylococcus aureus bacteraemia
Streptococcus pneumoniae sepsis or septic shock
Streptococcus pyogenes bloodstream infections, including toxic shock syndrome.
Regimens for bacteraemia caused by Clostridium species or Listeria monocytogenes are not included in this topic.
For drug choice for bacteraemia caused by Clostridium species, see Clostridial necrotising skin and soft tissue
infection. For drug choice for bacteraemia caused by L. monocytogenes, see Listeria monocytogenes
meningoencephalitis.
Directed antimicrobial therapy for neonates with sepsis or septic shock is beyond the scope of these guidelines—
seek expert advice.

Approach to managing candidaemia
The management of sepsis caused by Candida species is complex—seek expert advice. The choice of empirical
treatment is based on whether the patient is critically ill, the likelihood of Candida albicans infection (C. albicans
is usually susceptible to fluconazole), and local microbiology and susceptibility data. The superiority of one
treatment over another has not been convincingly demonstrated in clinical trials.
Importantly, yeast identified on blood culture should not be considered a contaminant.
If it is the likely source of infection, remove a central venous catheter as soon as possible, provided the potential
benefits of catheter removal outweigh potential harms.
Patients should be evaluated for endophthalmitis with a dilated funduscopic examination (preferably by an
ophthalmologist) within a week of candidaemia diagnosis; if the patient is neutropenic, the examination should be
performed after neutrophil recovery. If endophthalmitis is identified, seek advice from an infectious diseases
physician or clinical microbiologist regarding choice of antifungal therapy—additional intravitreal antifungal
therapy may be required.
Consider echocardiography to exclude Candida endocarditis.
For more information on managing candidaemia, including in neutropenic patients and neonates, see the
Australian and New Zealand consensus guidelines [Note 1] and the Infectious Diseases Society of America
guidelines [Note 2].
2014;44(12b):1315-32. [URL]
Note 2: Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical
practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of
America. Clin Infect Dis 2016;62(4):e1-50. [URL]
Initial therapy for candidaemia

The choice of initial therapy depends on whether the patient is critically ill. For critically ill patients, use an
echinocandin. For noncritically ill patients with Candida albicans infection (eg germ tube positive), use
fluconazole. For other noncritically ill patients, an echinocandin is usually used first-line but fluconazole is an
alternative for patients unlikely to be infected with a fluconazole-resistant Candida species (eg patients not
previously exposed to azole antifungals).
For antifungal choice for candidaemia of urinary tract origin, see also Antifungal agents for candidal UTI.
If initial echinocandin therapy is indicated, use:
daily [Note 3]
OR
1 caspofungin
adult 80 kg or less: 70 mg intravenously, for the first dose, then 50 mg intravenously, daily
adult more than 80 kg: 70 mg intravenously, daily
child 3 months or older: 70 mg/m2 up to 70 mg intravenously, for the first dose, then 50
mg/m2 up to 70 mg intravenously, daily [Note 4] [Note 5]
child younger than 3 months: 25 mg/m2 intravenously, daily [Note 4]
OR
If initial fluconazole therapy is indicated for noncritically ill patients, use:
fluconazole 800 mg (child: 12 mg/kg up to 800 mg) intravenously, for the first dose, then
Oral fluconazole therapy can be used instead of intravenous fluconazole therapy for initial therapy for stable
patients. Consider:
fluconazole 800 mg (child: 12 mg/kg up to 800 mg) orally, for the first dose, then 400 mg
(child: 6 mg/kg up to 400 mg) orally, daily.
Lipid formulations of amphotericin B are alternatives if there is resistance or intolerance to other antifungal agents.
Note 3: Data to support the use of anidulafungin in children are lacking. If anidulafungin is the treatment of
choice, seek expert advice on dosing.
Note 5: If treatment is well tolerated but response is inadequate, increase the maintenance dose to 70 mg/m2 (up
to 70 mg).
Note 6: For adults or children weighing 40 kg or more who have an inadequate response to treatment, increase
the dose to 200 mg. For children weighing less than 40 kg who have an inadequate response to treatment,
increase the dose to 4 mg/kg (up to 160 mg).
Continuation therapy for candidaemia
If the Candida isolate is subsequently identified as fluconazole-susceptible and the patient is not critically ill,
change therapy to fluconazole (intravenous or oral; see Initial therapy for candidaemia, above) if an echinocandin
was used initially.
For patients not already taking oral fluconazole for infection caused by Candida albicans or other fluconazole-
susceptible Candida species, following clinical improvement continue treatment with:
fluconazole 400 mg (child: 6 mg/kg up to 400 mg) orally, daily.
For continuation therapy for fluconazole-resistant Candida species, seek expert advice.
Duration of therapy for candidaemia

Take blood samples for repeat culture 24 to 48 hours after antifungal therapy is started, and repeat every 1 to 2
days until culture results are negative.
If there are no metastatic complications, continue treatment for 14 days after blood culture results are negative and
signs and symptoms of infection have resolved. If metastatic complications such as endophthalmitis or liver
abscess are present, prolonged treatment is required (eg 4 to 6 weeks).
Enterobacteriaceae (including E. coli and K. pneumoniae) sepsis or

septic shock
For sepsis or septic shock caused by Enterobacteriaceae (eg Escherichia coli, Klebsiella species, Proteus species),
treat according to the results of susceptibility testing when available.
While awaiting the results of susceptibility testing, treat according to the recommendations for the source of
infection (this can usually be identified and is most commonly the biliary or urinary tract), or seek expert advice.
For patients treated with gentamicin empirically, if neither the source of infection nor results of susceptibility
testing are available by 72 hours and the patient is not at high risk of infection with a multidrug-resistant bacterium
(see Box 2.30), ceftriaxone or cefotaxime is often a suitable alternative. For E. coli or K. pneumoniae isolates
resistant to broad-spectrum cephalosporins but susceptible to piperacillin+tazobactam and meropenem, use
meropenem because the risk of mortality is increased in patients treated with piperacillin+tazobactam [Note 7].
For duration of therapy, refer to the recommendations for the identified source of infection. If the response to
treatment is rapid, 5 to 7 days of therapy (empirical + directed) is adequate for patients who are not
immunocompromised and do not have a deep-seated or uncontrolled source of infection.
Note 7: Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, et al. Effect of Piperacillin-Tazobactam
vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection
and Ceftriaxone Resistance: A Randomized Clinical Trial. JAMA 2018;320(10):984-94. [URL]
Neisseria meningitidis (meningococcal) sepsis

Increasingly, Neisseria meningitidis infection has an atypical presentation—gastrointestinal symptoms and other
nonspecific features may predominate. Purpuric rash and meningitis symptoms may be absent.
For the management of meningococcal sepsis (including the role of clearance antibiotics for the patient and close
contacts), see Neisseria meningitidis (meningococcal) meningitis.
Pseudomonas aeruginosa sepsis or septic shock

For Pseudomonas aeruginosa sepsis or septic shock, combination therapy with two antipseudomonal drugs is
recommended until the results of susceptibility testing are available. Use:

PLUS EITHER
1 ceftazidime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly [Note 13]
OR

hourly [Note 15].
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, until the results of
susceptibility testing are available, use gentamicin plus ceftazidime (as above).
For patients with immediate severe or delayed severe hypersensitivity to penicillins, until the results of
susceptibility testing are available, use:

pre-existing kidney impairment: 7 mg/kg for the first dose. See Principles of
PLUS
Combination therapy is not necessary once susceptibility is known, but may be used for infections with a high
organism burden or for septic shock—seek expert advice. If monotherapy is used, gentamicin is not recommended
if appropriate alternative drugs are available because clinical outcomes are inferior with gentamicin compared to
an antipseudomonal beta lactam.
For duration of therapy, refer to the recommendations for the source of infection; if the source of infection is not
apparent, seek expert advice.
calculate the dose.
function.
administering the intermittent dose of ceftazidime as an extended infusion over 3 to 4 hours, or as a continuous
Salmonella typhi and paratyphi A, B and C bacteraemia (typhoid and

paratyphoid fever)
Typhoid and paratyphoid fevers (enteric fevers) (bloodstream infection with Salmonella typhi or paratyphi A, B or
C) are almost always acquired outside Australia.
Resistance to amoxicillin, chloramphenicol and trimethoprim+sulfamethoxazole has limited the options for
treatment. Reduced susceptibility to quinolones is common in infections acquired on the Indian subcontinent and
in Southeast Asia. While awaiting susceptibility results, azithromycin or ceftriaxone should be used for initial
therapy for infections acquired in these regions.
Use azithromycin or ceftriaxone for initial therapy of infection acquired on the Indian subcontinent or in Southeast Asia.
Clinical response to treatment may be delayed for several days, even for infections caused by susceptible bacteria.
Some patients with enteric fever become long-term carriers—seek expert advice.
In adults and children older than 1 year with uncomplicated typhoid or paratyphoid fever and who can tolerate
oral therapy, use:
1 azithromycin 1 g (child: 20 mg/kg up to 1 g) orally, daily for 5 to 7 days
OR (if susceptibility is confirmed)
16] [Note 17].
In adults and children older than 1 year with severe typhoid or paratyphoid fever or who are unable to tolerate
oral therapy, use intravenous therapy initially:
1 azithromycin 500 mg (child: 10 mg/kg up to 500 mg) intravenously, daily until oral
azithromycin can be tolerated (total duration of 5 to 7 days [intravenous + oral])
1 ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 12-hourly until oral
ciprofloxacin can be tolerated (total duration of 7 days [intravenous + oral]) [Note 16]
OR
2 ceftriaxone 2 g (child 1 year or older: 100 mg/kg up to 2 g) intravenously, daily; for

older: 50 mg/kg up to 1 g) intravenously, 12-hourly. When an adequate clinical response
is achieved and oral therapy can be tolerated, switch to oral azithromycin or ciprofloxacin,
depending on results of susceptibility testing (total duration at least 7 days [intravenous +
oral]).
For children aged 1 year or younger with typhoid or paratyphoid fever, use intravenous therapy for the entire
course of treatment:
1 azithromycin 10 mg/kg intravenously, daily for 7 days in children aged 3 to 12 months, or

10 days in children younger than 3 months
1 ciprofloxacin 10 mg/kg intravenously, 12-hourly for 7 days in children aged 3 to 12

months, or 10 days in children younger than 3 months [Note 16]
OR
2 cefotaxime 50 mg/kg intravenously, 8-hourly; for children with septic shock or requiring
intensive care support, use a 6-hourly dosing interval. Treat for 7 days in children aged 3
to 12 months, or 10 days in children younger than 3 months.
OR
2 ceftriaxone (child 1 month or older) 100 mg/kg intravenously, daily; for children with
septic shock or requiring intensive care support, use ceftriaxone 50 mg/kg intravenously,
12-hourly. Treat for 7 days in children aged 3 to 12 months, or 10 days in children
younger than 3 months.
Perform cerebrospinal fluid (CSF) analysis in all neonates and children younger than 3 months to exclude
neurological disease.

Approach to managing Staphylococcus aureus bacteraemia
Staphylococcus aureus bacteraemia is associated with significant morbidity and mortality; arrange a consult with
an infectious diseases physician because this improves outcomes.
Always assume patients with Gram-positive cocci in clusters in the blood have S. aureus bacteraemia, even if the
patient appears well.
The approach to managing S. aureus bacteraemia in adults is summarised in Box 2.32. Children with S. aureus
bacteraemia are managed differently to adults.
S. aureus bacteraemia is frequently complicated by metastatic infection (eg endocarditis, septic arthritis, lung
abscess). When treating patients with S. aureus bacteraemia and infection at another site, consider both the
recommendations in this topic and those for the other site of infection. In particular, consider whether the antibiotic
penetrates the metastatic site. For example, cefazolin poorly penetrates the central nervous system and should not
be used for S. aureus bacteraemia complicated by brain abscess or subdural empyema.
Infections associated with S. aureus bacteraemia include osteomyelitis, septic arthritis, staphylococcal pneumonia,
lung abscess, staphylococcal endocarditis, and cardiac implantable electronic device infections.
For management of staphylococcal toxic shock syndrome, see here.
Approach to managing adults with Staphylococcus aureus bacteraemia (Box 2.32)
Printable box
To manage an adult with S. aureus bacteraemia:
Consult an infectious diseases physician.

Immediately start empirical therapy with intravenous flucloxacillin plus vancomycin, provided the patient
is not hypersensitive to penicillins. Adjust therapy as soon as the susceptibilities of the isolate are known.
If possible, remove the source of infection (eg replace an intravenous catheter, drain an abscess).
Evaluate the patient for evidence of complicated S. aureus bacteraemia using the criteria in Duration of
therapy for Staphylococcus aureus bacteraemia.
Take blood samples for repeat culture 48 to 72 hours after starting antibiotics. Repeat every 2 days until
the first negative culture result.
Monitor clinical response and blood tests (full blood count, C-reactive protein, serum electrolytes and liver
enzymes) for the duration of treatment.
Arrange for a transthoracic echocardiogram (TTE) to be performed. A transoesophageal echocardiogram
(TOE) is recommended for some patients—see Assessing and monitoring patients with Staphylococcus
aureus bacteraemia.
Continue intravenous antibiotics for a minimum of 2 weeks; some patients require 4 to 6 weeks of
intravenous treatment—see Duration of therapy for Staphylococcus aureus bacteraemia. Because treatment
is prolonged, arrange insertion of a long-term vascular access device (eg a peripherally inserted central
catheter [PICC]).
Provide verbal and written advice to the patient and their family about the symptoms of relapse and the
need for early review if these symptoms occur.
Empirical therapy for Staphylococcus aureus bacteraemia
If Gram-positive cocci in clusters are identified by Gram stain of blood samples, use combination therapy while
awaiting results of culture and susceptibility testing:
PLUS

Use a 4-hourly flucloxacillin dosing interval for patients with septic shock or requiring intensive care support.
flucloxacillin in the above regimen with cefazolin:
Use a 6-hourly cefazolin dosing interval for adults (but not children) with septic shock or requiring intensive care
support.
monotherapy (see dosage above) [Note 18].
Modify therapy based on the results of culture and susceptibility testing—see Directed therapy for Staphylococcus
aureus bacteraemia.
Note 18: In a critical situation, a cefazolin-containing regimen can be considered in patients with immediate
severe hypersensitivity who are not suspected to have central nervous system infection, after undertaking a risk–
benefit analysis and assessment of potential side-chain cross-reactivity (see Cross-reactivity between beta
lactams). Seek expert advice.
Directed therapy for Staphylococcus aureus bacteraemia

Principles
For the treatment of S. aureus bacteraemia in adults, use intravenous antibiotics for the duration of therapy. In
children, oral continuation therapy is sometimes used—see Duration of therapy for Staphylococcus aureus
bacteraemia.
Community-based parenteral antimicrobial therapy may be appropriate after inpatient stabilisation and appropriate
investigation.
Adding rifampicin to the primary regimen for S. aureus bacteraemia is not recommended because a large
randomised controlled trial showed no benefit and a trend to increased adverse effects [Note 19]. Of note, few
patients with prosthetic valve endocarditis were included in this trial, so the results cannot be applied to this group.
Note 19: Thwaites GE, Scarborough M, Szubert A, Nsutebu E, Tilley R, Greig J, et al. Adjunctive rifampicin for
Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled
trial. Lancet 2018;391(10121):668-78. [URL]
Methicillin- and penicillin- susceptible S. aureus bacteraemia
Compared with other antimicrobials (such as vancomycin), beta lactams are associated with improved outcomes
(eg reduced mortality) when used to treat methicillin-susceptible S. aureus (MSSA) bacteraemia, including
penicillin-susceptible S. aureus (PSSA) bacteraemia.
For methicillin-susceptible S. aureus bacteraemia, use:
1 flucloxacillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly. For patients with

endocarditis, septic shock or requiring intensive care support, use a 4-hourly dosing
interval. See Duration of therapy
OR
2 cefazolin 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly. For adults with septic

shock or requiring intensive care support, use a 6-hourly dosing interval [Note 20]. See
Emerging evidence suggests that cefazolin is as effective as flucloxacillin for the treatment of methicillin-
susceptible S. aureus bacteraemia. However, there are no published randomised controlled trials comparing
cefazolin with flucloxacillin for this indication. Additionally, cefazolin does not reliably penetrate the blood brain
barrier, so should not be used as monotherapy for patients with suspected central nervous system infection.
Flucloxacillin continues to be recommended as first-line treatment because of greater clinical experience with its
use.
For isolates confirmed to be penicillin-susceptible by a clinical microbiologist, use:
benzylpenicillin 1.8 g (child: 50 mg/kg up to 1.8 g) intravenously, 4-hourly. See Duration

of therapy.
antimicrobial hypersensitivity). Management depends on the type of hypersensitivity and whether central nervous
system infection is suspected.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use cefazolin
(as above). If central nervous system infection is suspected, combine cefazolin with vancomycin (as for
methicillin-resistant S. aureus).
For patients with immediate severe hypersensitivity to penicillins, perform desensitisation if possible—
seek expert advice. Use vancomycin (as for methicillin-resistant S. aureus) until the patient has been
desensitised or if desensitisation is not possible.
For patients with delayed severe penicillin hypersensitivity, use vancomycin (as for methicillin-resistant S.
aureus).
Note 20: Do not use cefazolin as monotherapy for patients with suspected central nervous system infection,
because it does not reliably penetrate the blood brain barrier. If cefazolin is the drug of choice, it should be
combined with vancomycin (as for methicillin-resistant S. aureus).
Methicillin-resistant S. aureus bacteraemia
For methicillin-resistant S. aureus (MRSA) bacteraemia, use:

use. See also Duration of therapy.
Vancomycin continues to be the preferred treatment for methicillin-resistant S. aureus bacteraemia because other
antibiotics have not been shown to be superior to vancomycin for this indication. Some antibiotics (eg teicoplanin,
trimethoprim+sulfamethoxazole) have been shown to be inferior to vancomycin when used for methicillin-
resistant S. aureus bacteraemia, and should be avoided. Furthermore, most alternative treatment options (eg
ceftaroline, daptomycin, linezolid) are substantially more expensive.
Seek expert advice if the methicillin-resistant S. aureus isolate has reduced susceptibility to vancomycin; it may
not be possible to achieve adequate vancomycin exposure for clinical efficacy.
Check the vancomycin minimum inhibitory concentration (MIC) if response to therapy is delayed (positive blood
culture result on day 5 or later). The isolate may have reduced susceptibility to vancomycin. Therapy should be
changed if the minimum inhibitory concentration is 2 mg/L or more—seek expert advice.
Duration of therapy for Staphylococcus aureus bacteraemia
Adults
The duration of antibiotic therapy for adults with S. aureus bacteraemia depends on whether the patient has
complications of infection. Use intravenous antibiotics for the duration of therapy.
Treat adults with complicated S. aureus bacteraemia with at least 4 weeks of intravenous therapy; extend to 6
weeks if response to therapy is slow. Adults have complicated S. aureus bacteraemia if they meet any of the
following criteria:
a positive blood culture result 48 hours after starting appropriate antibiotics

fever 72 hours after starting appropriate antibiotics
abnormal valvular morphology or evidence of valvular lesions, regurgitation or endocarditis on transthoracic
echocardiogram (TTE) or transoesophageal echocardiogram (TOE)—see Assessing and monitoring patients
with Staphylococcus aureus bacteraemia
no identifiable source of infection or an identifiable source of infection that has not been addressed
evidence of metastatic infection (eg vertebral osteomyelitis, endocarditis)
intravascular prosthetic material (eg pacemaker, prosthetic cardiac valve, prosthetic arteriovenous graft).
Treat adults with uncomplicated S. aureus bacteraemia with 14 days of intravenous therapy. Patients have
uncomplicated bacteraemia if they do not meet any of the above criteria.
Children
There are few data to inform the duration of therapy for S. aureus bacteraemia in children. The duration of therapy
recommended in these guidelines is based on extensive clinical experience, and is consistent with the consensus
recommendations of the Australian and New Zealand Paediatric Infectious Diseases Australasian Stewardship of
Antimicrobials in Paediatrics group [Note 21].
Duration depends on whether the bacteraemia is caused by methicillin-resistant S. aureus and whether the patient
has complicated infection—indicated by persistent bacteraemia, a delayed response to therapy, or metastatic
infection (eg osteomyelitis, endocarditis).
With the exception of bone and joint infection (see discussion below), the treatment course must be completed
with intravenous therapy.
For methicillin-susceptible S. aureus bacteraemia in children without complications, 7 days of intravenous

therapy after the first negative blood culture result may be adequate.
For methicillin-resistant S. aureus bacteraemia in children without complications, a minimum duration of 14 days
of intravenous therapy is recommended.
A longer duration of therapy is generally required for complicated infection—seek expert advice.
While prolonged therapy is required for S. aureus bacteraemia associated with osteomyelitis or septic arthritis, the
duration of intravenous therapy may be shortened to 4 days if all of the following criteria apply:
bones or joints are the only focus of bacteraemia

bacteraemia resolved rapidly (blood culture results were negative at 48 to 72 hours)
the child is clinically improving.
The remainder of the treatment course can be completed with oral therapy if a suitable oral antibiotic formulation
is available.
Seek expert advice on the duration of intravenous and total therapy for each child. See also duration of therapy for
osteomyelitis or the suggested duration of therapy in Table 2.2 for septic arthritis.
Note 21: McMullan BJ, Andresen D, Blyth CC, Avent ML, Bowen AC, Britton PN, et al. Antibiotic duration
and timing of the switch from intravenous to oral route for bacterial infections in children: systematic review and
guidelines. Lancet Infect Dis 2016;16(8):e139-52. [URL]
Assessing and monitoring patients with Staphylococcus aureus bacteraemia

Take blood samples for repeat culture 48 to 72 hours after starting antibiotics, and repeat every 2 days until the first
negative culture result. In practice, sampling may be performed more frequently in children because bacteraemia
can clear quickly, and the duration of therapy is often measured from the time of the first negative blood culture
result. Close clinical review is essential to detect relapse or the development of metastatic infection.
If S. aureus bacteraemia is associated with an intravascular device, promptly remove the device. Exclude cardiac
implantable electronic device (CIED) infection in patients with a device in situ.
Infective endocarditis can complicate S. aureus bacteraemia and, in adults, must be excluded by
echocardiography. The choice of transthoracic echocardiogram (TTE) or transoesophageal echocardiogram (TOE)
is controversial. Transoesophageal echocardiogram is more sensitive but also more invasive. Increased sensitivity
is preferable for patients with abnormal or prosthetic heart valves; if there is poor visualisation of the heart valves
with transthoracic echocardiogram; or if there is a high suspicion of endocarditis. If endocarditis is confirmed, see
Staphylococcal endocarditis for treatment regimens and duration of therapy.
Echocardiography is most sensitive at days 5 to 7; however, request earlier echocardiography if the patient has
signs of endocarditis (eg heart murmur).
In children, do not perform echocardiography unless the child has an intracardiac or valvular abnormality,
prolonged fever, suspected endocarditis, or positive blood culture results beyond 72 hours. Transthoracic
echocardiogram, rather than transoesophageal echocardiogram, is usually preferred in children.
Re-evaluate adults and children with bacteraemia lasting 7 days or longer for endocarditis and other metastatic
foci.
Haematogenous seeding of prosthetic material (eg prosthetic joints) by S. aureus can result in metastatic infection
at the prosthetic site (eg arthroplasty device infections, prosthetic valve endocarditis).
Staphylococcal toxic shock syndrome

Staphylococcal toxic shock syndrome is a rare toxin-mediated disease that can develop after an apparently minor
infection, or in patients colonised with a toxin-producing Staphylococcus aureus strain. Approximately 50% of
cases are associated with tampon use in menstruating women and the remainder with a variety of foci. Clinical
symptoms resemble streptococcal toxic shock syndrome. Gastrointestinal symptoms, in particular profuse
diarrhoea, are also common.
For patients with staphylococcal toxic shock syndrome, immediately start appropriate resuscitation and organ
support, and empirical therapy with flucloxacillin and vancomycin (as for empirical therapy for Staphylococcus
aureus bacteraemia).
Despite a lack of clinical evidence, consider adjunctive clindamycin or lincomycin as a strategy to reduce bacterial
toxin production:
1 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly for the first
72 hours
OR
2 lincomycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly for the first 72
hours.
Consider intravenous immunoglobulin (IVIg), particularly in patients who do not respond to fluid resuscitation. If
available, use:
intravenous immunoglobulin (IVIg) (adult and child) 2 g/kg intravenously, as a single

dose as soon as possible but not later than 72 hours. It is reasonable to give the dose in
divided doses if it is not possible to give a single dose.
Modify therapy based on the results of susceptibility testing.
Data to inform the duration of antibiotic therapy are limited—seek expert advice.
Treatment of the source of infection is an important component of therapy.

Benzylpenicillin is the drug of choice for Streptococcus pneumoniae (pneumococcal) sepsis and septic shock not
associated with meningitis. At the dosage below, benzylpenicillin is active against strains of S. pneumoniae with
intermediate susceptibility to penicillin (minimum inhibitory concentration [MIC] less than 4 mg/L). At the time of
writing, S. pneumoniae strains with high-level penicillin resistance are uncommon in Australia.
If pneumococcal sepsis or septic shock is associated with meningitis and the results of susceptibility testing are
not available, empirical therapy is used—see Empirical therapy for meningitis in hospital (pathogen or
susceptibility unknown). If pneumococcal sepsis or septic shock is associated with meningitis and the results of
susceptibility testing are available, directed therapy is used—see Streptococcus pneumoniae (pneumococcal)
meningitis.
For pneumococcal sepsis not associated with meningitis, use:
benzylpenicillin 1.8 g (child: 50 mg/kg up to 1.8 g intravenously), 4-hourly.
1 ceftriaxone 2 g (child 1 month or older: 50 mg/kg up to 2 g) intravenously, daily. For

month or older: 50 mg/kg up to 1 g) intravenously, 12-hourly
OR
1 cefotaxime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly. For patients with

septic shock or requiring intensive care support, use cefotaxime 2 g (child 1 month or
older: 50 mg/kg up to 2 g) intravenously, 6-hourly.
1 moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, daily [Note 22]
OR
Oral moxifloxacin may be a suitable alternative to intravenous moxifloxacin if the patient can tolerate oral therapy.
For duration of therapy, refer to the recommendations for the source of infection; if the source of infection is not
apparent, seek expert advice.
Streptococcus pyogenes bloodstream infections, including toxic shock

syndrome
Overview of Streptococcus pyogenes bloodstream infections
Streptococcus pyogenes (group A streptococcus) bacteraemia is a form of invasive group A streptococcal infection
that usually follows infection at a primary site, most commonly the skin or soft tissues. Postpartum bacteraemia
can occur. Toxic shock syndrome is rare.
Diagnosis of streptococcal toxic shock syndrome requires isolation of S. pyogenes from a hypotensive patient
with two of the following signs: kidney impairment, coagulopathy, hyperbilirubinaemia, adult respiratory distress
syndrome, generalised rash or soft tissue necrosis. Children may present with fever, hypotension and rash, and
evidence of organ dysfunction.
Initial therapy
Patients have complicated S. pyogenes bacteraemia if they have sepsis, septic shock, toxic shock syndrome,
pneumonia, meningitis or necrotising fasciitis.
For complicated S. pyogenes bacteraemia, use:
benzylpenicillin intravenously
patients who do not require intensive care support: 1.8 g (child: 50 mg/kg up to 1.8 g) 4-
hourly
patients who require intensive care support: 2.4 g (child: 50 mg/kg up to 2.4 g) 4-hourly
PLUS EITHER
1 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly for a

minimum of 72 hours and until organ function has significantly improved
OR
2 lincomycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly for a

minimum of 72 hours and until organ function has significantly improved
PLUS with either of the above regimens for toxic shock syndrome or necrotising fasciitis

Despite limited clinical evidence, clindamycin or lincomycin is recommended to reduce bacterial toxin production.
Data to support the use of intravenous immunoglobulin (IVIg) for S. pyogenes toxic shock syndrome or
necrotising fasciitis are inconclusive. However, it is the consensus view of the Antibiotic Expert Groups that
intravenous immunoglobulin (IVIg) should be used when available.
Patients have uncomplicated S. pyogenes bacteraemia if they do not have sepsis, septic shock, toxic shock
syndrome, pneumonia, meningitis or necrotising fasciitis.
For uncomplicated S. pyogenes bacteraemia, monotherapy is appropriate. Use:
For patients with complicated or uncomplicated S. pyogenes bacteraemia who have immediate nonsevere or
delayed nonsevere hypersensitivity to penicillins, replace benzylpenicillin in the above regimens with cefazolin.
Use:

shock or requiring intensive care support, use a 6-hourly cefazolin dosing interval.
For patients with complicated or uncomplicated S. pyogenes bacteraemia who have immediate severe or delayed
severe hypersensitivity to penicillins, replace benzylpenicillin in the above regimens with vancomycin. Use:
Continuation therapy
Once the patient has clinically improved, switch to oral therapy. Use:
amoxicillin 1 g (child: 25 mg/kg up to 1 g) orally, 8-hourly.
For oral continuation therapy for patients hypersensitive to penicillins, seek expert advice.
Data to inform duration of antibiotic therapy are limited—seek expert advice. A total treatment duration (empirical
+ directed) of 7 to 10 days (intravenous + oral) is often adequate.
Nonantibiotic management
When S. pyogenes bacteraemia is associated with necrotising fasciitis, surgical debridement is required. If
available, hyperbaric oxygen therapy can be considered as an adjunct to surgical debridement, but should not delay
surgery.
Prophylaxis for close contacts

Consider prophylaxis for close contacts of patients with S. pyogenes bacteraemia (see Prevention of invasive group
A streptococcal infection for regimens).
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survival in necrotizing fasciitis with vasopressor-dependent shock: A propensity score-matched analysis from 130 US
hospitals. Clin Infect Dis 2017;64(7):877–885 .
Linnér A, Darenberg J, Sjölin J, Henriques-Normark B, Norrby-Teglund A. Clinical efficacy of polyspecific intravenous

immunoglobulin therapy in patients with streptococcal toxic shock syndrome: a comparative observational study. Clin
Infect Dis 2014;59(6):851–857 .
National Blood Authority Australia (NBA). Criteria for clinical use of immunoglobulin in Australia [Ig Governance v3.0.1].
Canberra: NBA; Accessed Aug 2018. https://www.criteria.blood.gov.au/.
Boils and carbuncles
Introduction to boils and carbuncles
Boils (furuncles) and carbuncles (boils with multiple heads) are hair follicle–associated cutaneous abscesses that
extend into the subcutaneous tissue. They are tender and painful, but seldom cause systemic symptoms. Boils and
carbuncles can occur in clusters on the axillae, groin or buttocks.
The pathogen is usually Staphylococcus aureus, occasionally in combination with Streptococcus pyogenes (group
A streptococcus).
Hidradenitis suppurativa is an important noninfectious differential diagnosis of acute furunculosis.
Managing boils and carbuncles

Incision and drainage is the key therapeutic intervention for boils and carbuncles, and achieves cure in
approximately 70% of smaller abscesses (diameter 5 cm or less). Adjunctive antibiotic treatment provides
additional benefit in terms of healing (increasing the rate of cure to approximately 80%) and preventing recurrence.
For abscesses with a diameter more than 5 cm, consider adjunctive antibiotic therapy. For abscesses with a
diameter 5 cm or less, weigh the potential benefits of adjunctive antibiotic therapy against potential harms (eg
diarrhoea, rash or more serious hypersensitivity reactions, bacterial resistance).
Incision and drainage is the key therapeutic intervention for boils and carbuncles.
If antibiotic therapy is used and there are limited local epidemiological data to guide empirical antibiotic choice,
take samples of purulent material from each lesion for microscopy and culture. Microscopy and culture should also
be performed if infection does not improve within 72 hours of starting antibiotic therapy.
For patients not at increased risk of community-associated methicillin-resistant S. aureus (MRSA) infection (see
Box 2.31), empirical therapy targeting methicillin-susceptible S. aureus (MSSA) is appropriate. Use:
OR
Cefalexin is often preferred to dicloxacillin or flucloxacillin in children, because the liquid formulation is better
[Note 1]. Use:
cefalexin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 5 days [Note 2].

OR
2 clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly for 5 days.
For patients at increased risk of community-associated MRSA (see Box 2.31), use
trimethoprim+sulfamethoxazole or clindamycin (as above).
Modify antibiotic therapy based on clinical response and results of microbiological testing. If community-
associated MRSA is identified in a patient taking flucloxacillin, dicloxacillin or cephalexin empirically, it may not
be necessary to modify therapy if the response to incision and drainage is adequate.
A duration of therapy of 5 days is recommended on the basis of extensive clinical experience. Although large
clinical trials continued therapy for 10 days, these trials were not designed to investigate the duration of therapy.
Note 2: For mild skin infection, administering the total daily dose of cefalexin in two 12-hourly doses is also effective (ie cefalexin 1 g [child: 25
mg/kg up to 1 g] orally, 12-hourly).
Key references
Bowen AC, Carapetis JR, Currie BJ, Fowler V Jr, Chambers HF, Tong SYC. Sulfamethoxazole-trimethoprim
(cotrimoxazole) for skin and soft tissue infections including impetigo, cellulitis, and abscess. Open Forum Infect Dis
2017;4(4):ofx232. .
Daum RS, Miller LG, Immergluck L, Fritz S, Creech CB, Young D, et al. A Placebo-Controlled Trial of Antibiotics for
Smaller Skin Abscesses. N Engl J Med 2017;376(26):2545–2555 .
Gottlieb M, DeMott JM, Hallock M, Peksa GD. Systemic antibiotics for the treatment of skin and soft tissue abscesses:
A systematic review and meta-analysis. Ann Emerg Med 2019;73(1):8–
16.10.1016/j.annemergmed.2018.02.011.29530658 .
Miller LG, Daum RS, Creech CB, Young D, Downing MD, Eells SJ, et al. Clindamycin versus trimethoprim-
sulfamethoxazole for uncomplicated skin infections. N Engl J Med 2015;372(12):1093–103.
Moran GJ, Krishnadasan A, Mower WR, Abrahamian FM, LoVecchio F, Steele MT, et al. Effect of cephalexin plus
trimethoprim-sulfamethoxazole vs cephalexin alone on clinical cure of uncomplicated cellulitis: a randomized clinical
trial. JAMA 2017;317(20):2088–96.
Talan DA, Lovecchio F, Abrahamian FM, Karras DJ, Steele MT, Rothman RE, et al. A randomized trial of clindamycin
versus trimethoprim-sulfamethoxazole for uncomplicated wound infection. Clin Infect Dis 2016;62(12):1505–13.
Talan DA, Mower WR, Krishnadasan A, Abrahamian FM, Lovecchio F, Karras DJ, et al. Trimethoprim-
sulfamethoxazole versus placebo for uncomplicated skin abscess. N Engl J Med 2016;374(9):823–32.
Wang W, Chen W, Liu Y, Siemieniuk RAC, Li L, Martínez JPD, et al. Antibiotics for uncomplicated skin abscesses:
systematic review and network meta-analysis. BMJ Open 2018;8(2):e020991. .
Cellulitis and erysipelas
Clinical presentation of cellulitis and erysipelas
Cellulitis and erysipelas present as diffuse, spreading areas of skin erythema. Lymphangitis, lymphadenopathy,
fever or other systemic features may be present.
In erysipelas, the affected area is raised, with a clear line of demarcation between infected and noninfected tissue.
It classically involves the facial skin in a butterfly pattern, but also commonly affects a lower limb. Erysipelas is
most commonly seen in infants, young children and older adults.
Cellulitis extends further into the dermis than erysipelas, involving the subcutaneous tissue. Cellulitis in children is
often periorbital.
Many conditions present similarly to cellulitis—always consider differential diagnoses.
Cellulitis can complicate wounds (eg cuts, abrasions), insect bites or scabies.
Conditions that can be misdiagnosed as cellulitis include: acute contact dermatitis; septic bursitis; gout; and acute
lipodermatosclerosis, which commonly occurs in obese people with venous insufficiency. Bilateral lower limb
cellulitis is rare; always consider differential diagnoses.
Aetiology of cellulitis and erysipelas

Erysipelas is almost always caused by Streptococcus pyogenes (group A streptococcus).
S. pyogenes, or another Streptococcus species (eg group B, C or G), is the most common cause of nonpurulent,
recurrent cellulitis (eg associated with lymphoedema) or spontaneous, rapidly spreading cellulitis. Cellulitis caused
by Staphylococcus aureus (including methicillin-resistant strains [MRSA]) is less frequent and is often associated
with penetrating trauma, ulceration or an abscess. Purulent cellulitis is typically caused by S. aureus.
In specific circumstances, other organisms can cause cellulitis (eg Aeromonas species following fresh water
exposure, Vibrio species following salt water exposure, Gram-negative bacteria in patients with chronic liver
disease). In immunocompromised patients, a broad range of organisms can cause infection including Gram-
negative bacteria, fungi and mycobacteria.
Principles of managing cellulitis and erysipelas

Nonantibiotic management
Assess patients with cellulitis associated with systemic features for necrotising fasciitis or myonecrosis.
Evaluate patients with cellulitis for drainable sources of infection (such as an abscess). If a drainable source is
identified, collect a sample for culture and susceptibility testing. It can be difficult to determine if there is an
underlying abscess with fluctuation if significant overlying induration is present; soft tissue ultrasonography can
aid diagnosis and should be considered if available.
Rest and elevation of the affected area improves clinical response. If the skin has eroded, use
nonadhesive dressings. Address contributing factors such as oedema (eg due to lymphoedema or cardiac failure) or
venous insufficiency.
Antibiotic choice
For management of periorbital and orbital cellulitis, see here.
Oral therapy is adequate for cellulitis and erysipelas not associated with systemic features of infection, and is
usually suitable for patients with a single systemic feature of infection.
Initial intravenous therapy is usually required for adults with two or more of the following systemic features of
infection:
temperature more than 38°C or less than 36°C
heart rate more than 90 beats/minute
respiratory rate more than 20 breaths/minute
white cell count more than 12 × 109/L or less than 4 × 109/L, or more than 10% immature (band) forms.
Intravenous therapy is also used for patients unable to tolerate oral therapy, and may be required for
immunocompromised patients or patients with comorbidities that increase the risk of rapid disease progression (eg
diabetes), even if they do not have two or more systemic features of infection.
For patients with cellulitis associated with two or more systemic features, antibiotic therapy targeting S. pyogenes
and S. aureus is adequate if cellulitis is not associated with hypotension, septic shock or rapid progression of
systemic features. Broader-spectrum therapy is required for cellulitis associated with hypotension, septic shock or
rapid worsening of systemic features.
If intravenous therapy is used initially, consider an early switch to oral therapy if the patient is stable; in some
cases, one or two doses of intravenous therapy is sufficient.
Response to therapy
Local symptoms (eg erythematous rash) can worsen for up to 48 hours after effective therapy is started, but
systemic features should improve. Therefore, when assessing response to treatment, consider systemic features as
well as the extent of cellulitis. If the patient remains systemically well but local symptoms worsen, it may not be
necessary to adjust antibiotic therapy.
Local symptoms may not respond to antibiotic therapy for up to 5 days. However, if there is no improvement in
local symptoms at 48 hours, reconsider the diagnosis, look for a drainable source of infection, and reconsider
antibiotic choice (see Aetiology of cellulitis and erysipelas).
If reassessment does not change the diagnosis or empirical regimen, or locate a drainable source of infection, and
the patient has clearly not improved, consider switching to intravenous therapy. Community-based parenteral
antimicrobial therapy may be appropriate. Clinical prerequisites for community-based therapy of cellulitis include:
a collection or abscess requiring surgical drainage is not clinically suspected

limb compromise from swelling is not a risk
infection of the deeper tissues, such as myositis, fasciitis or osteomyelitis has been excluded
the patient does not have risk factors for rapid progression of infection (such as poorly controlled diabetes or
significant immune compromise).
Because of the strong inflammatory response characteristic of cellulitis, it is common for patients to have residual
signs of inflammation at the end of treatment.
Empirical therapy for cellulitis and erysipelas without systemic features

For cellulitis and erysipelas without systemic features, antibiotic choice depends on whether the infection is likely
to be caused by Streptococcus pyogenes or Staphylococcus aureus (including community-associated methicillin-
resistant S. aureus [CA-MRSA]) (see Aetiology of cellulitis and erysipelas). It is usually appropriate to stop
antibiotic therapy after 5 days, even if mild signs of inflammation remain; extend therapy if the infection has not
clinically improved by the end of the treatment course.
For erysipelas, or if S. pyogenes is suspected based on clinical presentation (eg nonpurulent, recurrent or
spontaneous, rapidly spreading cellulitis), use:
1 phenoxymethylpenicillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 5
days
OR
1 procaine benzylpenicillin 1.5 g (child: 50 mg/kg up to 1.5 g) intramuscularly, daily for at

least 3 days.
Use:
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly for 5 days [Note 2].
For purulent cellulitis (eg associated abscess), or if S. aureus is suspected based on clinical presentation (eg
penetrating trauma, associated ulcer), use:
OR
[Note 1]. Use:
For patients at increased risk of MRSA infection (see Box 2.31), or who have immediate (nonsevere or severe)
or delayed severe hypersensitivity to penicillins, use:

OR
2 clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly for 5 days [Note 2].
Empirical therapy for cellulitis and erysipelas with systemic features

The following advice applies to patients with cellulitis or erysipelas associated with two or more systemic
symptoms but not associated with hypotension, septic shock or rapid progression of systemic features. Assess
patients for necrotising fasciitis or myonecrosis.
Ceftriaxone and cefotaxime have a broad spectrum of activity that is not required for cellulitis that is likely to be
caused by streptococci or staphylococci.
For erysipelas, or if Streptococcus pyogenes is suspected based on clinical presentation (eg nonpurulent, recurrent
or spontaneous, rapidly spreading cellulitis), use:
For purulent cellulitis (eg associated abscess), or if Staphylococcus aureus is suspected based on clinical
presentation (eg penetrating trauma, associated ulcer), use:
For patients with purulent cellulitis or in whom S. aureus is suspected based on clinical presentation, who are at
increased risk of methicillin-resistant S. aureus (MRSA) infection (see Box 2.31), use:
use.
In some regions, based on local community-associated MRSA (CA-MRSA) susceptibility patterns, clindamycin or
lincomycin is a suitable alternative to vancomycin:
OR
benzylpenicillin or flucloxacillin with cefazolin. use:
For patients with immediate severe or delayed severe hypersensitivity to penicillins, replace benzylpenicillin or
flucloxacillin with vancomycin (see dosage above).
If community-based parenteral antimicrobial therapy is appropriate for adult patients, use:
1 cefazolin 2 g intravenously, daily
PLUS
probenecid 1 g orally, daily
OR
1 cefazolin 2 g intravenously, 12-hourly.
Community-based parenteral antimicrobial therapy is rarely used for children with cellulitis; if community-based
intravenous therapy is necessary, consult a service experienced in providing care for children for advice on choice
of therapy.
When systemic features have improved, switch to oral therapy (see Cellulitis and erysipelas without systemic
features); if systemic symptoms rapidly resolve, one or two doses of intravenous therapy may be sufficient. A total
duration of therapy of 5 to 10 days (intravenous + oral) is recommended.
Empirical therapy for cellulitis associated with hypotension, septic

shock or rapid progression of systemic features
Broad-spectrum therapy is required initially for patients with cellulitis associated with hypotension, septic shock or
rapid progression of systemic features. For initial empirical therapy, use the regimens in necrotising skin and soft
tissue infections. Seek expert advice for ongoing therapy.
Start antibiotic therapy within 1 hour of the patient presenting to medical care or, for a ward-based patient,
developing sepsis or septic shock; antibiotics should be given immediately after appropriate samples are taken for
A total duration of therapy of up to 2 weeks (intravenous + oral) is recommended.
Preventing recurrent cellulitis

Factors that predispose patients to recurrent cellulitis include tinea infection of the feet, fissured dermatitis,
lymphoedema and lymphatic malformation.
Examine patients’ feet for tinea infection.
For patients with leg oedema, venous insufficiency or a leg ulcer, see Assessing patients with an ulcer or wound.
Patients with persistent risk factors for recurrent cellulitis can be provided with a prescription for
phenoxymethylpenicillin (see Cellulitis and erysipelas without systemic features) so they can start treatment as
soon as they develop symptoms. Alternatively, for patients with frequent recurrences, prophylaxis can be
considered:
phenoxymethylpenicillin 250 mg orally, twice daily for up to 6 months initially, then

reviewed regularly.
Key references
2017;4(4):ofx232. .
Bruun T, Oppegaard O, Kittang BR, Mylvaganam H, Langeland N, Skrede S. Etiology of cellulitis and clinical prediction
of streptococcal disease: A prospective study. Open Forum Infect Dis 2016;3(1):ofv181. .
Hepburn MJ, Dooley DP, Skidmore PJ, Ellis MW, Starnes WF, Hasewinkle WC. Comparison of short-course (5 days)
and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med 2004;164(15):1669–74.
Dis 2016;16(8):e139–52.
Moran GJ, Krishnadasan A, Mower WR, Abrahamian FM, LoVecchio F, Steele MT, et al. Effect of cephalexin plus
trimethoprim-sulfamethoxazole vs cephalexin alone on clinical cure of uncomplicated cellulitis: A randomized clinical
trial. JAMA 2017;317(20):2088–2096 .
Pallin DJ, Binder WD, Allen MB, Lederman M, Parmar S, Filbin MR, et al. Clinical trial: comparative effectiveness of
cephalexin plus trimethoprim-sulfamethoxazole versus cephalexin alone for treatment of uncomplicated cellulitis: a
randomized controlled trial. Clin Infect Dis 2013;56(12):1754–1762 .
Raff AB, Kroshinsky D. Cellulitis: A review. JAMA 2016;316(3):325–37 .
Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, et al. Practice guidelines for the
diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of
America. Clin Infect Dis 2014;59(2):e10–52.
Chickenpox
Immunocompetent patients without complications of chickenpox
Management of chickenpox (varicella) in immunocompetent patients without complications depends on the age of
the patient.
Neonates are at an increased risk of severe disease and complications of chickenpox. For the management of
perinatal varicella infections, see the Australasian Society for Infectious Diseases (ASID) guideline Management
of Perinatal Infections [URL].
Neonates are at increased risk of severe disease and complications of chickenpox.
Beyond the neonatal period, children without significant pre-existing skin disease do not require antiviral therapy
for chickenpox because the benefits of treatment are only marginal. Children with significant pre-existing skin
disease (eg eczema) need antiviral therapy because they are at greater risk of severe chickenpox (including
extensive cutaneous chickenpox) and complications (eg pneumonitis, encephalitis, hepatitis).
To treat chickenpox in immunocompetent children with significant pre-existing skin disease, irrespective of the
duration of rash, use:
1 aciclovir 20 mg/kg up to 800 mg orally, 5 times daily for 7 days
OR
1 valaciclovir (child older than 2 years) 20 mg/kg up to 1 g orally, 8-hourly for 7 days [Note
1].
Valaciclovir is not licensed in Australia for use in children younger than 12 years; however, it is licensed
internationally for use in younger children (over 2 years).
Adults are at greater risk of severe disease and complications of chickenpox. Consider treatment for
immunocompetent nonpregnant adults if it can be started within 36 hours of the onset of rash. Treatment is
recommended for pregnant women if it can be started within 72 hours of the onset of rash. For adults, use:
1 valaciclovir 1 g orally, 8-hourly for 7 days
OR
1 famciclovir 500 mg orally, 8-hourly for 7 days
OR
2 aciclovir 800 mg orally, 5 times daily for 7 days.
There are more safety data to support the use of aciclovir in pregnancy compared with valaciclovir or famciclovir.
However, there is some evidence and clinical experience that valaciclovir (a prodrug of aciclovir) is safe in
pregnancy, and some prescribers prefer it because the 8-hourly dosing regimen is easier for patients to follow.
Superinfection of chickenpox skin lesions with Streptococcus pyogenes (group A streptococcus) or Staphylococcus
aureus can occur and should be treated as for impetigo or cellulitis. Avoid the use of nonsteroidal anti-
inflammatory drugs (NSAIDs) in children with chickenpox; a number of studies have suggested a link between
skin and soft tissue complications of chickenpox and the use of NSAIDs.
Varicella vaccine or high-titre varicella-zoster immunoglobulin (ZIG) can be used to prevent or reduce the severity
of chickenpox in contacts without immunity who have been exposed to a patient with chickenpox. See the
Australian Immunisation Handbook [URL] for detailed information about postexposure management.
Note 1: An oral liquid formulation of valaciclovir is not commercially available; for formulation options for children, see the Don’t Rush to Crush
Handbook, published by the Society of Hospital Pharmacists of Australia [URL].
Immunocompetent patients with complications of chickenpox and

immunocompromised patients with chickenpox
For immunocompetent patients with complications of chickenpox (eg pneumonitis, encephalitis, hepatitis),
irrespective of the duration of rash, or immunocompromised patients with chickenpox (including those with
HIV infection), irrespective of the duration of rash or severity of disease, use initially:
2] [Note 3].
Switch to oral therapy after clinical improvement and continue treatment for a minimum of 7 days (intravenous +
oral). In those with slow improvement and for those with significant immune compromise, therapy may be
required for a total of up to 14 days. When switching to oral treatment, use:
1 valaciclovir 1 g (child older than 2 years: 20 mg/kg up to 1 g) orally, 8-hourly (total

duration of at least 7 days [intravenous + oral]) [Note 4]
OR
1 famciclovir 500 mg orally, 8-hourly (total duration of at least 7 days [intravenous + oral])
OR
2 aciclovir 800 mg (child: 20 mg/kg up to 800 mg) orally, 5 times daily (total duration of at
least 7 days [intravenous + oral]).
Valaciclovir is not licensed in Australia for use in children younger than 12 years; however, it is licensed
internationally for use in younger children (over 2 years). Famciclovir is not used in children.
Superinfection of chickenpox skin lesions with Streptococcus pyogenes or Staphylococcus aureus can occur and
should be treated as for impetigo or cellulitis. Avoid the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in
children with chickenpox; a number of studies have suggested a link between skin and soft tissue complications of
chickenpox and the use of NSAIDs.
Varicella vaccine or high-titre varicella-zoster immunoglobulin (ZIG) can be used to prevent or reduce the severity
of chickenpox in contacts without immunity who have been exposed to a patient with chickenpox. See the
Australian Immunisation Handbook [URL] for detailed information about postexposure management.
Patients with undiagnosed HIV infection may present initially with chickenpox. In patients who need to be started
on therapy for HIV, see Chickenpox in adults with HIV infection for advice on starting antiretroviral therapy.
If starting treatment for chickenpox in patients with HIV infection taking antiretroviral therapy, check for potential
for drug interactions when prescribing antiviral drugs (see Antiretroviral drug interactions).
Note 3: A dose of 500 mg/m2 is approximately equal to 20 mg/kg for children younger than 5 years and 15 mg/kg for children 5 years to 12 years.
Note 4: An oral liquid formulation of valaciclovir is not commercially available; for formulation options for
Key references
Canadian Agency for Drugs and Technologies in Health (CADTH). Acyclovir versus valacyclovir for herpes virus in
children and pregnant women: A review of the clinical evidence and guidelines. Ottawa (ON): CADTH; 2014.
Kechagia IA, Kalantzi L, Dokoumetzidis A. Extrapolation of valacyclovir posology to children based on

pharmacokinetic modeling. Pediatr Infect Dis J 2015;34(12):1342–8.
Macartney K, Heywood A, McIntyre P. Vaccines for post-exposure prophylaxis against varicella (chickenpox) in
children and adults. Cochrane Database Syst Rev 2014;(6):CD001833.
Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of
birth defects. JAMA 2010;304(8):859–66.
Tunbridge AJ, Breuer J, Jeffery KJ. Chickenpox in adults - clinical management. J Infect 2008;57(2):95–102 .
UK Medicines Information (UKMi). Do NSAIDs increase the risk of severe skin reactions in children with chickenpox?
[Medicines Q&A 442.1]. London: National Health Service; 2016 [Updated 2018]. https://www.sps.nhs.uk/articles/do-
nsaids-increase-the-risk-of-severe-skin-reactions-in-children-with-chickenpox/
Infections of chronic ulcers and wounds
Introduction to chronic ulcer and wound infections
All chronic ulcers and wounds are colonised with bacteria. Do not perform microbiological investigations or
start antibiotic therapy unless there are clinical signs of infection (eg systemic features, spreading cellulitis;
see also Factors affecting ulcer and wound healing). If there are clinical signs of infection, collect samples of
pus (which must be distinguished from ulcer exudate) or infected tissue for culture; culture of a superficial
swab may identify organisms that are colonising the wound rather than causing infection (eg Pseudomonas
aeruginosa identified by culture of a superficial swab of a lower limb ulcer).
For an overview of the approach to managing ulcers and wounds, see Fundamentals of ulcer and wound
management.
For infected diabetic foot ulcers, see Diabetic foot infection. For Mycobacterium ulcerans (Buruli ulcer)
infection, see Mycobacterium ulcerans (Buruli ulcer).
Venous ulcer infections

For noninfected venous ulcers, do not perform culture or start antibiotic therapy (including topical therapy);
antibiotics are unnecessary and may cause harm (eg hypersensitivity reactions, bacterial resistance; see also
Types of adverse effects of antimicrobials). Avoid cytotoxic antiseptics (eg sodium hypochlorite, hydrogen
peroxide) because they may impede wound healing.
For mild infection (eg infection of the skin or subcutaneous tissue without systemic signs or symptoms), treat
as for cellulitis and erysipelas without systemic features.
For detailed information about managing venous leg ulcers, see Venous leg ulcers.
Key references
International Wound Infection Institute (IWII). Wound infection in clinical practice. London: Wounds International;
2016. https://www.woundsinternational.com/resources/details/iwii-wound-infection-clinical-practice.
Diabetic foot infection
Aetiology of diabetic foot infection
Acute diabetic foot infection in patients who have not recently received antibiotics is usually caused by
Staphylococcus aureus or streptococci. The risk of infection with a Gram-negative pathogen is increased in
patients who have recently received antibiotics. Chronic infections (present for 4 weeks or more) are often
polymicrobial, involving Gram-positive and Gram-negative aerobic and anaerobic bacteria.
Assessing diabetic foot ulcers for infection

The International Working Group on the Diabetic Foot [Note 1] and the Infectious Diseases Society of America
[Note 2] advise that for an ulcer to be considered infected, at least two of the following features should be present:
local swelling or induration

erythema extending more than 0.5 cm in any direction from the wound
local tenderness or pain
local warmth
purulent discharge.
Other causes of inflammation (eg trauma, gout, thrombosis) should be considered.
Culture of tissue samples obtained by biopsy or aspiration can guide antibiotic therapy. However, culture of a
superficial swab of an ulcer base may identify organisms that are colonising the wound rather than causing
infection, so interpret results with care. Do not collect specimens from noninfected ulcers because antibiotic
therapy is not indicated.
Do not collect specimens for culture from noninfected ulcers.
Infection severity determines antibiotic choice. The following severity scoring system is supported by the
International Working Group on the Diabetic Foot [Note 1] and the Infectious Diseases Society of America [Note
2]:
mild diabetic foot infection involves only the skin and subcutaneous tissue. Erythema extends no more than
2 cm from the wound margin and there are no systemic features of infection
moderate diabetic foot infection involves structures deeper than the skin or subcutaneous tissues (eg
muscle, bone, joint, tendon) or erythema that extends more than 2 cm from the wound margin. Infection is
not associated with systemic inflammatory response syndrome (SIRS) (as described below)
severe diabetic foot infection is an infection associated with systemic inflammatory response syndrome
(SIRS) (ie 2 or more of: abnormal temperature [more than 38°C or less than 36°C]; heart rate more than 90
beats/minute; respiratory rate more than 20 breaths/minute; white cell count more than 12 × 109/L or less
than 4 × 109/L, or more than 10% immature [band] forms).
Note 1: Lipsky BA, Aragon-Sanchez J, Diggle M, Embil J, Kono S, Lavery L, et al. IWGDF guidance on the
diagnosis and management of foot infections in persons with diabetes. Diabetes Metab Res Rev 2016;32 Suppl
1:45-74. [URL]
Note 2: Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG, et al. 2012 Infectious Diseases
Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin
Infect Dis 2012;54(12):e132-73. [URL]
Approach to managing diabetic foot infection

Diabetic foot infection should always be considered serious; it is often worse than it appears. Specialised
multidisciplinary management that includes interventions to promote wound healing is recommended—see
Wounds on a high-risk foot.
Do not treat noninfected ulcers (see Assessing diabetic foot ulcers for infection) with antibiotic therapy.
Do not treat noninfected ulcers with antibiotic therapy.
Avoid cytotoxic antiseptics (eg sodium hypochlorite, hydrogen peroxide) because they can impede wound healing.
Empirical therapy for mild diabetic foot infection

Antibiotic choice for mild diabetic foot infection (see Assessing diabetic foot ulcers for infection) depends on its
time course (acute or chronic) and whether the patient has recently received antibiotics. While treatment for
anaerobic or Gram-negative organisms is not required for acute mild diabetic foot infection, it is necessary for
chronic mild diabetic foot infection, and for patients with acute infection who have recently been treated with
antibiotics.
For patients with acute, mild diabetic foot infection who have not recently received antibiotics and are at low risk
of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31), use:
1 dicloxacillin 500 mg orally, 6-hourly
OR
1 flucloxacillin 500 mg orally, 6-hourly.
Use:
cefalexin 500 mg orally, 6-hourly.
For patients with immediate (nonsevere or severe) or delayed severe hypersensitivity to penicillins or who are at
increased risk of MRSA infection (see Box 2.31), use:
clindamycin 450 mg orally, 8-hourly.
Alternatively, trimethoprim+sulfamethoxazole can be used for patients at increased risk of MRSA infection (see
Box 2.31):
trimethoprim+sulfamethoxazole 160+800 mg orally, 12-hourly.
For patients at low risk of MRSA infection who have chronic, mild diabetic foot infection or have acute, mild
diabetic foot infection and have recently received antibiotics, use:
amoxicillin+clavulanate 875+125 mg orally, 12-hourly.
For patients with delayed nonsevere hypersensitivity to penicillins, a cefalexin-containing regimen can be used in
most cases [Note 3]. Use:
cefalexin 500 mg orally, 6-hourly
PLUS
metronidazole 400 mg orally, 12-hourly.
For patients with immediate (nonsevere or severe) or delayed severe hypersensitivity to penicillins or who are at
increased risk of MRSA infection (see Box 2.31), use:
trimethoprim+sulfamethoxazole 160+800 mg orally, 12-hourly
PLUS
metronidazole 400 mg orally, 12-hourly.
Modify therapy based on the results of culture and susceptibility testing. Continue antibiotic therapy until infection
is resolved but not necessarily until the ulcer is healed. Typically a duration of therapy of 1 to 2 weeks is
sufficient.
Empirical therapy for moderate diabetic foot infection

Patients with moderate diabetic foot infection (see Assessing diabetic foot ulcers for infection) require initial
intravenous therapy. However, oral therapy is appropriate for patients with moderate infection of a chronic
diabetic foot ulcer who have osteomyelitis without systemic inflammatory response syndrome (SIRS). Antibiotic
choice depends on the results of culture and susceptibility testing. While awaiting results, use the oral antibiotics
recommended for chronic mild diabetic foot infection (ie amoxicillin+clavulanate, cefalexin plus metronidazole,
trimethoprim+sulfamethoxazole plus metronidazole). Prolonged treatment is necessary—see Duration of therapy
for osteomyelitis.
If Pseudomonas aeruginosa infection is suspected (eg recent colonisation or infection with P. aeruginosa), treat as
for severe diabetic foot infection.
For other patients with moderate infection who are at low risk of MRSA (see Box 2.31), use:
amoxicillin+clavulanate 1+0.2 g intravenously, 8-hourly. If the bone is infected, use a dose

of 1+0.2 g intravenously, 6-hourly [Note 4] .
PLUS
metronidazole 500 mg intravenously, 12-hourly.
For patients with immediate severe or delayed severe hypersensitivity to penicillins or who are at increased risk
of MRSA infection (see Box 2.31), use trimethoprim+sulfamethoxazole plus metronidazole, as for mild infection.
If oral therapy cannot be used, use ciprofloxacin plus clindamycin or lincomycin, as for severe infection.
After significant improvement, switch to oral therapy. If the results of culture and susceptibility testing are not
available, see mild diabetic foot infection for antibiotic choice. If the wound involves deeper tissues (such as
bones, joints or tendons), maximum dosages of oral antibiotics are required—seek expert advice.
Duration of therapy: continue antibiotic therapy until the infection has resolved, but not necessarily until the
wound has healed. Typically a total duration of 1 to 2 weeks (intravenous + oral) is sufficient for moderate
infections; however, a longer duration of therapy is needed for wounds involving the deeper tissues. For the
suggested duration of intravenous and oral therapy, see Duration of therapy for osteomyelitis for infection
involving bone, and Table 2.2 for infection involving a joint. Stop antibiotic therapy 2 to 5 days after amputation if
infected bone is entirely removed.
If prolonged intravenous antibiotic therapy is essential in patients who are clinically stable, consider community-
based parenteral antimicrobial therapy.
intravenous amoxicillin+clavulanate. For adults with bone infection, a reasonable alternative regimen is 2+0.2 g
Empirical therapy for severe diabetic foot infection

For patients with severe diabetic foot infection (see Assessing diabetic foot ulcers for infection), use:
piperacillin+tazobactam 4+0.5 g intravenously, 6-hourly.

PLUS EITHER
1 clindamycin 900 mg intravenously, 8-hourly
OR
2 lincomycin 900 mg intravenously, 8-hourly.
If oral therapy is possible, consider replacing intravenous ciprofloxacin with oral ciprofloxacin. Use:
ciprofloxacin 750 mg orally, 12-hourly.
Vancomycin may be required for severe limb or life-threatening infection in patients at increased risk of
methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31). Add to the above regimens:

Modify therapy based on the results of culture and susceptibility testing. If results are not available by 72 hours
and intravenous therapy is still required, consider monotherapy with amoxicillin+clavulanate (as for moderate
infection) if the patient is clinically improving; it is not necessary to continue treatment with activity against
Pseudomonas aeruginosa and MRSA.
After significant improvement, switch to oral therapy. If the results of culture and susceptibility testing are not
available, see mild diabetic foot infection for antibiotic choice. If the wound involves the deeper tissues (such as
bones, joints or tendons), maximum dosages of oral antibiotics are required—seek expert advice.
Duration of therapy: continue antibiotic therapy until the infection has resolved, but not necessarily until the
wound has healed. Typically a total duration of 3 weeks (intravenous + oral) is sufficient for severe infections;
however, a longer duration of therapy is needed for wounds involving the deeper tissues. For the suggested
duration of therapy, see Duration of therapy for osteomyelitis for infection involving bone, and Table 2.2 for
infection involving a joint. Stop antibiotic therapy 2 to 5 days after amputation if infected bone is entirely
removed.
If prolonged intravenous antibiotic therapy is essential in patients who are clinically stable, consider community-
Key references
Barwell ND, Devers MC, Kennon B, Hopkinson HE, McDougall C, Young MJ, et al. Diabetic foot infection: Antibiotic
therapy and good practice recommendations. Int J Clin Pract 2017;71(10):[epub] .
Lipsky BA, Aragón-Sánchez J, Diggle M, Embil J, Kono S, Lavery L, et al. IWGDF guidance on the diagnosis and
management of foot infections in persons with diabetes. Diabetes Metab Res Rev 2016;32 Suppl 1:45–74 .
Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG, et al. 2012 Infectious Diseases Society of
America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis
2012;54(12):e132–e173 .
Malone M, Johani K, Jensen SO, Gosbell IB, Dickson HG, Hu H, et al. Next generation DNA sequencing of tissues
from infected diabetic foot ulcers. EBioMedicine 2017;21:142–149 .
Peters EJ, Lipsky BA, Aragón-Sánchez J, Boyko EJ, Diggle M, Embil JM, et al. Interventions in the management of
infection in the foot in diabetes: a systematic review. Diabetes Metab Res Rev 2016;32 Suppl 1:145–153 .
Uçkay I, Gariani K, Dubois-Ferrière V, Suvà D, Lipsky BA. Diabetic foot infections: recent literature and cornerstones of
management. Curr Opin Infect Dis 2016;29(2):145–152 .
Impetigo
Aetiology of impetigo
Impetigo occurs most often in children and is contagious. It has two distinct presentations:
crusted or nonbullous impetigo—presents as yellow crusts and erosions that are itchy or irritating, but not
painful
bullous impetigo—presents as irritating blisters that erode rapidly. Bullous impetigo is usually caused by
Staphylococcus aureus.
In nonendemic settings (nonremote communities), impetigo is most commonly caused by S. aureus, and less
commonly by Streptococcus pyogenes (group A streptococcus). Infection may also be caused by both S. aureus
and S. pyogenes.
In endemic settings, such as remote communities in central and northern Australia, impetigo is typically caused by
S. pyogenes, even if S. aureus is identified by culture (including community-associated methicillin-resistant S.
aureus [CA-MRSA]).
Approach to managing impetigo

Patients with impetigo require antibiotic treatment.
Patients with mild impetigo do not require an initial skin swab before empirical antibiotic therapy is started, but
should have a swab taken for culture and susceptibility testing if there is no response to empirical therapy.
Patients with more severe disease require a skin swab for culture and susceptibility testing before empirical
antibiotic therapy is started.
Treat dermatosis if present (eg dermatitis, scabies, head lice).
Antibiotic therapy for impetigo in nonendemic settings

For patients in nonendemic settings (nonremote communities) who have localised skin sores, use:
mupirocin 2% ointment or cream topically to crusted areas, 8-hourly for 5 days.
For patients in nonendemic settings (nonremote communities) who have multiple skin sores or recurrent
infection, use:
1 dicloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 days. Stop
therapy earlier if infection has resolved
OR
1 flucloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 days. Stop
therapy earlier if infection has resolved.
[Note 1]. Use:
1 cefalexin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly for 7 days. Stop
therapy earlier if infection has resolved
OR
1 cefalexin 1 g (child: 25 mg/kg up to 1 g) orally, 12-hourly for 7 days. Stop therapy earlier
if infection has resolved.
OR

320+1600 mg) orally, daily for 5 days.
If impetigo does not respond to dicloxacillin, flucloxacillin or cefalexin, change treatment to

trimethoprim+sulfamethoxazole (see dosage above) because infection may be caused by community-associated
MRSA.
If impetigo does not respond to trimethoprim+sulfamethoxazole, modify therapy based on the results of culture
and susceptibility testing.
Recurrent impetigo may be associated with nasal carriage of S. aureus. It may also reflect reinfection following
acquisition of S. aureus or S. pyogenes from a close contact. Following treatment of the recurrent infection,
eradication of staphylococcal carriage may be indicated (see Recurrent staphylococcal skin infection).
Antibiotic therapy for impetigo in endemic settings

For patients in endemic settings (eg remote communities in central and northern Australia), use:
1 benzathine benzylpenicillin intramuscularly, as a single dose [Note 2] [Note 3]

OR

OR

320+1600 mg) orally, daily for 5 days.
benzylpenicillin.
Note 3: Benzathine benzylpenicillin is long acting; do not confuse benzathine benzylpenicillin with benzylpenicillin which is short acting.
Key references
2017;4(4):ofx232. .
Bowen AC, Tong SY, Andrews RM, O'Meara IM, McDonald MI, Chatfield MD, et al. Short-course oral co-trimoxazole
versus intramuscular benzathine benzylpenicillin for impetigo in a highly endemic region: an open-label, randomised,
controlled, non-inferiority trial. Lancet 2014;384(9960):2132–2140 .
America. Clin Infect Dis 2014;59(2):e10–e52 .
Lactational mastitis
Lactational mastitis
Acute mastitis is usually associated with breastfeeding and is often caused by Staphylococcus aureus. Poor infant
positioning, milk stasis and nipple damage are contributing factors. Breastfeeding or expressing milk (manually or
via a pump) from the infected breast is safe and should be continued.
If mastitis is not associated with breastfeeding, seek expert advice for management.
In patients without systemic symptoms, increased breastfeeding and gently expressing milk from the affected
breast may prevent progression and resolve infection without antibiotics.
In patients with systemic symptoms, or symptoms or signs that have not resolved after 24 to 48 hours of increased
breastfeeding and expressing of milk, early antibiotic therapy is important to prevent abscess formation. Combine
antibiotic therapy with increased breastfeeding and expressing of milk.
Use:
1 dicloxacillin 500 mg orally, 6-hourly. If symptoms and signs resolve rapidly, 5 days of
therapy may be sufficient; otherwise continue treatment for 10 days
OR
1 flucloxacillin 500 mg orally, 6-hourly. If symptoms and signs resolve rapidly, 5 days of
therapy may be sufficient; otherwise continue treatment for 10 days.
Use:
cefalexin 500 mg orally, 6-hourly. If symptoms and signs resolve rapidly, 5 days of
clindamycin 450 mg orally, 8-hourly. If symptoms and signs resolve rapidly, 5 days of
If infection does not resolve with antibiotic therapy, evaluate the patient for an abscess and consider whether
infection is caused by another pathogen.
If the patient has severe cellulitis, see Cellulitis associated with systemic features for initial treatment. Switch to
oral therapy (as above) when symptoms are resolving.
Necrotising skin and soft tissue infections
Diagnosing necrotising skin and soft tissue infections
A number of clinical syndromes can be associated with rapidly progressive necrotising skin and soft tissue
infections, such as necrotising fasciitis (necrosis of the soft tissues), myonecrosis (necrosis of the muscles) or
gangrene (extensive necrosis). Diagnosis is difficult and expert advice is essential.
Diagnosis of necrotising skin and soft tissue infections is difficult. Expert advice is essential.
Necrotising skin and soft tissue infections can be:
monomicrobial—potential pathogens include streptococci (especially Streptococcus pyogenes [group A

streptococcus]), Clostridium perfringens and other Clostridium species, Staphylococcus aureus, Vibrio
vulnificus and other Vibrio species, and Aeromonas hydrophila. Gas gangrene refers to clostridial
myonecrosis.
polymicrobial—includes synergistic gangrene, when infection involves mixed aerobe–anaerobe bacteria (eg
Escherichia coli, Bacteroides fragilis, streptococci and staphylococci). Fournier gangrene refers to
synergistic gangrene of the genitalia, usually following genital trauma (eg postpartum) or spread from a
perianal, retroperitoneal or urinary tract infection.
Consider necrotising skin and soft tissue infections in patients who are critically ill with a skin and soft tissue
infection.
Consider necrotising infection in patients who are critically ill with a skin and soft tissue infection.
Penetrating and crush injuries are particularly likely to lead to necrotising skin and soft tissue infection, but
necrotising infection can also follow surgical procedures. Life-threatening S. pyogenes necrotising fasciitis can
occur spontaneously or follow varicella infection (chickenpox). Diabetes is also a risk factor for necrotising skin
and soft tissue infection.
Clinical features that suggest a necrotising skin and soft tissue infection include:
constant severe pain, even if skin inflammation is initially limited

bullae
skin necrosis or bruising
hard (‘wooden’) subcutaneous tissue that is painful on palpation
oedema beyond the margin of erythema
cutaneous anaesthesia
gas in the soft tissues (detected by palpation [skin or soft tissue crepitus] or imaging)
systemic features, including fever, leucocytosis, elevated C-reactive protein (CRP), delirium or acute kidney
impairment
rapidly spreading infection.
If the diagnosis is uncertain, early surgical consultation is recommended; surgical exploration and collection of
deep tissue samples for microscopy and culture can provide a definitive diagnosis.
Principles of managing necrotising skin and soft tissue infections

Surgical removal of devitalised tissue and urgent antibiotic therapy are essential for managing necrotising skin and soft tissue
infection. Seek expert advice.
Seek expert advice for the treatment of necrotising skin and soft tissue infection. Surgical removal of devitalised
tissue and urgent antibiotic therapy are essential for management; typically, multiple debridements are required.
Empirical antibiotic therapy is used while the pathogen(s) and affected tissues are determined. If hyperbaric
oxygen therapy is used as an adjunct to surgical debridement, it should not delay surgery.
Empirical therapy for necrotising skin and soft tissue infection
For empirical therapy for necrotising skin and soft tissue infection not associated with water exposure, in
combination with surgical debridement, as a three-drug regimen, use:
1 meropenem 1 g (child: 20 mg/kg up to 1 g) intravenously, 8-hourly
OR
1 piperacillin +tazobactam 4+0.5 g (child: 100 +12.5 mg/kg up to 4+0.5 g) intravenously, 6-

hourly

PLUS EITHER
OR
If infection is associated with a wound that has been immersed in water, ciprofloxacin is included in the empirical
regimen, because Aeromonas isolates often produce carbapenemase enzymes. Use:
meropenem 1 g (child: 20 mg/kg up to 1 g) intravenously, 8-hourly
PLUS

PLUS
ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 8-hourly [Note 1]
PLUS EITHER
OR
A meropenem-containing regimen may be suitable for patients hypersensitive to penicillins [Note 2].
Clindamycin or lincomycin is recommended for empirical therapy of necrotising skin and soft tissue infection
because of a theoretical reduction in bacterial toxin production; however, clinical evidence is limited. It is not
necessary to include benzylpenicillin in the empirical regimen.
The Antibiotic Expert Groups recommend that intravenous immunoglobulin be used if Streptococcus pyogenes
necrotising fasciitis is suspected (typically infection involving a limb and associated with nonpenetrating trauma or
an injury that breaks the skin)—see Streptococcus pyogenes necrotising fasciitis for dosage.
Modify therapy based on the results of Gram stain, culture and susceptibility testing of a surgical deep tissue
sample. See the regimens for S. pyogenes, clostridial or community-associated methicillin-resistant Staphylococcus
aureus (CA-MRSA) infection.
Duration of therapy: continue intravenous treatment until further debridement is no longer necessary, there has
been clinical improvement, and the patient has been afebrile for 48 to 72 hours; then switch to oral antibiotic
therapy. The choice of oral therapy is guided by the microbiological diagnosis or expert advice. Continue oral
therapy until the infection has resolved, but not necessarily until the wound has healed.
choice.
Streptococcus pyogenes necrotising fasciitis

For Streptococcus pyogenes necrotising fasciitis, in combination with surgical debridement, as a three-drug
regimen, use:
benzylpenicillin 2.4 g (child: 50 mg/kg up to 2.4 g) intravenously, 4-hourly. See below for
duration of therapy
PLUS EITHER
1 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly. Switch to

oral clindamycin as tolerated
OR
2 lincomycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly. Switch to

oral clindamycin as tolerated

Clindamycin or lincomycin is recommended for S. pyogenes necrotising fasciitis because of a theoretical reduction
in bacterial toxin production; however, clinical evidence is limited. When oral clindamycin is tolerated, replace
intravenous clindamycin or lincomycin with:
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 6-hourly until intravenous
therapy is stopped.
Of three recent studies, two strongly support the use of intravenous immunoglobulin (IVIg) to treat S. pyogenes
necrotising fasciitis, and one does not. It is the consensus view of the Antibiotic Expert Groups that IVIg should be
used when available.
cefazolin intravenously; see below for duration of therapy

adult: 2 g 6-hourly
child: 50 mg/kg up to 2 g 8-hourly.
Duration of therapy: continue intravenous benzylpenicillin or cefazolin until further debridement is no longer
necessary, there has been clinical improvement, and the patient has been afebrile for 48 to 72 hours. Once these
criteria are met, switch to oral amoxicillin and stop clindamycin (intravenous or oral) or lincomycin. Use:
amoxicillin 1 g (child: 25 mg/kg up to 1 g) orally, 8-hourly.
Continue oral amoxicillin until the infection has resolved, but not necessarily until the wound has healed.
Consider prophylaxis for close contacts of patients with S. pyogenes necrotising fasciitis (see Prevention of
invasive group A streptococcal infection for regimens).
Clostridial necrotising skin and soft tissue infection

Necrotising skin and soft tissue infection caused by Clostridium species can occur after a traumatic wound with
associated vascular compromise. It should be considered in people wounded in natural disasters if evacuation and
debridement is delayed.
The diagnosis of gas gangrene is clinical. Identifying clostridia by culture and gas in the soft tissues (detected by
palpation [skin and soft tissue crepitus] or radiography) supports the diagnosis.
For clostridial necrotising skin and soft tissue infection, in combination with surgical debridement, use:
PLUS EITHER
OR
For patients hypersensitive to penicillins, replace benzylpenicillin with metronidazole. Use:
Clinical outcome data indicate that clindamycin is superior to benzylpenicillin; however, benzylpenicillin is
included in the empirical regimen in case the infecting isolate is resistant to clindamycin or lincomycin.
Duration of therapy: continue intravenous treatment until further debridement is no longer necessary, there has
been clinical improvement, and the patient has been afebrile for 48 to 72 hours; then switch to oral antibiotic
therapy guided by susceptibility results. Continue oral therapy until the infection has resolved, but not necessarily
until the wound has healed.
Community-associated methicillin-resistant Staphylococcus aureus

necrotising skin and soft tissue infection
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an uncommon cause of
necrotising skin and soft tissue infection—seek expert advice.
For community-associated MRSA infection, in combination with surgical debridement, use:

duration of therapy
PLUS EITHER
1 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly. Switch to

oral clindamycin as tolerated (see dosage below)
OR
2 lincomycin 600 mg (child: 15 mg/kg up at 600 mg) intravenously, 8-hourly. Switch to oral
clindamycin as tolerated (see dosage below).
Clindamycin or lincomycin is recommended for community-associated MRSA necrotising skin and soft tissue
infection because of a theoretical reduction in bacterial toxin production; however, clinical evidence is limited.
When oral clindamycin is tolerated, replace intravenous clindamycin or lincomycin with:
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 6-hourly until intravenous
therapy is stopped.
Duration of therapy: if infection was associated with S. aureus bacteraemia, continue intravenous vancomycin for
at least 4 weeks.
If infection was not associated with S. aureus bacteraemia, continue intravenous vancomycin until further
debridement is no longer necessary, there has been clinical improvement, and the patient has been afebrile for 48
to 72 hours. Once these criteria are met, switch to oral antibiotic therapy guided by susceptibility results. Continue
oral therapy until the infection has resolved, but not necessarily until the wound has healed.
Key references
Andreoni F, Zürcher C, Tarnutzer A, Schilcher K, Neff A, Keller N, et al. Clindamycin affects Group A Streptococcus
virulence factors and improves clinical outcome. J Infect Dis 2017;215(2):269–277 .
Carapetis JR, Jacoby P, Carville K, Ang SJ, Curtis N, Andrews R. Effectiveness of clindamycin and intravenous
immunoglobulin, and risk of disease in contacts, in invasive group a streptococcal infections. Clin Infect Dis
2014;59(3):358–65.
Kadri SS, Swihart BJ, Bonne SL, Hohmann SF, Hennessy LV, Louras P, et al. Impact of intravenous immunoglobulin
on survival in necrotizing fasciitis with vasopressor-dependent shock: A propensity score-matched analysis from 130
US hospitals. Clin Infect Dis 2017;64(7):877–85.
Linner A, Darenberg J, Sjolin J, Henriques-Normark B, Norrby-Teglund A. Clinical efficacy of polyspecific intravenous

immunoglobulin therapy in patients with streptococcal toxic shock syndrome: a comparative observational study. Clin
Infect Dis 2014;59(6):851–7.
Stevens DL, Laine BM, Mitten JE. Comparison of single and combination antimicrobial agents for prevention of
experimental gas gangrene caused by Clostridium perfringens. Antimicrob Agents Chemother 1987;31(2):312–316
.
Stevens DL, Maier KA, Laine BM, Mitten JE. Comparison of clindamycin, rifampin, tetracycline, metronidazole, and
penicillin for efficacy in prevention of experimental gas gangrene due to Clostridium perfringens. J Infect Dis
1987;155(2):220–228 .
Recurrent staphylococcal skin infection
Recurrent staphylococcal skin infection
Boils (furuncles) and other skin infections caused by Staphylococcus aureus may recur. Recurrent infections are
more likely in patients who smoke or have poorly controlled diabetes.
For patients with recurrent staphylococcal skin infections, emphasise basic skin care and personal hygiene
measures (eg covering open wounds, regular bathing and hand washing with soap or alcohol-based hand washes,
not sharing personal hygiene items).
Consider and address dermatological conditions (eg eczema) that can promote ongoing S. aureus colonisation.
Treat acute lesions (eg boils and carbuncles, folliculitis, impetigo).
Decolonisation regimens are used for some patients with recurrent staphylococcal skin infections but should not be
used until acute lesions have healed. Decolonisation aims to eradicate staphylococcal carriage, but is only
successful in around half of patients treated.
Before decolonisation is attempted, collect nasal and/or perineal swabs to confirm S. aureus colonisation. Extended
susceptibility testing is not required for the initial attempt at decolonisation because rates of mupirocin resistance
are low in Australia.
Decolonising household contacts, in addition to the index case, is more effective in preventing recurrent infections
than decolonising the index case alone. Therefore, consider household decolonisation if a household contact has a
history of recurrent staphylococcal skin infection.
For decolonisation, use:
mupirocin 2% nasal ointment inside each nostril, twice daily for 5 days
PLUS EITHER
for use in showers—an antiseptic wash or soap containing chlorhexidine 2%, wash once
daily for at least 5 days; pay particular attention to areas of hairy skin
OR
for use in baths—60 mL of sodium hypochlorite solution (household bleach) [Note 1] per
bathtub, wash once daily for at least 5 days.
Advise patients to wash bed linen in hot water and repeat at least weekly, and wash towels in hot water after each
use.
If household decolonisation is not performed initially and infection recurs in the index case, consider household
decolonisation.
If infection recurs despite decolonisation of both the index case and household contacts, treatment with an oral
rifampicin-based regimen, together with the topical decolonisation regimen above, is required. The specific oral
regimen should be based on the susceptibility of the isolate—seek expert advice. Although this approach can
reduce colonisation, data demonstrating a reduced risk of infection recurrence are lacking.
An alternative to repeated decolonisation combined with an oral rifampicin-based regimen, is 12 months of

mupirocin 2% nasal ointment applied inside each nostril twice daily for the first 5 days of every month.
Note 1: The clinical trial that demonstrated efficacy for this approach used 1/4 of a cup (approximately 60 mL) of 6% sodium hypochlorite solution
(household bleach) per bathtub.
Key references
Creech CB, Al-Zubeidi DN, Fritz SA. Prevention of recurrent staphylococcal skin infections. Infect Dis Clin North Am
2015;29(3):429–464 .
Ellis MW, Griffith ME, Dooley DP, McLean JC, Jorgensen JH, Patterson JE, et al. Targeted intranasal mupirocin to
prevent colonization and infection by community-associated methicillin-resistant Staphylococcus aureus strains in
soldiers: a cluster randomized controlled trial. Antimicrob Agents Chemother 2007;51(10):3591–3598 .
Falagas ME, Bliziotis IA, Fragoulis KN. Oral rifampin for eradication of Staphylococcus aureus carriage from healthy
and sick populations: a systematic review of the evidence from comparative trials. Am J Infect Control
2007;35(2):106–114 .
Fritz SA, Camins BC, Eisenstein KA, Fritz JM, Epplin EK, Burnham CA, et al. Effectiveness of measures to eradicate
Staphylococcus aureus carriage in patients with community-associated skin and soft-tissue infections: a randomized
trial. Infect Control Hosp Epidemiol 2011;32(9):872–880 .
Fritz SA, Hogan PG, Hayek G, Eisenstein KA, Rodriguez M, Epplin EK, et al. Household versus individual approaches
to eradication of community-associated Staphylococcus aureus in children: a randomized trial. Clin Infect Dis
2012;54(6):743–751 .
children. Clin Infect Dis 2011;52(3):e18–e55 .
Loeb MB, Main C, Eady A, Walker-Dilks C. Antimicrobial drugs for treating methicillin-resistant Staphylococcus aureus
colonization. Cochrane Database Syst Rev 2003;(4):CD003340. .
Raz R, Miron D, Colodner R, Staler Z, Samara Z, Keness Y. A 1-year trial of nasal mupirocin in the prevention of
recurrent staphylococcal nasal colonization and skin infection. Arch Intern Med 1996;156(10):1109–1112 .
Shingles
Shingles
Shingles (herpes zoster) is caused by reactivation of the varicella-zoster virus. It is uncommon in childhood;
incidence increases with age. Shingles is characterised by a rash that presents with blisters in a dermatomal
distribution on an erythematous base. The blisters erupt over a week and then heal over 2 weeks. The majority of
patients with shingles are not immunocompromised; however, in immunocompromised patients, systemic
symptoms and a multidermatomal rash can complicate infection.
If the rash has been present for less than 72 hours, antiviral treatment reduces acute pain, duration of the rash, viral
shedding and ocular complications. Whether antiviral therapy reduces the incidence of postherpetic neuralgia is
contentious.
If there is ocular involvement, consult an ophthalmologist. See Herpes zoster ophthalmicus for information on
management.
Antiviral therapy is indicated for immunocompetent adults and adolescents who present within 72 hours of onset
of rash, and for all immunocompromised adults and adolescents (including those with HIV infection) regardless of
duration of rash [Note 1]. In children, shingles is generally less painful and most children do not require treatment;
however, treat all immunocompromised children, and immunocompetent children with severe or rapidly
progressing infection.
When antiviral therapy is indicated for shingles, use:
1 valaciclovir 1 g (child older than 2 years: 20 mg/kg up to 1 g) orally, 8-hourly for 7 days
[Note 2]
OR
1 famciclovir 500 mg orally, 8-hourly for 7 days. For immunocompromised patients, the
duration is 10 days
OR
2 aciclovir 800 mg (child: 20 mg/kg up to 800 mg) orally, 5 times daily for 7 days.
There is evidence that famciclovir and valaciclovir are more effective than aciclovir in reducing acute pain in
patients with shingles.
For children—valaciclovir is not licensed in Australia for use in children younger than 12 years; however, it is
licensed internationally for use in younger children (over 2 years). Famciclovir is not used in children.
In pregnancy—there are more safety data to support the use of aciclovir in pregnancy compared with valaciclovir
or famciclovir. However, there is some evidence and clinical experience that valaciclovir (a prodrug of aciclovir) is
safe in pregnancy, and some prescribers prefer it because the 8-hourly dosing regimen is easier for patients to
follow.
For immunocompromised patients with disseminated disease, admit to hospital for intravenous aciclovir
therapy. Use:
3] [Note 4].
After significant clinical improvement, switch to oral antiviral therapy (as above) to complete a total of 10 to 14
days of treatment (intravenous + oral).
For patients with HIV infection, maintenance therapy (secondary prophylaxis) is usually not required, but can be
considered after a second episode of shingles—seek expert advice.
Superinfection of shingles skin lesions with Streptococcus pyogenes (group A streptococcus) or Staphylococcus
aureus can occur and should be treated as for impetigo or cellulitis. If other organisms are identified on culture,
alternative antimicrobials may be required.
Manage acute pain with analgesia (see Acute herpes zoster pain). There are a number of strategies for managing
postherpetic neuralgia—seek expert advice.
A live-attenuated shingles vaccine is available for patients 60 years or older, and may be indicated even if the
patient has previously had shingles. For detailed information, including contraindications, see the Australian
Immunisation Handbook [URL].
Patients with undiagnosed HIV infection may present initially with shingles. In patients who need to be started on
therapy for HIV, see Shingles in adults with HIV infection for advice on starting antiretroviral therapy.
If starting treatment for chickenpox in patients with HIV infection taking antiretroviral therapy, check for potential
for drug interactions when prescribing antiviral drugs (see Antiretroviral drug interactions).
Note 1: Patients with undiagnosed HIV infection may present initially with herpes zoster infection. In patients who need to be started on therapy for
HIV, see Shingles in adults with HIV infection for advice on starting antiretroviral therapy. In patients with HIV infection taking antiretroviral therapy,
check the potential for drug interactions when prescribing other drugs (see Antiretroviral drug interactions).
Note 2: An oral liquid formulation of valaciclovir is not commercially available; for formulation options for
of Hospital Pharmacists of Australia [URL]
Key references
Canadian Agency for Drugs and Technologies in Health. Acyclovir versus valacyclovir for herpes virus in children and
pregnant women: A review of the clinical evidence and guidelines. Ottawa ON: 2014 Canadian Agency for Drugs and
Technologies in Health.; 2014.
Canadian Pain Society Study Day participants. Safety and effectiveness of the herpes zoster vaccine to prevent
postherpetic neuralgia: 2014 Update and consensus statement from the Canadian Pain Society. Pain Res Manag
2015;20(1):46–7.
Che H, Lukas C, Morel J, Combe B. Risk of herpes/herpes zoster during anti-tumor necrosis factor therapy in patients
with rheumatoid arthritis. Systematic review and meta-analysis. Joint Bone Spine 2014;81(3):215–21.
Gagliardi AM, Andriolo BN, Torloni MR, Soares BG. Vaccines for preventing herpes zoster in older adults. Cochrane
Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of
birth defects. JAMA 2010;304(8):859–66.
Werner RN, Nikkels AF, Marinovic B, Schafer M, Czarnecka-Operacz M, Agius AM, et al. European consensus-based
(S2k) Guideline on the management of herpes zoster - guided by the European Dermatology Forum (EDF) in
cooperation with the European Academy of Dermatology and Venereology (EADV), Part 2: Treatment. J Eur Acad
Dermatol Venereol 2017;31(1):20–9.
Staphylococcal scalded skin syndrome
Staphylococcal scalded skin syndrome
Staphylococcal scalded skin syndrome usually affects neonates and young children. The prognosis in
neonates and young children is good. In contrast, adults with staphylococcal scalded skin syndrome usually
have comorbidities (eg diabetes, chronic kidney disease, immune compromise) and infection is associated
with a mortality of over 40%.
In adults (but not children), blood culture results are typically positive for Staphylococcus aureus. Toxins
produced by S. aureus disrupt keratinocyte cell-to-cell adhesion, causing skin tenderness and generalised
erythema with blistering and desquamation (usually appearing in the flexures and around the nose and mouth,
before becoming generalised). Nikolsky sign (when tangential pressure exfoliates the skin) may be present.
Fever, irritability and malaise often occur.
A skin biopsy can help differentiate staphylococcal scalded skin syndrome from toxic epidermal necrolysis.
Close observation, intravenous fluid resuscitation, pain relief and antibiotics are required. Patients should be
managed in a closely monitored, high-acuity area, such as an emergency department resuscitation area, high-
dependency unit, or intensive care unit. Seek expert advice for antibiotic choice; empirical therapy should
treat both methicillin-susceptible and methicillin-resistant S. aureus.
Surgical site infections
Aetiology of surgical site infections
Most surgical site infections are caused by organisms already colonising the patient at the time of surgery.
Infection is most commonly caused by skin flora, including Staphylococcus aureus, and, in clean–contaminated
procedures (where the gastrointestinal, respiratory or genitourinary tracts are entered), Gram-negative bacilli and
anaerobes.
Principles of managing surgical site infections

For minor skin infections, measures such as surgical drainage and irrigation with sodium chloride 0.9% are often
adequate for cure. Antibiotic therapy is necessary for:
skin infection with associated cellulitis or infection of the subcutaneous tissues (see here)
infection of the deep soft tissues (eg fascia, muscles) or infection with systemic features (see here)
surgical site infection associated with sepsis or septic shock (for definitions of sepsis and septic shock, see
here for adults, or here for neonates, infants and children; for antibiotic choice, see here).
Collect samples for Gram stain and culture before starting antibiotic therapy. More severe surgical site infections
(including those involving the deep soft tissues) may require surgical exploration, drainage, irrigation and
debridement; delayed wound closure is often necessary.
Advice on managing postoperative organ/space infection (involving structures deeper than the fascia or muscle) is
included elsewhere in these guidelines (eg peritonitis due to perforated viscus, mediastinitis, arthroplasty device
infection, infected aneurysm, vascular graft or endovascular device infection).
Do not use topical antibiotics for surgical site infections, because they are associated with the emergence of
resistant organisms and can cause hypersensitivity reactions. Topical antiseptics do not offer an advantage over
drainage and debridement, and cytotoxic antiseptics (eg sodium hypochlorite, hydrogen peroxide) can impede
wound healing.
Empirical therapy for superficial surgical site infection

General principles
The following advice applies to patients with superficial surgical site infection for which antibiotic therapy is
indicated (ie skin infection with associated cellulitis, or infection of the subcutaneous tissues). Antibiotic choice
depends on whether Gram-positive bacteria or Gram-negative or anaerobic bacteria are suspected.
The regimens below (with the exception of clindamycin and the trimethoprim+sulfamethoxazole–based regimen)
are not effective against methicillin-resistant Staphylococcus aureus (MRSA). Add therapy for MRSA for patients
at increased risk of MRSA (see Box 2.31) or who do not improve with empirical therapy. Antibiotic choice
depends on the susceptibility of the patient’s isolate or local susceptibility data.
Gram-positive bacteria
For superficial surgical site infection, if Gram-positive bacteria are suspected (eg the procedure did not enter the
gastrointestinal, respiratory or genitourinary tracts), use:
1 dicloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly. See below for
duration of therapy
OR
1 flucloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly. See below for
tolerated. In most cases, it can also be used for patients with delayed nonsevere hypersensitivity to
cefalexin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly. See below for
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly. See below for
Duration of therapy: continue antibiotic therapy for 5 days; a longer duration may be required depending on
clinical response. If there is a poor response to empirical therapy, review whether the pathogen is adequately
treated and re-evaluate the wound for evidence of deeper tissue involvement.
Gram-negative or anaerobic bacteria
For superficial surgical site infection, if Gram-negative or anaerobic bacteria are suspected (eg the procedure
entered the gastrointestinal, respiratory or genitourinary tracts), use:

875+125 mg) orally, 12-hourly [Note 2]. See below for duration of therapy.
For patients with delayed nonsevere hypersensitivity to penicillins, a cefalexin-based regimen can be used in most
cases [Note 3]. Use:
cefalexin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly. See below for
duration of therapy
PLUS
metronidazole 400 mg (child: 10 mg/kg up to 400 mg) orally, 12-hourly. See below for

160+800 mg) orally, 12-hourly. See below for duration of therapy
PLUS
metronidazole 400 mg (child: 10 mg/kg up to 400 mg) orally, 12-hourly. See below for
Duration of therapy: continue antibiotic therapy for 5 days; a longer duration may be required depending on
clinical response. If there is a poor response to empirical therapy, review whether the pathogen is adequately
treated and re-evaluate the wound for evidence of deeper tissue involvement.
Note 2: Amoxicillin+clavulanate may be suitable for children aged 1 month to younger than 2 months, but a different dosage is required.
Empirical therapy for deep incisional surgical site infection or surgical

site infection with systemic features
General principles
For deep incisional surgical site infections (involving the fascia or muscle) or surgical site infections with systemic
features, but not sepsis or septic shock, it is usually necessary to combine antibiotic therapy with source control (eg
drainage, irrigation, debridement). Antibiotic choice depends on whether Gram-positive bacteria or Gram-negative
or anaerobic bacteria are suspected.
Gram-positive bacteria
For deep incisional surgical site infection, or surgical site infection with systemic features, if Gram-positive
bacteria are suspected (eg the procedure did not enter the gastrointestinal, respiratory or genitourinary tracts), use:
flucloxacillin 2 g (child: 50 mg/kg up to 2 g) intravenously, 6-hourly. See below for switch

to oral therapy and duration of therapy.
If the patient is at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31)
or infection is associated with a prosthetic implant, add vancomycin to the above regimen. Use:
use. See below for switch to oral therapy and duration of therapy.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use cefazolin (with
or without vancomycin [as above]):
cefazolin 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly. See below for switch to

oral therapy and duration of therapy.
Modify therapy based on the results of culture and susceptibility testing. If susceptibility results are not available
by 72 hours and empirical intravenous therapy is still required, continue flucloxacillin or cefazolin as monotherapy.
Switch to oral antibiotic therapy when systemic features have resolved and source control has been achieved—
see Empirical therapy for superficial surgical site infection for appropriate regimens.
The total duration of therapy depends on clinical response.
Gram-negative or anaerobic bacteria

For deep incisional surgical site infection, or surgical site infection with systemic features, if Gram-negative or
anaerobic bacteria are suspected (eg the procedure entered the gastrointestinal, respiratory or genital tracts), use:
amoxicillin+clavulanate intravenously; see below for switch to oral therapy and duration
of therapy
child younger than 3 months and 4 kg or more, or 3 months or older: 25+5 mg/kg up to
1+0.2 g 8-hourly.
If Pseudomonas aeruginosa is suspected (eg based on previous culture results or local epidemiology), use:

hourly. See below for switch to oral therapy and duration of therapy.
If the patient it at increased risk of MRSA infection (see Box 2.31) or infection is associated with a prosthetic
implant, add vancomycin to the above regimens. Use:
use. See below for switch to oral therapy and duration of therapy.
by 72 hours and empirical intravenous therapy is still required, continue amoxicillin+clavulanate or
piperacillin+tazobactam as monotherapy. Switch to oral antibiotic therapy when systemic features have resolved
and source control has been achieved—see Empirical therapy for superficial surgical site infection.
The total duration of therapy depends on clinical response.
Empirical therapy for surgical site infection associated with sepsis or

septic shock
Start antibiotic therapy within 1 hour of the patient presenting to medical care or, for a ward-based patient,
developing sepsis or septic shock; antibiotics should be given immediately after appropriate samples are taken for
For surgical site infections associated with sepsis or septic shock, it is usually necessary to combine antibiotic
therapy with source control (eg drainage, irrigation, debridement).
For empirical therapy for surgical site infection associated with sepsis or septic shock, use:

hourly
PLUS

by 72 hours and empirical intravenous therapy is still required—seek expert advice. The total duration of therapy
depends on clinical response.
Key references
Principles of managing surgical site infections
Young PY, Khadaroo RG. Surgical site infections. Surg Clin North Am 2014;94(6):1245–1264 .
Bite wound infections, including clenched-fist injury
infections
Aetiology of bite and clenched-fist injury infections
Bites, including clenched-fist injuries (in which the hand is lacerated by contact with another person's teeth), often
become infected. The bacteria associated with human bites (including clenched-fist injuries) are Staphylococcus
aureus, Eikenella corrodens, Streptococcus species and beta-lactamase–producing anaerobic bacteria. The bacteria
associated with animal bites are Pasteurella species, S. aureus, Capnocytophaga canimorsus, Streptococcus
species and anaerobic bacteria. Cat bites have a higher incidence of deep infection than dog bites.
A different spectrum of bacteria is associated with marine animal bites—see Aetiology of water-immersed wound
infections.
Principles of management of bites and clenched-fist injuries

The recommended management of bites and clenched-fist injuries is thorough cleaning, irrigation, debridement,
elevation and immobilisation.
Carefully examine bite wounds and clenched-fist injuries to identify deeper injuries, devitalised tissue and retained
foreign bodies, particularly for bites inflicted by animals with small teeth.
Postexposure rabies or lyssavirus prophylaxis is required for some bites, for example bat bites (see the Australian
Immunisation Handbook for further information). For human bite injuries with associated blood exposure,
consider the need for postexposure prophylaxis against bloodborne viruses (eg hepatitis B, HIV).
For patients with bite or clenched-fist injuries, ensure that tetanus immunisation is up-to-date (see Table 2.63).
Antibiotic therapy is required for infected bites and clenched-fist injuries (see Localised infection or Infection
associated with systemic symptoms or deeper tissues). Before starting antibiotic therapy, collect infected tissue for
Gram stain and aerobic and anaerobic culture; specify that the sample is from a bite or clenched-fist wound on the
laboratory request.
For bites and clenched-fist injuries that are not infected, antibiotic therapy is usually not necessary for otherwise
healthy individuals if the risk of wound infection is low (eg small wounds not involving deeper tissues that present
within 8 hours and can be adequately debrided and irrigated). Give presumptive therapy if the risk of wound
infection is high, including if:
presentation to medical care is delayed by 8 hours or more

the wound is a puncture wound that cannot be debrided adequately
the wound is on the hands, feet or face
the wound involves deeper tissues (eg bones, joints, tendons)
the wound involves an open fracture—see Open fractures for management
the patient is immunocompromised (eg due to asplenia or immunosuppressive medications), or has alcoholic
liver disease or diabetes
the wound is a cat bite.
For wounds on the hands, feet or face, or if infection progresses despite antibiotic therapy, consider surgical
consultation. Surgical advice may also be sought on the appropriateness of primary versus delayed wound closure.
Presumptive therapy for bites and clenched-fist injuries

If antibiotic therapy is indicated (see Principles of management of bites and clenched-fist injuries), use:

875+125 mg) orally, 12-hourly for 3 days [Note 1].
In the community setting, if there is likely to be a delay in accessing oral therapy, give an immediate dose of
intramuscular procaine benzylpenicillin. Use:
procaine benzylpenicillin 1.5 g (child: 50 mg/kg up to 1.5 g) intramuscularly, as a single

dose while awaiting oral therapy.
Start continuation therapy with oral amoxicillin+clavulanate (see dosage above) as soon as it is available.
If oral absorption is likely to be impaired (eg following major trauma), use intravenous therapy:
amoxicillin+clavulanate intravenously
child younger than 3 months and 4 kg or more, or 3 months or older: 25+5 mg/kg up to
1+0.2 g 8-hourly.
Switch to oral amoxicillin+clavulanate (see dosage above) as soon as oral absorption is adequate and oral therapy
is tolerated.
For patients hypersensitive to penicillins, or at increased risk of methicillin-resistant Staphylococcus aureus

(MRSA) infection (see Box 2.31), for whom oral therapy is indicated, use:
metronidazole 400 mg (child: 10 mg/kg up to 400 mg) orally, 12-hourly for 3 days
PLUS EITHER
adult: 100 mg
OR

For patients hypersensitive to penicillins who require intravenous or intramuscular therapy, seek expert advice.
Empirical therapy for localised bite and clenched-fist injury infections

For empirical therapy of localised bite or clenched-fist injury infection not associated with systemic features or
involving deeper tissues (such as bones, joints or tendons), use:

875+125 mg) orally, 12-hourly for 5 days [Note 3]. A longer duration of treatment may be
required depending on clinical response.
For patients hypersensitive to penicillins, or at increased risk of methicillin-resistant Staphylococcus aureus

(MRSA) infection (see Box 2.31), use:
1 metronidazole 400 mg (child: 10 mg/kg up to 400 mg) orally, 12-hourly for 5 days. A
longer duration of treatment may be required depending on clinical response
PLUS EITHER
1 doxycycline orally, 12-hourly for 5 days. A longer duration of treatment may be

required depending on clinical response [Note 4]
adult: 100 mg
OR
2 trimethoprim+sulfamethoxazole 160+800 mg (child 1 month or older: 4+20 mg/kg

up to 160+800 mg) orally, 12-hourly for 5 days. A longer duration of treatment may
be required depending on clinical response
5] [Note 6]. A longer duration of treatment may be required depending on clinical
response
PLUS
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly for 5 days [Note
7]. A longer duration of treatment may be required depending on clinical response.
Modify therapy based on the results of Gram stain, culture and susceptibility testing.
If infection progresses despite antibiotic therapy, seek expert advice; surgical consultation or intravenous therapy
may be required.
Empirical therapy for bite and clenched-fist injury infections associated

with systemic features or deeper tissues
For empirical therapy of bite or clenched-fist injury infection associated with systemic features or involving
deeper tissues (such as bones, joints, or tendons), use:
amoxicillin+clavulanate intravenously; for duration of therapy, see below

adult: 1+0.2 g 8-hourly. If the bone is infected, use a dose of 1+0.2 g 6-hourly [Note 8]
child 3 months or older: 25+5 mg/kg up to 1+0.2 g intravenously, 8-hourly. If the bone is
infected, use a dose of 25+5 mg/kg up to 1+0.2 g 6-hourly [Note 9].
Amoxicillin+clavulanate is preferred to piperacillin+tazobactam because it has a narrower spectrum of activity;

however, if amoxicillin+clavulanate is not available, a reasonable alternative is:

hourly. For duration of therapy, see below.
For patients at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31), add
vancomycin to the above regimens. Use:
vancomycin intravenously, see Principles of vancomycin use for dosage and principles of
use.
vancomycin (see dosage below).
For patients hypersensitive to penicillins, use oral ciprofloxacin plus clindamycin as for localised
infection because these drugs have excellent oral bioavailability; for duration of therapy, see below. If oral therapy
is not possible, use:
For duration of therapy, see below
PLUS EITHER
1 clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly. For duration
of therapy, see below
OR
2 lincomycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly. For duration
of therapy, see below.
For patients hypersensitive to penicillins who are at increased risk of MRSA infection (see Box 2.31), use:
For duration of therapy, see below
PLUS
use
PLUS
Modify therapy based on the results of Gram stain, culture and susceptibility testing. Once the patient is stable (eg
systemic features are resolved, source control is achieved and oral therapy is tolerated), switch to oral therapy if
not used initially. Use the regimens for localised infection if the pathogen is unknown.
For bite or clenched-fist injury infections associated with systemic features, total treatment duration is usually 14
days (intravenous + oral). For bite or clench fist injury infections involving the deeper tissues, a longer duration of
therapy is needed. For the suggested duration of intravenous and oral therapy, see here for infection involving
bone, and Table 2.2 for infection involving a joint.
intravenous amoxicillin+clavulanate. For children with bone infection who weigh 40 kg or more, a reasonable
alternative regimen is 2+0.2 g intravenously, 8-hourly.
Key references
Andrews JM, Jevons G, Brenwald N, Fraise A. BSAC Working Party on Sensitivity Testing. Susceptibility testing
Pasteurella mulida by BSAC standardized methodology. J Antimicrob Chemother 2004;54(5):962–4.
Aziz H, Rhee P, Pandit V, Tang A, Gries L, Joseph B. The current concepts in management of animal (dog, cat, snake,
scorpion) and human bite wounds. J Trauma Acute Care Surg 2015;78(3):641–8.
Lion C, Escande F, Burdin JC. Capnocytophaga canimorsus infections in human: review of the literature and cases
report. Eur J Epidemiol 1996;12(5):521–33.
Rasmussen D, Landon A, Powell J, Brown GR. Evaluating and treating mammalian bites. JAAPA 2017;30(3):32–6.
Open fractures
Approach to managing open fractures
Open fractures are those where the bone has broken the skin or mucous membrane and the fracture is exposed to a
contaminated environment. Urgent surgical consultation is essential. Timely thorough surgical debridement and
irrigation to remove nonviable tissue and contaminating material, followed by fracture stabilisation and soft tissue
envelope restoration, are critical for preventing infection.
For patients with open fractures, ensure that tetanus immunisation is up-to-date (see Table 2.63).
Antibiotic prophylaxis is not required for an open fracture involving only the distal phalanx of a finger, provided
the fracture is promptly managed (ie within 8 hours of injury) with thorough irrigation and meticulous
debridement, which may include repair of the nail bed. Studies supporting this approach excluded human and
animal bite injuries; such injuries require antibiotic prophylaxis—see Bite wound infections, including clenched-
fist injury infections.
Antibiotic prophylaxis is not required for open fractures of the distal phalanx that have been promptly and adequately debrided.
For open facial fractures that do not require operative management, antibiotic prophylaxis is not indicated. For
open facial fractures that require operative management, surgical antibiotic prophylaxis is recommended;
see Surgical prophylaxis for oral maxillofacial surgery. Prophylaxis between injury and the perioperative period is
usually not necessary; however, limited evidence supports the use of antibiotic prophylaxis for complex and
potentially contaminated injuries, especially those involving both skin or mucous membranes and the cranial
cavity (eg multiple open fractures, penetrating trauma, a significantly comminuted mandible). Unless there is
established infection, there is no benefit to continuing antibiotics postoperatively.
Open fractures of the skull may expose bone and brain to the external environment, or respiratory and alimentary
flora; management is complex—seek expert advice. See also Surgical prophylaxis for neurosurgery.
For other open fractures, systemic antibiotic prophylaxis reduces the incidence of infection; start prophylaxis
immediately after injury for maximum benefit. The choice of antibiotic prophylaxis depends on the nature and
extent of tissue damage. While Staphylococcus aureus is most commonly identified in infected open fractures, a
broader range of pathogens are seen in infections of fractures associated with extensive tissue damage and heavy
contamination, or that have been immersed in water (eg injuries sustained in a natural disaster, marine injuries). A
different spectrum of pathogens is also seen in human and animal bite injuries; such injuries require targeted
antibiotic prophylaxis—see Bite wound infections, including clenched-fist injury infections.
The recommendations in these guidelines are appropriate for the Australian context, where severe injuries often
occur in rural and remote locations and, consequently, transfer times to tertiary care are prolonged. For this reason,
the addition of metronidazole is recommended for heavily contaminated severe injuries.
Historically, prophylaxis also targeted Gram-negative bacteria; however, recent studies have not demonstrated
benefit with this strategy and show an increased risk of selecting multidrug-resistant pathogens. Targeted
prophylaxis is, however, recommended for aquatic Gram-negative bacteria.
The prophylactic regimens for open fractures provide an adequate spectrum for surgical antibiotic prophylaxis;
however, adjust the timing of the dose to optimise plasma and tissue concentrations at the time of surgical incision,
and for the duration of the procedure—for more information, see Timing of surgical antibiotic prophylaxis.
Empirical antibiotic therapy is required for patients who develop clinical evidence of infection. Surgical
management is required to determine the depth and extent of infection, remove remaining foreign bodies, drain
collections, debride nonviable tissue, and provide or maintain fracture stability. Collection of samples for culture
and susceptibility testing is critical to guide directed therapy because there is a broad range of potential pathogens,
and prolonged antibiotic therapy is often required. Tissue samples are preferred to swabs, and for the highest yield,
samples should be taken before antibiotic therapy is started.
Antibiotic prophylaxis for open fractures

Administer antibiotic prophylaxis as soon as possible, ideally within 3 hours of injury. Duration of prophylaxis
depends on injury severity; the Gustilo–Anderson system of classifying injury severity is widely used and, despite
intra-observer variability, correlates with infection rate.
Prophylaxis for nonsevere injuries comparable to Gustilo–Anderson type I or II (open fractures resulting from
indirect injury or direct, low-energy injury) can be discontinued at definitive wound closure. Do not continue
prophylaxis for more than 24 hours after definitive closure of a severe injury comparable to Gustilo–Anderson
type III (including open fractures resulting from high-energy injury or exhibiting high-energy fracture patterns
[severe comminution or segmental bone loss] with extensive soft tissue injury, or a traumatic amputation).
Regardless of injury severity, the total duration of prophylaxis should be no more than 72 hours, even if soft tissue
coverage is not achievable.
The total duration of prophylaxis should be no more than 72 hours.
For prophylaxis, use:
If the wound has been immersed in water (eg injuries sustained in a natural disaster, marine injuries), use:
cefepime 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly.
If there is likely to be a delay in accessing cefepime, give an immediate dose of cefazolin (as above), because the
benefit of prophylaxis is greatest when it is given immediately after injury. Switch to cefepime as soon as it is
available.
Additional anaerobic activity is recommended for severe injuries that are heavily contaminated with material
embedded in bone or deep soft tissues (eg agriculture injuries, injuries involving sewage). For such injuries, add
metronidazole to the above regimens. Use:
The above regimens are suitable for patients with immediate nonsevere or delayed nonsevere hypersensitivity to
penicillins.
For prophylaxis for patients with immediate severe or delayed severe hypersensitivity to penicillins, use:
OR
2 lincomycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly
PLUS with either of the above regimens if the wound has been immersed in water
For patients with immediate severe or delayed severe hypersensitivity to penicillins who have adequate oral
absorption and can tolerate oral therapy, use:
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly
PLUS if the wound has been immersed in water
ciprofloxacin 750 mg (child: 20 mg/kg up to 750 mg) orally, 12-hourly [Note 1] [Note 2].
Empirical therapy for open fractures
For patients with superficial soft tissue infection, see Post-traumatic wound infections for antibiotic choice and
For empirical intravenous therapy of suspected bone infection or deep soft tissue infection contiguous with bone,
use:

hourly.
If the wound has been immersed in water (eg injuries sustained in a natural disaster, marine injuries, sewage-
contaminated injuries), use:
PLUS
If the patient has sepsis or septic shock (for definitions, see here for adults, or here for infants and children), or is at
increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31), add vancomycin
to the above regimens. Use:
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use cefepime and
metronidazole with or without vancomycin (as above).
For patients with immediate severe or delayed severe hypersensitivity to penicillins who do not have sepsis or
septic shock and are at low risk for MRSA infection (see Box 2.31), use:
PLUS EITHER
OR
For patients with immediate severe or delayed severe hypersensitivity to penicillins who have sepsis or septic
shock, or are at increased risk of MRSA infection (see Box 2.31), seek expert advice for treatment choice.
Modify therapy according to the results of culture and susceptibility testing, and the extent of deep tissue
involvement. For directed therapy of deep soft tissue and bone infection caused by Staphylococcus aureus, see
Directed therapy for native bone and joint infection for antibiotic choice and dosage. For other organisms and
polymicrobial infection, seek expert advice.
Patients with deep soft tissue infection contiguous with bone or established bone infection require a longer
duration of intravenous antibiotic therapy followed by oral continuation therapy (for the suggested duration of
therapy, see here or, if there is metalwork present, here).
Key references
Bremmer D, Bookstaver B, Cairns M, Lindley K, Durkin M, Koon D, et al. Impact of body mass index and bacterial
resistance in osteomyelitis after antibiotic prophylaxis of open lower-extremity fractures. Surg Infect (Larchmt)
2017;18(3):368–73.
Chang Y, Kennedy SA, Bhandari M, Lopes LC, Bergamaschi Cde C, de Oliveira ESM, et al. Effects of antibiotic
prophylaxis in patients with open fracture of the extremities: A systematic review of randomized controlled trials. JBJS
Rev 2015;3(6): .
Dunkel N, Pittet D, Tovmirzaeva L, Suvà D, Bernard L, Lew D, et al. Short duration of antibiotic prophylaxis in open
fractures does not enhance risk of subsequent infection. Bone Joint J 2013;95-B(6):831–7 .
Fatovich DM, Phillips M, Langford SA, Jacobs IG. A comparison of metropolitan vs rural major trauma in Western
Australia. Resuscitation 2011;82(7):886–90.
Ghoshal A, Enninghorst N, Sisak K, Balogh ZJ. An interobserver reliability comparison between the Orthopaedic
Trauma Association’s open fracture classification and the Gustilo and Anderson classification. Bone Joint J 2018;100-
B(2):242–6.
Gustilo RB, Anderson JT. Prevention of infection in the treatment of one thousand and twenty-five open fractures of
long bones: retrospective and prospective analyses. J Bone Joint Surg Am 1976;58(4):453–8.
Gustilo RB, Mendoza RM, Williams DN. Problems in the management of type III (severe) open fractures: a new
classification of type III open fractures. J Trauma 1984;24(8):742–6.
Hoff WS, Bonadies JA, Cachecho R, Dorlac WC. East Practice Management Guidelines Work Group: update to
practice management guidelines for prophylactic antibiotic use in open fractures. J Trauma 2011;70(3):751–4.
Hospenthal DR, Murray CK, Andersen RC, Bell RB, Calhoun JH, Cancio LC, et al. Guidelines for the prevention of
infections associated with combat-related injuries: 2011 update: endorsed by the Infectious Diseases Society of
America and the Surgical Infection Society. J Trauma 2011;71(2 Suppl 2):S210–34.
Hull PD, Johnson SC, Stephen DJ, Kreder HJ, Jenkinson RJ. Delayed debridement of severe open fractures is
associated with a higher rate of deep infection. Bone Joint J 2014;96-B(3):379–84 .
Isaac SM, Woods A, Danial IN, Mourkus H. Antibiotic prophylaxis in adults with open tibial fractures: What is the
evidence for duration of administration? A systematic review. J Foot Ankle Surg 2016;55(1):146–50 .
Kargel JS, Dimas VM, Kao DS, Heggers JP, Chang P, Phillips LG. Empiric antibiotic therapy for seawater injuries: a
four-seasonal analysis. Plast Reconstr Surg 2008;121(4):1249–55.
Kim PH, Leopold SS. In brief: Gustilo-Anderson classification. [corrected]. Clin Orthop Relat Res 2012;470(11):3270–
4.
Lack WD, Karunakar MA, Angerame MR, Seymour RB, Sims S, Kellam JF, et al. Type III open tibia fractures:
immediate antibiotic prophylaxis minimizes infection. J Orthop Trauma 2015;29(1):1–6.
Lloyd BA, Murray CK, Shaikh F, Carson ML, Blyth DM, Schnaubelt ER, et al. Antimicrobial prophylaxis with combat-
related open soft-tissue injuries. Mil Med 2018.
McAuliffe GN, Hennessy J, Baird RW. Relative frequency, characteristics, and antimicrobial susceptibility patterns of
Vibrio spp., Aeromonas spp., Chromobacterium violaceum, and Shewanella sp. in the northern territory of Australia,
2000-2013. Am J Trop Med Hyg 2015;92(3):605–10.
Metcalfe D, Aquilina AL, Hedley HM. Prophylactic antibiotics in open distal phalanx fractures: systematic review and
meta-analysis. J Hand Surg Eur Vol 2016;41(4):423–30 .
Nanchahal J, Nayagam S, Khan U, Moran C, Barrett S, Sanderson F. Standards for the management of open fractures
of the lower limb. London: Royal Society of Medicine Press Ltd; 2009. http://www.bapras.org.uk/professionals/clinical-
guidance/open-fractures-of-the-lower-limb.
National Institute for Clinical Excellence (NICE). Fractures (complex): assessment and management [NG37]. London:
NICE; 2016, Updated Nov 2017. https://www.nice.org.uk/guidance/ng37.
Prodromidis AD, Charalambous CP. The 6-Hour rule for surgical debridement of open tibial fractures: A systematic
review and meta-analysis of infection and nonunion rates. J Orthop Trauma 2016;30(7):397–402 .
Srour M, Inaba K, Okoye O, Chan C, Skiada D, Schnüriger B, et al. Prospective evaluation of treatment of open
fractures: effect of time to irrigation and debridement. JAMA Surg 2015;150(4):332–6 .
Whitehouse MR, McDaid C, Kelly MB, Moran CG, Costa ML. The effect of timing of antibiotic delivery on infection rates
related to open limb fractures: a systematic review. Emerg Med J 2017;34(9):613–20 .
Yun HC, Murray CK, Nelson KJ, Bosse MJ. Infection after orthopaedic trauma: Prevention and treatment. J Orthop
Trauma 2016;30 Suppl 3:S21–S6.
Zhu H, Li X, Zheng X. A descriptive study of open fractures contaminated by seawater: Infection, pathogens, and
antibiotic resistance. Biomed Res Int 2017;2017:2796054. .
Post-traumatic wound infections
Approach to managing traumatic wounds
The following advice applies to patients with extremity wounds; for patients with other wounds (eg penetrating
abdominal wounds, chest trauma), seek expert advice.
For patients with traumatic wounds, ensure that tetanus immunisation is up-to-date (see Table 2.63).
Careful cleaning and debridement of traumatic wounds is important to prevent infection; immobilisation and
elevation are also beneficial.
Consider necrotising skin and soft tissue infection in patients with sepsis or septic shock associated with a
traumatic wound].
Antibiotics are not routinely required for traumatic wounds. They are used as:
prophylaxis for wounds requiring surgical management or that are significantly contaminated (eg penetrating
injuries through footwear, stab wounds)
presumptive therapy for bites and clenched-fist injuries at high risk of infection
prophylaxis for open fractures
treatment of established infection (see localised infection, infection associated with systemic features or
deeper tissues or sepsis or septic shock associated with a traumatic wound).
If antibiotic therapy is indicated for a traumatic wound that has been immersed in water, see Water-immersed
wound infections for antibiotic choice.
Collect samples for Gram stain and culture before antibiotic therapy is started.
Likely pathogens in post-traumatic wound infection include Staphylococcus aureus and Streptococcus pyogenes
(group A streptococcus). Anaerobic post-traumatic wound infection (eg Clostridium perfringens infection) is rare
but may follow severe injuries if the wound is heavily contaminated. A broader range of pathogens are seen in
infections of traumatic wounds that have been immersed in water, including soil- or sewage-contaminated water
(eg injuries sustained in a natural disaster, marine injuries).
Requirement for tetanus prophylaxis (Table 2.63)
Type of wound Is tetanus toxoid Is tetanus

vaccine indicated? immunoglobulin
[NB1] indicated?
Patient has received 3 or more doses of tetanus toxoid vaccine
less than 5 years since last dose of all no no [NB2]
tetanus toxoid vaccine
5 to 10 years since last dose of tetanus clean minor no no
toxoid vaccine all others yes no [NB2]
more than 10 years since last dose of all yes no [NB2]
tetanus toxoid vaccine
Patient has received less than 3 doses of tetanus toxoid vaccine or vaccination history is unknown
clean minor yes no
all others yes yes
NB1: Tetanus toxoid is only available in combination with other antigens.
NB2: Give tetanus immunoglobulin to people with humoral immune deficiency and people with HIV (regardless of CD4 cell count) if they have a wound
that is not a clean minor wound.
Source: Australian Immunisation Handbook. Refer to website for most current advice.
© 2018 Commonwealth of Australia as represented by the Department of Health
Prophylaxis for traumatic wounds

General principles
Antibiotic prophylaxis is not routinely required for traumatic wounds that do not require surgical management and
are not significantly contaminated. Careful cleaning and debridement is the mainstay of therapy for these wounds.
For wounds that require prophylaxis, combining careful cleaning and debridement with antibiotics reduces the
incidence of early infections. Administer antibiotic prophylaxis as soon as possible, ideally within 3 hours of
injury.
The duration of prophylaxis depends on injury severity (muscular, skeletal and soft tissue trauma, crush injuries,
penetrating injuries, and stab wounds are usually severe), adequacy of debridement and whether soft tissue
coverage is achievable.
Wounds requiring surgical management

For patients with wounds requiring surgical management, intravenous therapy is required. Use:
Additional anaerobic activity is recommended for heavily contaminated severe injuries, such as agricultural
injuries; add metronidazole to cefazolin:
The above regimens are suitable for patients with immediate nonsevere or delayed nonsevere hypersensitivity to
penicillins.
For patients with immediate severe or delayed severe hypersensitivity to penicillins, even if anaerobic activity is
required, use:
OR
The regimens in this section provide an adequate spectrum for surgical antibiotic prophylaxis; however, adjust the
timing of the dose to optimise plasma and tissue concentrations at the time of surgical incision, and for the
duration of the procedure—for more information, see Timing of surgical antibiotic prophylaxis.
Duration of therapy: prophylaxis for nonsevere injuries can be discontinued at definitive wound closure. Do not
continue prophylaxis for severe injuries for more than 24 hours after definitive wound closure. Regardless of
injury severity, the total duration of prophylaxis should be no more than 72 hours, even if soft tissue coverage is
not achievable.
Wounds not requiring surgical management
For patients with significantly contaminated wounds that do not require surgical management, oral antibiotic
therapy can be used in combination with careful cleaning and debridement. Use:
1 dicloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly
OR
1 flucloxacillin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 6-hourly.
Use:
clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly [Note 2].
Duration of therapy: for deep, penetrating injuries that cannot be adequately debrided (eg penetrating nail
injuries), give prophylaxis for 72 hours. For all other wounds, give prophylaxis for 24 hours.
of Hospital Pharmacists of Australia. [URL]
Empirical therapy for localised post-traumatic wound infection

The following advice applies to patients with localised post-traumatic wound infection not associated with
systemic symptoms or involving deeper tissues (such as bones, joints or tendons).
Seek expert advice for penetrating injuries through footwear. While Staphylococcus aureus is the most common
pathogen in these infections, empirical treatment regimens should include antibiotics with activity against Gram-
negative bacteria (including Pseudomonas aeruginosa).
For empirical therapy for patients at low risk of methicillin-resistant S. aureus (MRSA) infection (see Box 2.31),
use:
OR
For patients with delayed nonsevere hypersensitivity to penicillins who are at low risk of MRSA infection,
cefalexin can be used in most cases [Note 3]. Use:
For patients with immediate (nonsevere or severe) or delayed severe hypersensitivity to penicillins who are at
low risk of MRSA infection, and patients at increased risk of MRSA infection, use:

OR
2 clindamycin 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly for 5 days [Note 4].
of Hospital Pharmacists of Australia. [URL]
Empirical therapy for post-traumatic wound infection associated with

systemic features or deeper tissues
General principles
Empirical antibiotic choice for post-traumatic wound infection associated with systemic features or deeper tissues
(such as bones, joints or tendons) depends on the patient's risk of MRSA infection (see Box 2.31). It is further
affected by the type of injury (eg whether the wound is heavily contaminated). Modify therapy based on the results
of culture and susceptibility testing.
Switch to oral therapy (see here) as soon as possible (eg 48 hours after surgery); if P. aeruginosa infection is
confirmed, seek expert advice for oral continuation therapy.
Total duration of treatment (intravenous + oral) is 5 to 7 days, depending on clinical response; however, a longer
duration of therapy is needed for wounds involving the deeper tissues (such as bones, joints or tendons). For the
suggested duration of intravenous and oral therapy, see here for infection involving bone, and Table 2.2 for
infection involving a joint.
Patients at low risk of MRSA infection
For empirical therapy of post-traumatic wound infection associated with systemic features or involving deeper
tissues, for patients at low risk of MRSA infection, use:
Regimens with additional anaerobic activity are required for heavily contaminated severe injuries or if there has
been significant tissue maceration. Use:
adult: 1+0.2 g 8-hourly. If the bone is infected, use a dose of 1+0.2 g 6-hourly [Note 5]
child 3 months or older: 25+5 mg/kg up to 1+0.2 g 8-hourly. If the bone is infected, use a
dose of 25+5 mg/kg up to 1+0.2 g 6-hourly [Note 6]
1 cefazolin 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly
PLUS
For penetrating injuries through footwear, treatment for Gram-negative bacteria (including Pseudomonas
aeruginosa) is required. Use:

hourly.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins who have not
sustained a penetrating injury through footwear, use cefazolin with or without metronidazole as appropriate (see
dosage above).
For patients with immediate severe or delayed severe hypersensitivity to penicillins who have not sustained a
penetrating injury through footwear, use:
OR
For patients hypersensitive to penicillins who have sustained a penetrating injury through footwear, use:
PLUS EITHER
OR
See General principles for duration of therapy, including switch to oral therapy.
intravenous amoxicillin+clavulanate. For children with bone infection who weigh 40 kg or more, a reasonable
alternative regimen is 2+0.2 g intravenously, 8-hourly.
Patients at increased risk of MRSA infection

For empirical therapy of post-traumatic wound infection associated with systemic features or involving deeper
tissues in patients at increased risk of MRSA infection, use:
use.
For heavily contaminated severe injuries or significant tissue maceration, use:
use
PLUS
For patients who have sustained a penetrating injury through footwear, use:
use
PLUS
metronidazole 500 mg (child: 12.5 mg/kg up to 500 mg) intravenously, 12-hourly
PLUS
See General principles for duration of therapy, including switch to oral therapy.
Empirical therapy for sepsis or septic shock associated with a traumatic

wound
Treat patients with sepsis or septic shock associated with a traumatic wound (for definitions, see here for adults, or
here for neonates, infants and children) as for necrotising skin and soft tissue infection—see Empirical therapy for
necrotising skin and soft tissue infection.
Key references
Dellinger EP, Caplan ES, Weaver LD, Wertz MJ, Droppert BM, Hoyt N, et al. Duration of preventive antibiotic
administration for open extremity fractures. Arch Surg 1988;123(3):333–339.
Dunkel N, Pittet D, Tovmirzaeva L, Suvà D, Bernard L, Lew D, et al. Short duration of antibiotic prophylaxis in open
fractures does not enhance risk of subsequent infection. Bone Joint J 2013;95-B(6):831–837.
Hoff WS, Bonadies JA, Cachecho R, Dorlac WC. East Practice Management Guidelines Work Group: update to
practice management guidelines for prophylactic antibiotic use in open fractures. J Trauma 2011;70(3):751–754.
Hospenthal DR, Murray CK, Andersen RC, Bell RB, Calhoun JH, Cancio LC, et al. Guidelines for the prevention of
infections associated with combat-related injuries: 2011 update: endorsed by the Infectious Diseases Society of
America and the Surgical Infection Society. J Trauma 2011;71(2 Suppl 2):S210–S234.
Isaac SM, Woods A, Danial IN, Mourkus H. Antibiotic prophylaxis in adults with open tibial fractures: What is the
evidence for duration of administration? A systematic review. J Foot Ankle Surg 2016;55(1):146–150.
Lloyd BA, Murray CK, Shaikh F, Carson ML, Blyth DM, Schnaubelt ER, et al. Antimicrobial prophylaxis with combat-
related open soft-tissue injuries. Mil Med 2018;[epub].
Prodromidis AD, Charalambous CP.The 6-hour rule for surgical debridement of open tibial fractures: A systematic
review and meta-analysis of infection and nonunion rates. J Orthop Trauma 2016;30(7):397–402.
Rubin G, Chezar A, Raz R, Rozen N.Nail puncture wound through a rubber-soled shoe: a retrospective study of 96
adult patients. J Foot Ankle Surg 2010;49(5):421–5.
Pre-emptive treatment following a penetrating eye
injury
Pre-emptive treatment following a penetrating eye injury
Pre-emptive treatment following a penetrating eye injury is indicated due to the risk of endophthalmitis.
Risk factors for post-traumatic endophthalmitis include: delayed primary repair of the injury (more than 12 hours);
presence of an intraocular foreign body; injuries occurring in a rural location or contaminated with organic matter;
rupture of the lens capsule; and vitreous prolapse through the wound.
Do not use topical antibiotics if an open globe injury is suspected because preservatives are toxic to the intraocular
contents.
While there is no definitive evidence on the most effective pre-emptive treatment, intravitreal ceftazidime plus
vancomycin may reduce infection rate in high-risk cases if they can be safely administered at the time of surgery.
It is common practice to start systemic antibiotics when a patient presents for care following a penetrating eye
injury. Consider:
1 moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) orally, daily for 5 to 7 days [Note 1]
[Note 2]
OR
2 ciprofloxacin 750 mg (child: 20 mg/kg up to 750 mg) orally, twice daily for 5 to 7 days
[Note 3] [Note 4].
Moxifloxacin has better intraocular penetration than ciprofloxacin; however, ciprofloxacin can be used if
moxifloxacin is not available.
Following surgical repair, it is also common practice to start topical antibiotic therapy. Use:
1 ciprofloxacin 0.3% eye drops, 1 drop into the affected eye, four times a day for 7 days
OR
1 ofloxacin 0.3% eye drops, 1 drop into the affected eye, four times a day for 7 days
OR (if available)
1 cefazolin 5% plus gentamicin 0.9% eye drops, 1 drop into the affected eye, four times a
day for 7 days
OR (if there is a low risk of endophthalmitis)
1 chloramphenicol 0.5% eye drops, 1 drop into the affected eye, four times a day for 7 days.
Topical antibiotic drops can be administered more frequently than four times a day, depending on the nature of the
injury and the risk of infection.
Note 1: Moxifloxacin is not licensed for use in children on the basis of animal studies that showed an adverse effect on cartilage development with
quinolone use; however, there are few data from human trials to support this finding. Moxifloxacin can be used in children when it is the drug of
choice.
Note 2: An oral liquid formulation of moxifloxacin is not commercially available; for formulation options for children or people with swallowing
choice.
Prophylaxis after skull fracture
Prophylaxis after skull fracture
There is no evidence that antibiotic prophylaxis for basilar skull fracture reduces meningitis, mortality (all-
cause or meningitis-related), or the need for surgical correction, even in the presence of a cerebrospinal fluid
(CSF) leak.
Key references
Ratilal BO, Costa J, Pappamikail L, Sampaio C. Antibiotic prophylaxis for preventing meningitis in patients with
basilar skull fractures. Cochrane Database Syst Rev 2015;(4):CD004884.
Water-immersed wound infections
Aetiology of water-immersed wound infections
Skin infection or sepsis following immersion of a wound in water (eg in fishermen, swimmers or aquarium
owners, or with a marine animal bite [including shark or crocodile bites] or coral cut) may involve:
Aeromonas species (source: fresh or brackish water, and mud; exposure risks: caving, natural disasters and
medicinal leech therapy)
Mycobacterium marinum (most common source: fish tanks)
Shewanella putrefaciens
Vibrio vulnificus, Vibrio alginolyticus and other noncholera vibrios (source: salt or brackish water)
Staphylococcus aureus, including methicillin-resistant strains
Streptococcus pyogenes (group A streptococcus) (source: coral cuts).
Principles of management of water-immersed wounds

Careful cleaning, and debridement if necessary, of wounds that have been immersed in water is important to
prevent infection.
For patients with traumatic water-immersed wounds, ensure that tetanus immunisation is up-to-date (see Table
2.63).
Preventative antibiotics are not routinely required for wounds that have been immersed in water. Prophylaxis is
required for traumatic water-immersed wounds that require surgical management or are significantly contaminated.
Presumptive therapy is required for marine animal bite wounds at high risk of infection (see Principles of
management of bites and clenched fist injuries for risk factors).
Consider early empirical therapy for patients with risk factors for developing severe infections (eg liver disease,
iron overload, immune compromise due to immunosuppressive medications, diabetes or malignancy).
Water-immersed wound infections can progress rapidly and even localised infections require close monitoring.
Combined medical and surgical management is often required. Seek expert advice if infection is associated with
systemic symptoms or involves deeper tissues (such as bones, joints or tendons), or if localised infection
progresses.
The appropriate antibiotic regimen for definitive therapy depends on the pathogen. Collect samples of infected
tissue or wound exudate for Gram stain, culture and susceptibility testing before antibiotic therapy is started.
For nonantibiotic management of penetrating venomous marine wounds, see Marine envenoming.
Antibiotic choice for water-immersed wound infections

If prophylaxis or presumptive therapy is indicated (see Principles of management of water-immersed wounds) and
oral therapy is appropriate, use the antibiotics recommended for localised water-immersed wound infections. If
intravenous therapy is appropriate, use the antibiotics recommended for infections associated with systemic
features or deeper tissues. See Prophylaxis for traumatic wounds or Presumptive therapy for bites and clenched-fist
injuries for duration of therapy.
Antibiotic choice for infected wounds depends on infection severity (see Localised infection or Infection
associated with systemic symptoms or deeper tissues]), the water source in which the wound was immersed, and
whether the patient has risk factors for developing severe disease (eg cirrhosis, iron overload, immune
compromise). Treat patients with risk factors for developing severe disease with the regimens for infection
associated with systemic symptoms or involving deeper tissues even if the infection is localised, because of the
risk of fulminant infection.
Empirical therapy for localised water-immersed wound infections

General principles
The following advice applies to patients with localised water-immersed wound infection not associated with
systemic symptoms or involving deeper tissues such as the bones, joints or tendons.
Treat patients with risk factors for developing severe disease (eg liver disease, iron overload, immune compromise
due to immunosuppressive medications, diabetes or malignancy) as for Infection associated with systemic
symptoms or involving deeper tissues even if the infection is localised.
Seawater-immersed wounds
For empirical therapy for localised infection of seawater-immersed wounds (including coral cuts) not associated
with systemic features or involving deeper tissues, use:
doxycycline orally, 12-hourly [Note 1]

adult: 100 mg
PLUS EITHER
OR
suitable formulation. If an alternative is required for children younger than 8 years, use:
ciprofloxacin (child younger than 8 years) 12.5 mg/kg up to 500 mg orally, 12-hourly
[Note 2] [Note 3].
tolerated. In most cases, it can also be used for patients with delayed nonsevere hypersensitivity to
For patients at increased risk of MRSA infection (see Box 2.31), trimethoprim+sulfamethoxazole can be used in
place of the above regimens. Use:
trimethoprim+sulfamethoxazole 320+1600 mg (child 1 month or over: 8+40 mg/kg up to

Modify therapy based on the results of culture and susceptibility testing; see Aeromonas species, Vibrio
species and Mycobacterium marinum.
If a pathogen is not identified, the duration of therapy is determined by clinical response. A duration of 5 days is
likely to be appropriate.
reaction involved amoxicillin or ampicillin, because cross-reactivity between these drugs is possible.
Fresh, brackish, aquarium or soil- or sewage-contaminated water–immersed wounds

For empirical therapy for localised infection of fresh, brackish or aquarium water–immersed wounds not
associated with systemic features or involving deeper tissues, use:
1 trimethoprim+sulfamethoxazole 320+1600 mg (child 1 month or over: 8+40 mg/kg up to

2 ciprofloxacin 500 mg (child: 12.5 mg/kg up to 500 mg) orally, 12-hourly [Note 5] [Note
6]
PLUS EITHER
OR
For patients at increased risk of MRSA infection (see Box 2.31), use trimethoprim+sulfamethoxazole (see dosage
above).
For empirical therapy for localised infection of wounds immersed in soil- or sewage-contaminated water (eg
following a flood or natural disaster) not associated with systemic features or involving deeper tissues, add
metronidazole to the above regimens:
If a pathogen is not identified, the duration of therapy is determined by clinical response. A duration of 5 days is
likely to be appropriate.
Empirical therapy for water-immersed wound infections associated

with systemic features or deeper tissues
General principles
Intravenous therapy is required for initial empirical therapy for infection associated with systemic features or
involving deeper tissues (such as bones, joints or tendons), and for patients with localised infection who have risk
factors for severe disease (eg liver disease, iron overload, immune compromise due to immunosuppressive
medications, diabetes or malignancy).
Antibiotic choice depends on whether the wound is associated with significant trauma or has been immersed in
soil- or sewage-contaminated water.
For empirical therapy for patients with sepsis or septic shock (for definitions, see here for adults, or here for
neonates, infants and children), see Empirical therapy for necrotising skin or soft tissue infection.
Wounds not associated with significant trauma and not exposed to soil- or sewage-
contaminated water
For empirical therapy for patients without significant trauma whose wounds have not been exposed to soil- or
sewage-contaminated water, use:
PLUS
For patients at increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (see Box 2.31), add
vancomycin to the empirical regimen. Use:
use.
In some regions, based on local susceptibility data, clindamycin is a suitable alternative to vancomycin (see dosage
below).
cefazolin 2 g (child: 50 mg/kg up to 2 g) intravenously, 8-hourly
PLUS
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins who are at increased
risk of MRSA infection (see Box 2.31), add vancomycin (see dosage above) to cefazolin and ciprofloxacin. In
some regions, based on local susceptibility data, clindamycin is a suitable alternative to vancomycin (see dosage
below).
clindamycin 600 mg (child: 15 mg/kg up to 600 mg) intravenously, 8-hourly
PLUS
For patients with immediate severe or delayed severe hypersensitivity to penicillins who are at increased risk of
MRSA infection (see Box 2.31), replace clindamycin with vancomycin (see dosage above). In some regions,
based on local susceptibility data, clindamycin is a suitable alternative to vancomycin.
If a pathogen is not identified, the duration of empirical therapy is determined by clinical response. Switch to oral
therapy (as for localised infection) as soon as possible. A total duration of therapy (intravenous + oral) of 5 to 7
days is likely to be appropriate; however, a longer duration of therapy is needed for wounds involving the deeper
tissues (such as bones, joints or tendons).
Wounds associated with significant trauma or exposed to soil- or sewage-contaminated

water
For empirical therapy for patients whose wounds are associated with significant trauma (including shark and
crocodile bites) or have been exposed to soil- or sewage-contaminated water (eg following a flood or natural
disaster), use:
PLUS
For patients at increased risk of MRSA infection (see Box 2.31), add vancomycin (see dosage below) to the above
regimen. If local epidemiology suggests clindamycin is a suitable alternative to vancomycin, use cefepime plus
clindamycin (see dosage below); it is not necessary to include metronidazole for additional anaerobic activity.
For patients with immediate nonsevere or delayed nonsevere hypersensitivity to penicillins, use the appropriate
cefepime-based regimen as above.
PLUS EITHER
OR
For patients with immediate severe or delayed severe hypersensitivity to penicillins who are at increased risk of
MRSA infection (see Box 2.31), use:
PLUS
use
PLUS
However, if local epidemiology suggests clindamycin is a suitable alternative to vancomycin, use ciprofloxacin
plus clindamycin (see dosage above); it is not necessary to include metronidazole for additional anaerobic activity.
If a pathogen is not identified, the duration of empirical therapy is determined by clinical response. Switch to oral
therapy (as for localised infection) as soon as possible. A total duration of therapy (intravenous + oral) of 5 to 7
days is likely to be appropriate; however, a longer duration of therapy is needed for wounds involving the deeper
tissues (such as bones, joints or tendons).
Directed therapy for water-immersed wound infection

Aeromonas species
If Aeromonas species are identified on culture, for susceptible species, use:
10]
OR

The total duration of therapy (empirical + directed) for uncomplicated infection is 14 days. Longer courses may
be required for severe infection depending on clinical response.
Vibrio species
Management of skin infections caused by Vibrio species includes incision, drainage and multiple debridements.
For patients with severe infection and sepsis, aggressive surgical debridement or amputation may be required for
source control.
Treat patients with risk factors for developing severe disease (eg liver disease, iron overload, immune compromise
due to immunosuppressive medications, diabetes or malignancy) as if they have infection associated with systemic
symptoms or involving deeper tissues even if infection is localised, because of the risk of fulminant infection.
Antibiotic therapy should be guided by antimicrobial susceptibility. Alternative regimens may be required—seek
expert advice.
For localised infection not associated with systemic features or involving deeper tissues, for susceptible species,
use:
1 doxycycline orally, 12-hourly [Note 11]
adult: 100 mg
OR
13] .
For patients with infection associated with systemic features or involving deeper tissues (such as bones, joints or
tendons), and for patients with localised infection who have risk factors for severe disease, the appropriate
regimen depends on whether oral therapy is appropriate. For patients with adequate oral absorption, for susceptible
species, as a two-drug regimen, use:
1 ceftriaxone 2 g (child: 50 mg/kg up to 2 g) intravenously, 12-hourly
OR
1 doxycycline orally, 12-hourly [Note 11]
adult: 100 mg
OR
13].
Intravenous therapy must be used if oral absorption is likely to be impaired (eg following major trauma). For
susceptible species, as a two-drug regimen, use:
1 ceftriaxone 2 g (child: 50 mg/kg up to 2 g) intravenously, 12-hourly
OR
1 doxycycline 100 mg (child 8 years or older: 2 mg/kg up to 100 mg) intravenously, 12-
hourly [Note 14]
OR
2 ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) intravenously, 12-hourly [Note 12].
The duration of treatment is determined by clinical response and whether deeper tissues are involved, and can
exceed 2 weeks. Switch to oral therapy (as for localised infection, above) when the source of infection is
controlled, sepsis is resolved and oral antibiotics can be tolerated.
Note 14: Intravenous doxycycline is not registered for use in Australia but is available via the Special Access
Scheme.
Key references
Diaz JH. Skin and soft tissue infections following marine injuries and exposures in travelers. J Travel Med
2014;21(3):207–213.
Finkelstein R, Oren I. Soft tissue infections caused by marine bacterial pathogens: epidemiology, diagnosis, and
management. Curr Infect Dis Rep 2011;13(5):470–477.
Horseman MA, Surani S. A comprehensive review of Vibrio vulnificus: an important cause of severe sepsis and skin
and soft-tissue infection. Int J Infect Dis 2011;15(3):e157–66.
McAuliffe GN, Hennessy J, Baird RW. Relative frequency, characteristics, and antimicrobial susceptibility patterns of
Vibrio spp., Aeromonas spp., Chromobacterium violaceum, and Shewanella spp. in the northern territory of Australia,
2000-2013. Am J Trop Med Hyg 2015;92(3):605–610.
Pöyhönen H, Nurmi M, Peltola V, Alaluusua S, Ruuskanen O, Lähdesmäki T. Dental staining after doxycycline use in
America. Clin Infect Dis 2014;59(2):e10–e52.
Wong KC, Brown AM, Luscombe GM, Wong SJ, Mendis K Antibiotic use for Vibrio infections: important insights from
surveillance data. BMC Infect Dis 2015;15:226.
Zhu H, Li X, Zheng X. A descriptive study of open fractures contaminated by seawater: infection, pathogens, and
antibiotic resistance. Biomed Res Int 2017;2017:2796054.
Antibiotic choice for urinary tract infection in
adults
Aetiology of UTI in adults
Uncomplicated urinary tract infections (UTIs) mainly occur in nonpregnant women who do not have a
functional or anatomical abnormality of the urinary tract. Acute uncomplicated cystitis and pyelonephritis are
most commonly caused by Escherichia coli (70 to 95% of cases) and Staphylococcus saprophyticus (5 to 10%
of cases).
Complicated UTIs occur in patients with anatomical or functional abnormalities (eg neurogenic bladder,
nephrolithiasis). E. coli is the most common pathogen (20 to 50% of cases), but a wider range of bacteria (eg
Klebsiella, Proteus, Pseudomonas species) also cause infection. Symptomatic candidal UTIs are uncommon
(see Candiduria and candidal urinary tract infection in adults).
Rationale for empirical therapy for UTI in adults

Approach to empirical therapy choice for UTI
Recommendations for empirical antibiotic therapy for urinary tract infection (UTI) are based on factors
including efficacy, convenience, cost, availability, and harms associated with antibiotic use (eg adverse effects
in the patient, development of antibiotic resistance; see also Types of adverse effects of antimicrobials).
If available, the susceptibility of organisms recently identified in samples from the patient guides empirical
antibiotic choice.
Empirical therapy choice is also guided by the resistance rates of common pathogens (in particular
Escherichia coli) and a consideration of the risk of adverse outcomes from clinical failure. As the prevalence
of a pathogen’s resistance to an antibiotic increases, the likelihood of treatment failure increases, which
outweighs the benefits of using the narrower-spectrum drug empirically for serious infections. Pyelonephritis
has a higher likelihood of serious complications, so a lower resistance threshold is required than for cystitis.
Empirical oral antibiotic therapy for UTI

At the time of writing, approximately 20% of E. coli urine isolates from adults in the community are resistant
to trimethoprim. Trimethoprim continues to be recommended as empirical therapy for acute cystitis because
the risk of adverse outcomes from treatment failure is low. Trimethoprim is no longer recommended as
empirical therapy for nonsevere pyelonephritis because it is a more serious infection with a higher risk of
adverse outcomes from treatment failure.
Amoxicillin+clavulanate has an unnecessarily broad spectrum of activity for empirical therapy of cystitis. The
use of broad-spectrum antibiotics selects for antibiotic-resistant organisms and increases the risk of
Clostridium difficile infection.
Do not use oral fosfomycin, nitrofurantoin or norfloxacin to treat pyelonephritis; these drugs do not achieve
adequate concentrations in kidney tissue.
Empirical intravenous antibiotic therapy for UTI

Gentamicin in combination with amoxicillin (or ampicillin) is first-line empirical intravenous therapy for UTI.
This combination is preferred to broad-spectrum cephalosporins because:
gentamicin is active against a greater percentage of Enterobacteriaceae, and is more rapidly bactericidal
ceftriaxone and cefotaxime do not have any activity against Pseudomonas aeruginosa or enterococci
gentamicin with amoxicillin (or ampicillin) is less likely to contribute to the development of C. difficile
infection and the selection of antibiotic-resistant bacteria.
UTI caused by multidrug-resistant Gram-negative bacteria
There is worldwide emergence of multidrug-resistant Escherichia coli, particularly extended-spectrum beta-
lactamase (ESBL)-producing strains, causing urinary tract infections (UTIs) and associated bacteraemias.
For risk factors for UTI caused by a multidrug-resistant Gram-negative bacterium, see Box 2.30. Additional
risk factors include recent antibiotic exposure or lack of response to initial antibiotic therapy.
Oral treatment options for ESBL-producing E. coli isolates are limited; co-resistance among oral antibiotics,
including trimethoprim and quinolones, is common. Nitrofurantoin, fosfomycin and pivmecillinam [Note 1]
retain activity against the majority of ESBL-producing isolates. Amoxicillin+clavulanate is an option for UTIs
caused by susceptible ESBL-producing E. coli.
Intravenous treatment options for ESBL-producing E. coli isolates are limited; ESBL-producing E. coli are
resistant to extended-spectrum cephalosporins and are often resistant to other antibiotics, including
aminoglycosides and quinolones.
Note 1: Pivmecillinam is not registered for use in Australia but is available via the Special Access Scheme.
Key references
Australian Group on Antimicrobial Resistance (AGAR). Gram-negative Sepsis Outcome Programme 2017 report.
[Perth, W.A.?]: AGAR; 2018. http://agargroup.org.au/agar-surveys .
Bonkat G, Pickard R, Cai T, Bruyère F, Geerlings SE, et al. EAU Guidelines on urological infections. Arnhem,NL:
European Association of Urology; 2018. http://uroweb.org/guideline/urological-infections/ .
Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al. International clinical practice guidelines for
the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious
Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis
2011;52(5):e103–e120 .
Harris PN, Tambyah PA, Paterson DL. β-lactam and β-lactamase inhibitor combinations in the treatment of
extended-spectrum β-lactamase producing Enterobacteriaceae: time for a reappraisal in the era of few antibiotic
options. Lancet Infect Dis 2015;15(4):475–485 .
Hooton TM. Clinical practice. Uncomplicated urinary tract infection. N Engl J Med 2012;366(11):1028–1037
.
Osthoff M, McGuinness SL, Wagen AZ, Eisen DP. Urinary tract infections due to extended-spectrum beta-
lactamase-producing Gram-negative bacteria: identification of risk factors and outcome predictors in an Australian
tertiary referral hospital. Int J Infect Dis 2015;34:79–83 .
Petty NK, Ben Zakour NL, Stanton-Cook M, Skippington E, Totsika M, Forde BM, et al. Global dissemination of a
multidrug resistant Escherichia coli clone. Proc Natl Acad Sci U S A 2014;111(15):5694–5699 .
Rogers BA, Ingram PR, Runnegar N, Pitman MC, Freeman JT, Athan E. Community-onset Escherichia coli
infection resistant to expanded-spectrum cephalosporins in low-prevalence countries. Antimicrob Agents
Chemother 2014;58(4):2126–2134 .
Turnidge JD, Gottlieb T, Mitchell DH, Coombs GW, Daly DA, Bell JM, et al. Community-onset Gram-negative
Surveillance Program annual report, 2012. Commun Dis Intell Q Rep 2014;38(1):E54–E58 .
Acute cystitis in adults
Diagnosis and management of acute cystitis in special patient groups
Further information about the diagnosis and management of acute cystitis is available for the following groups:
aged-care facility residents, see Urinary tract infection in aged-care facility residents
patients with urinary catheters, see Catheter-associated bacteriuria and urinary tract infection in adults
patients with urinary stents, see Bacteriuria and urinary tract infection in adults with urinary stents.
For the treatment of acute cystitis in pregnancy, see Acute cystitis in pregnancy.
Diagnosis of acute cystitis in adults

Clinical features of acute cystitis in adults
Clinical features of cystitis include acute dysuria, frequency, urgency and, occasionally, suprapubic tenderness.
Consider acute pyelonephritis in patients with flank pain, vomiting, fever (38°C or higher) or costovertebral
tenderness.
Consider the possibility of a sexually transmitted infection (eg urethritis, cervicitis), which may present with
similar features to acute cystitis.
Consider vulvovaginitis in women with vaginal discharge. If vaginal discharge is absent and at least two symptoms
of cystitis are present (ie acute dysuria, urgency, or frequency), the probability of cystitis is greater than 90%.
Cystitis in men is uncommon; its prevalence increases with age and is often related to abnormalities of the urinary
tract. Consider prostatitis, particularly in men with fever (38°C or higher), obstructive urinary symptoms or
prostate tenderness on gentle digital rectal examination.
Investigations for acute cystitis in adults
Before starting antibiotics to treat cystitis, obtain a urine sample for culture and susceptibility testing from:
pregnant women (see Acute cystitis in pregnancy)

men
aged-care facility residents (see Urinary tract infection in aged-care facility residents)
patients who have recently taken antibiotics
patients with recurrent infection (see Treatment and prevention of recurrent urinary tract infection in adults)
patients with risk factors for multidrug-resistant bacteria (see UTI caused by multidrug-resistant Gram-
negative bacteria).
Also obtain a urine sample for culture and susceptibility testing from patients who do not respond to empirical
antibiotic therapy.
For nonpregnant women with a first episode of acute uncomplicated cystitis, urine culture and susceptibility testing
may not be necessary; empirical therapy can be started based on symptoms alone.
For patients with symptoms of a UTI, the presence of bacteriuria can help to confirm the diagnosis. The
established definition of significant bacteriuria is 108 or more colony forming units (CFU)/L from a midstream
urine sample. Lower bacterial counts (105 CFU/L or more) may be indicative of UTI in:
women with symptoms of a UTI

patients with a UTI caused by organisms other than Escherichia coli and Proteus species
men
patients already taking antimicrobial therapy.
The growth of mixed bacterial types on urine culture or the presence of large numbers of squamous epithelial cells
on microscopy usually indicates contamination with normal genital tract flora.
If pyuria is absent on microscopy, the diagnosis of acute cystitis is unlikely.
Urological evaluation is required for men with recurrent UTIs or an inadequate response to appropriate antibiotics.
Urological evaluation may not be required in young healthy men with a single episode of uncomplicated cystitis
who have a prompt response to antibiotics.
Do not perform post-treatment urine culture to confirm resolution of infection for asymptomatic people, except for
pregnant women and men with prostatitis.
Treatment of acute cystitis in adults

Nonantibiotic therapy for acute cystitis in adults
Offer analgesia to patients with symptoms of acute cystitis; see the paracetamol and nonsteroidal anti-
inflammatory drug regimens here.
The safety and efficacy of urinary alkalinising agents for the symptomatic treatment of urinary tract infection
(UTI) has not been established. Urinary alkalinising agents significantly reduce the antimicrobial effect of
nitrofurantoin, and should not be used with quinolones because there is an increased risk of crystalluria.
Cranberry products, ascorbic acid and methenamine hippurate are not effective for the treatment of acute UTI.
Empirical antibiotic therapy for nonpregnant women with acute cystitis

Most women under the age of 65 who are treated symptomatically (without antibiotic therapy) for acute
uncomplicated cystitis become symptom free within 1 week. If antibiotic therapy is not given, the risk of acute
pyelonephritis or sepsis following uncomplicated cystitis is low, but may be reduced by antibiotic therapy.
For empirical therapy of acute uncomplicated cystitis in nonpregnant women, use:
1 trimethoprim 300 mg orally, daily for 3 days [Note 1]
OR
2 nitrofurantoin 100 mg orally, 6-hourly for 5 days [Note 2].
See Antibiotic choice for urinary tract infection in adults for a discussion of drug choice.
If trimethoprim and nitrofurantoin cannot be used, for empirical therapy of acute uncomplicated cystitis in
nonpregnant women, use:
cefalexin 500 mg orally, 12-hourly for 5 days.
If urine culture and susceptibility testing were performed and the pathogen is resistant to empirical therapy, do not
modify therapy if symptoms of cystitis are improving.
Enterococcus species and Streptococcus agalactiae (group B streptococcus) rarely cause acute uncomplicated
cystitis in premenopausal women; specific treatment directed against these organisms may not be required.
If the pathogen is resistant to empirical therapy and symptoms of cystitis are not improving, use the narrowest
spectrum antibiotic to which the pathogen is susceptible. If the pathogen is susceptible, suitable alternatives are:
OR
2 trimethoprim+sulfamethoxazole 160+800 mg orally, 12-hourly for 3 days
OR
3 amoxicillin+clavulanate 500+125 mg orally, 12-hourly for 5 days.
If resistance to all of the above drugs is confirmed, provided the pathogen is susceptible, suitable alternatives are:
1 fosfomycin 3 g orally, as a single dose

OR
1 norfloxacin 400 mg orally, 12-hourly for 3 days
OR
Do not use quinolones for first-line treatment because their use is associated with the development of resistance,
and they are the only oral drugs available for infections caused by Pseudomonas aeruginosa and some multidrug-
resistant bacteria.
Fosfomycin is active against many multidrug-resistant Gram-negative bacteria and should be reserved for resistant
infections to reduce the risk of resistance developing.
Do not perform post-treatment urine culture to confirm resolution of infection for asymptomatic nonpregnant
women.
Note 1: If the patient has been treated with trimethoprim in the previous 3 months, or had a trimethoprim-resistant Escherichia coli isolate during this
time, use an alternative antibiotic for empirical therapy.
Note 2: An alternative regimen is 100 mg 12-hourly for 5 days. This is from a study using Macrobid®, a formulation unavailable in Australia. The
Macrobid® product information states that urine concentrations from this product are similar to those obtained with formulations available in
Australia; however, no data are available to confirm this claim.
Empirical antibiotic therapy for men with acute cystitis
Cystitis in men is uncommon and evidence to guide antibiotic recommendations is lacking. Antibiotic
recommendations for men with acute cystitis are extrapolated from the recommendations for nonpregnant women.
The prevalence of cystitis in men increases with age and is often related to abnormalities of the urinary tract.
Consider prostatitis, particularly in men with fever (38°C or higher), obstructive urinary symptoms or prostate
tenderness on gentle digital rectal examination.
For empirical therapy of acute cystitis in men in whom prostatitis is unlikely, while awaiting the results of urine
culture, use:
1 trimethoprim 300 mg orally, daily for 7 days [Note 3]
OR
2 nitrofurantoin 100 mg orally, 6-hourly for 7 days [Note 4] [Note 5].
If trimethoprim and nitrofurantoin cannot be used, for empirical therapy of acute cystitis in men in whom
prostatitis is unlikely, use:
cefalexin 500 mg orally, 12-hourly for 7 days.
If culture and susceptibility testing indicate the pathogen is resistant to empirical therapy, do not modify therapy if
symptoms of cystitis are improving.
If the pathogen is resistant to empirical therapy, symptoms of cystitis are not improving and prostatitis is
unlikely, use the narrowest spectrum antibiotic to which the pathogen is susceptible. If the pathogen is susceptible,
suitable alternatives are:
OR
2 trimethoprim+sulfamethoxazole 160+800 mg orally, 12-hourly for 7 days
OR
If resistance to all of the above drugs is confirmed, provided the pathogen is susceptible and prostatitis is unlikely,
suitable alternatives are:
1 norfloxacin 400 mg orally, 12-hourly for 7 days
OR
Fosfomycin is an option for the treatment of acute cystitis in men caused by some multidrug-resistant bacteria—
seek expert advice; evidence is limited and the dosage regimen is not well established.
Do not perform post-treatment urine culture to confirm resolution of infection for asymptomatic men with acute
cystitis.
Note 3: If the patient has been treated with trimethoprim in the previous 3 months, or had a trimethoprim-resistant E. coli isolate during this time, use
an alternative antibiotic for empirical therapy.
Note 4: Do not use nitrofurantoin unless the patient is afebrile and prostatitis is considered unlikely, because therapeutic concentrations of
nitrofurantoin are not reached in the prostate.
Note 5: An alternative regimen is 100 mg 12-hourly for 5 days. This is from a study using Macrobid®, a formulation unavailable in Australia. The
Macrobid® product information states that urine concentrations from this product are similar to those obtained with formulations available in
Australia; however, no data are available to confirm this claim.
Key references
Diagnosis of acute cystitis in adults
Bonkat G, Pickard R, Bartoletti R, Cai T, Bruyère F, Geerlings SE, et al. EAU Guidelines on urological infections.
Arnhem,NL: European Association of Urology. 2018. https://uroweb.org/guideline/urological-infections/
Burd EM, Kehl KS. A critical appraisal of the role of the clinical microbiology laboratory in the diagnosis of urinary tract
infections. J Clin Microbiol 2011;49(9-Suppl):S34–S38 https://jcm.asm.org/content/49/9_Supplement/S34 .
Grigoryan L, Trautner BW, Gupta K. Diagnosis and management of urinary tract infections in the outpatient setting: a
review. JAMA 2014;312(16):1677–1684 .
Hooton TM, Roberts PL, Cox ME, Stapleton AE. Voided midstream urine culture and acute cystitis in premenopausal
women. N Engl J Med 2013;369(20):1883–1891
National Institute for Health and Care Excellence (NICE). Urinary tract infections in adults: Quality standard [QS90].
London: NICE; 2015. https://www.nice.org.uk/guidance/qs90 .
Schaeffer AJ, Nicolle LE. Urinary Tract Infections in Older Men. N Engl J Med 2016;374(22):2192. .
Tomas ME, Getman D, Donskey CJ, Hecker MT. Overdiagnosis of Urinary Tract Infection and Underdiagnosis of
Sexually Transmitted Infection in Adult Women Presenting to an Emergency Department. J Clin Microbiol
2015;53(8):2686–2692 .
Treatment of acute cystitis in adults
Avent ML, Rogers BA, Cheng AC, Athan E, Francis JR, Roberts MJ, et al. Fosfomycin: what was old is new again.
Intern Med J 2018;48(12):1425–1429 .
Bjerrum L, Lindbæk M. Which treatment strategy for women with symptoms of urinary tract infection?. BMJ
2015;351:h6888. .
Cunha BA, Cunha CB, Lam B, Giuga J, Chin J, Zafonte VF, et al. Nitrofurantoin safety and effectiveness in treating
acute uncomplicated cystitis (AUC) in hospitalized adults with renal insufficiency: antibiotic stewardship implications.
Eur J Clin Microbiol Infect Dis 2017;36(7):1213–1216 .
Drekonja DM, Rector TS, Cutting A, Johnson JR. Urinary tract infection in male veterans: treatment patterns and
outcomes. JAMA Intern Med 2013;173(1):62–68 .
Gágyor I, Bleidorn J, Kochen MM, Schmiemann G, Wegscheider K, Hummers-Pradier E. Ibuprofen versus fosfomycin
for uncomplicated urinary tract infection in women: randomised controlled trial. BMJ 2015;351:h6544. .
Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al. International clinical practice guidelines for the
treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases
Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis
2011;52(5):e103–e120 .
Hooton TM, Roberts PL, Cox ME, Stapleton AE. Voided midstream urine culture and acute cystitis in premenopausal
women. N Engl J Med 2013;369(20):1883–1891 .
Huttner A, Kowalczyk A, Turjeman A, Babich T, Brossier C, Eliakim-Raz N, et al. Effect of 5-Day Nitrofurantoin vs
Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A
Randomized Clinical Trial. JAMA 2018;319(17):1781–1789 .
Huttner A, Verhaegh EM, Harbarth S, Muller AE, Theuretzbacher U, Mouton JW. Nitrofurantoin revisited: a systematic
review and meta-analysis of controlled trials. J Antimicrob Chemother 2015;70(9):2456–2464 .
Keating GM. Fosfomycin trometamol: a review of its use as a single-dose oral treatment for patients with acute lower
urinary tract infections and pregnant women with asymptomatic bacteriuria. Drugs 2013;73(17):1951–1966 .
Knottnerus BJ, Geerlings SE, Moll van Charante EP, ter Riet G. Women with symptoms of uncomplicated urinary tract
infection are often willing to delay antibiotic treatment: a prospective cohort study. BMC Fam Pract 2013;14:71.
.
Kronenberg A, Bütikofer L, Odutayo A, Mühlemann K, da Costa BR, Battaglia M, et al. Symptomatic treatment of
uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial. BMJ
2017;359:j4784. .
National Institute for Health and Care Excellence (NICE). Urinary tract infection (lower): antimicrobial prescribing
[NG109]. London: NICE; October 2018. https://www.nice.org.uk/guidance/ng109.
O'Kane DB, Dave SK, Gore N, Patel F, Hoffmann TC, Trill JL, et al. Urinary alkalisation for symptomatic uncomplicated
urinary tract infection in women. Cochrane Database Syst Rev 2016;4:CD010745. .
Schaeffer AJ, Nicolle LE. Urinary Tract Infections in Older Men. N Engl J Med 2016;374(22):2192. .
Turnidge JD, Gottlieb T, Mitchell DH, Coombs GW, Daly DA, Bell JM. Community-onset Gram-negative Surveillance
Program annual report, 2012. Commun Dis Intell Q Rep 2014;38(1):E54–E58 .
Zalmanovici Trestioreanu A, Green H, Paul M, Yaphe J, Leibovici L. Antimicrobial agents for treating uncomplicated
urinary tract infection in women. Cochrane Database Syst Rev 2010;(10):CD007182. .
Acute pyelonephritis in adults
This topic covers the diagnosis and management of acute pyelonephritis in adults. Specific information about the
diagnosis and management of acute pyelonephritis in the following groups is covered separately:
aged-care facility residents, see Urinary tract infection in aged-care facility residents
patients with catheters, see Catheter-associated bacteriuria and urinary tract infection in adults
patients with urinary stents, see Bacteriuria and urinary tract infection in adults with urinary stents.
Diagnosis of acute pyelonephritis in adults

Clinical features of acute pyelonephritis in adults
Clinical features suggestive of acute pyelonephritis include:
flank pain
nausea and vomiting
costovertebral angle tenderness.
Acute pyelonephritis may present with or without symptoms of acute cystitis (eg acute dysuria, frequency,
urgency).
Consider prostatitis in men, particularly those with fever (38°C or higher), obstructive urinary symptoms or
prostate tenderness on gentle digital rectal examination.
Investigations for acute pyelonephritis in adults

Obtain a urine sample for culture and susceptibility testing from patients with acute pyelonephritis before starting
antibiotics. Collect blood samples for culture and susceptibility testing in hospitalised patients.
The diagnosis of acute pyelonephritis is unlikely if pyuria is absent on microscopy.
Consider imaging (eg ultrasound) to exclude urinary obstruction, kidney stone disease or kidney abscess,
particularly if the patient remains febrile after 72 hours of treatment.
Urological evaluation is required for men with acute pyelonephritis.
Post-treatment urine culture is not required for asymptomatic patients, except for pregnant women and men with
prostatitis.
Treatment of acute pyelonephritis in adults

Choice of empirical therapy for acute pyelonephritis in adults
In addition to the factors informing empirical therapy for urinary tract infections (UTIs) described in Antibiotic
choice for urinary tract infection in adults, empirical therapy for acute pyelonephritis in adults depends on disease
severity and, for women, pregnancy status—see Acute pyelonephritis in pregnancy for the treatment of
pyelonephritis in pregnant women.
Initial intravenous therapy (see Treatment of severe pyelonephritis in adults) is usually required for patients with
any of the following features:
inability to tolerate oral therapy

systemic symptoms (eg tachycardia, nausea, vomiting)
sepsis or septic shock (see Sepsis and septic shock from a urinary tract source in adults).
Oral therapy is appropriate for patients who do not have any of the above features; see Treatment of nonsevere
pyelonephritis in adults.
Treatment of nonsevere pyelonephritis in adults
For the treatment of pyelonephritis in pregnant women, see Acute pyelonephritis in pregnancy.
Pyelonephritis is considered nonsevere if the patient does not have fever (38°C or higher), systemic features (eg
tachycardia, nausea, vomiting), or sepsis or septic shock. Nonsevere pyelonephritis may be treated with oral
antibiotics without hospitalisation.
For empirical therapy of nonsevere pyelonephritis in adults while awaiting the results of investigations, use:
amoxicillin+clavulanate 875+125 mg orally, 12-hourly for 14 days. If clinical response is

rapid, stop therapy after 10 days.
For adults with penicillin hypersensitivity, use:
Modify empirical therapy based on the results of culture and susceptibility testing. If the pathogen is susceptible to
any of the following narrower-spectrum antibiotics, stop the empirical regimen and switch to:
1 amoxicillin 500 mg orally, 8-hourly for 14 days. If clinical response is rapid, stop therapy
after 10 days
OR
1 trimethoprim 300 mg orally, daily for 14 days. If clinical response is rapid, stop therapy
after 10 days
OR
2 cefalexin 500 mg orally, 6-hourly for 14 days. If clinical response is rapid, stop therapy
after 10 days
OR
3 trimethoprim+sulfamethoxazole 160+800 mg orally, 12-hourly for 14 days. If clinical

response is rapid, stop therapy after 10 days.
If resistance to all of the above drugs is confirmed or the pathogen is Pseudomonas aeruginosa, use:
Assess the response to therapy within 24 to 48 hours; if the patient has not improved and results of culture and
susceptibility testing are unavailable, reconsider the diagnosis, consider if the patient is at risk of a UTI caused by
multidrug-resistant Gram-negative bacteria and consider switching to intravenous therapy—see Treatment of
severe pyelonephritis in adults below.
Do not perform post-treatment urine culture to confirm resolution of infection for asymptomatic patients, except
for men with prostatitis.
Treatment of severe pyelonephritis in adults

For the treatment of pyelonephritis in pregnant women, see Acute pyelonephritis in pregnancy.
Pyelonephritis is considered severe if the patient has fever (38°C or higher), systemic symptoms (eg tachycardia,
nausea, vomiting), or sepsis or septic shock (see Early recognition of sepsis or septic shock in adults for
definitions).
For the treatment of adults with sepsis or septic shock, see Sepsis and septic shock from a urinary tract source in
adults.
For empirical therapy of severe pyelonephritis in adults, while awaiting the results of investigations, use:
gentamicin intravenously, see Principles of aminoglycoside use for dosage and principles
of use
PLUS EITHER
OR
If gentamicin is contraindicated (see Box 2.42), as monotherapy, use:
OR
For adults with penicillin hypersensitivity, use gentamicin as a single drug (as above) for empirical therapy.
Modify empirical therapy based on the results of culture and susceptibility testing. If susceptibility results are not
and use ceftriaxone or cefotaxime as above.
Switch to oral therapy (see regimens in Treatment of nonsevere pyelonephritis in adults) once the patient is
clinically stable—see Guidance for antimicrobial intravenous to oral switch.
The total duration of therapy (intravenous + oral) is 10 to 14 days, depending on clinical response. Limited data
suggest that a shorter course (ie 7 days) of a quinolone (ie ciprofloxacin) is adequate for the treatment of
pyelonephritis.
Community-based parenteral antimicrobial therapy should only be used when appropriate oral antibiotics are not
available (eg for multidrug-resistant infections)—seek expert advice.
Do not perform post-treatment urine culture to confirm resolution of infection for asymptomatic patients, except
for men with prostatitis.
Key references
Australian Group on Antimicrobial Resistance (AGAR). Gram-negative Sepsis Outcome Programme 2017 report.
Perth, WA: AGAR; 2018. https://agargroup.org.au/agar-surveys .
Bonkat G, Pickard R, Bartoletti R, Cai T, Bruyère F, Geerlings F, et al. EAU Guidelines on urological infections.
Arnhem, NL: European Association of Urology; 2018. https://uroweb.org/guideline/urological-infections/ .
Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al. International clinical practice guidelines for the
treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases
Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis
2011;52(5):e103–e120 .
Johnson JR, Russo TA. Acute Pyelonephritis in Adults. N Engl J Med 2018;378(1):48–59 .
National Institute for Health and Care Excellence (NICE). Pyelonephritis (acute): antimicrobial prescribing [NG111] .
London: NICE; October 2018. https://www.nice.org.uk/guidance/ng111 .
National Institute for Health and Care Excellence (NICE). Urinary tract infections in adults: Quality standard [QS90].
London: NICE; October 2018. https://www.nice.org.uk/guidance/qs90 .
Park SH, Choi SM, Chang YK, Lee DG, Cho SY, Lee HJ, et al. The efficacy of non-carbapenem antibiotics for the
treatment of community-onset acute pyelonephritis due to extended-spectrum β-lactamase-producing Escherichia coli.
J Antimicrob Chemother 2014;69(10):2848–2856 .
Scottish Intercollegiate Guidelines Network (SIGN). Management of suspected bacterial urinary tract infection in adults:
a national clinical guideline (SIGN 88). Edinburgh: SIGN; 2012. https://www.sign.ac.uk/sign-88-management-of-
suspected-bacterial-urinary-tract-infection-in-adults.html.
Turnidge JD, Gottlieb T, Mitchell DH, Coombs GW, Daly DA, Bell JM. Community-onset Gram-negative Surveillance
Program annual report, 2012. Commun Dis Intell Q Rep 2014;38(1):E54–E58 .
Sepsis and septic shock from a urinary tract source in
adults
Empirical therapy for sepsis and septic shock from a urinary tract
source in adults
For adults with sepsis or septic shock from a urinary tract source (see Early recognition of sepsis or septic shock in
adults for definitions), start antibiotic therapy within 1 hour of presentation to medical care or, for ward-based
patients, development of sepsis or septic shock, immediately after urine and blood samples are taken for culture.
appropriateness of antibiotic therapy daily, with consideration given to the patient’s clinical status and the
For empirical therapy of adults with sepsis or septic shock from a urinary tract source, use:

PLUS EITHER
OR
care support, use ceftriaxone 1 g intravenously, 12-hourly
OR

intensive care support, use cefotaxime 2 g intravenously, 8-hourly.
For adults with penicillin hypersensitivity, use gentamicin as a single drug (as above) and then seek expert
advice.
Urinary tract sepsis caused by multidrug-resistant Gram-negative bacteria (eg extended-spectrum beta-lactamase
(ESBL)-producing bacteria) is an emerging problem. If infection with these bacteria is strongly suspected (see UTI
caused by multidrug-resistant Gram-negative bacteria), replace the empirical therapy regimen with:
meropenem 1 g intravenously, 8-hourly [Note 4].

Outcomes are inferior when piperacillin+tazobactam, rather than meropenem, is used to treat infection caused by
ESBL-producing bacteria.
Carbapenem resistance in Gram-negative bacteria is currently uncommon in Australia, but is emerging globally. If
infection with a carbapenem-resistant organism is suspected or confirmed, seek expert advice.
For patients presenting with sepsis or septic shock from an apparent urinary tract source, perform imaging to
exclude urinary obstruction or kidney stone disease.
calculate the dose.
function.
treatment options.
Key references
Australian Group on Antimicrobial Resistance (AGAR). Gram-negative Sepsis Outcome Programme 2017
report [Perth, W.A.?]. AGAR; 2018. http://agargroup.org.au/agar-surveys.
Arnhem,NL: European Association of Urology; 2018. http://uroweb.org/guideline/urological-infections/.
Turnidge JD, Gottlieb T, Mitchell DH, Coombs GW, Daly DA, Bell JM, et al. Community-onset Gram-negative
Surveillance Program annual report, 2012. Commun Dis Intell Q Rep 2014;38(1):E54–E58 .
Treatment and prevention of recurrent urinary tract
infection in adults
Diagnosis and management of recurrent UTI in adults
Obtain urine samples for culture and susceptibility testing from patients with recurrent symptomatic urinary tract
infection (UTI). Recurrent asymptomatic bacteriuria is not a UTI and does not require antibiotic therapy except in
specific circumstances—see Asymptomatic bacteriuria in adults.
Urological evaluation is required for men with recurrent UTI; chronic bacterial prostatitis is a common cause of
recurrent UTI.
For women with recurrent UTI, investigations including cystoscopy and diagnostic imaging have limited value
(see the Canadian Urological Association [CUA] Guidelines for the Diagnosis and Management of Recurrent
Urinary Tract Infection in Women [URL] for further information about investigations).
For recurrent UTI during pregnancy, see Recurrent UTI and bacteriuria in pregnancy.
Treatment of recurrent UTI in nonpregnant adults

Treat an acute episode of recurrent urinary tract infection (UTI) as for cystitis or pyelonephritis, as appropriate (see
Acute cystitis in adults or Acute pyelonephritis in adults).
Patient-initiated treatment—antibiotics taken at the onset of symptoms (see Empirical antibiotic therapy for
nonpregnant women with acute cystitis for regimens) may be appropriate for women who have frequent
symptomatic UTIs (ie two or more infections within 6 months, or three or more infections within 12 months).
Patient-initiated treatment reduces overall antibiotic use compared to antibiotic prophylaxis. Advise women to
seek medical review if symptoms do not resolve within 48 hours of completing treatment.
Prevention of recurrent UTI in nonpregnant women

Nonantibiotic strategies to prevent recurrent UTI
Increasing water intake (by up to 1.5 L daily) may reduce the risk of recurrent urinary tract infection (UTI) in
premenopausal women with inadequate fluid intake (less than 1.5 L daily).
Intravaginal oestrogen in postmenopausal women has been shown to have beneficial effects on vaginal flora and
reduced the incidence of recurrent UTI in small randomised controlled trials. See Intravaginal oestrogen
therapy for suitable regimens.
Cranberry products are not recommended for the prevention of UTI. Cranberry capsules did not reduce the
incidence of UTI in a randomised clinical trial in elderly women in aged-care facilities [Note 1].
Ascorbic acid does not appear to be effective in preventing UTI.
The evidence for methenamine hippurate for the prevention of UTI is poor and inconsistent. Methenamine
hippurate may reduce the incidence of symptomatic UTI in women without urinary tract abnormalities; however,
further research is needed before it can be recommended. Methenamine hippurate is not effective for the
prevention of UTI in patients with urinary tract abnormalities.
Other approaches are being investigated, including use of D-mannose, probiotics, vaccines, immunostimulants and
colonisation with a ‘nonvirulent’ E. coli, but further evaluation is required.
Note 1: Juthani-Mehta M, Van Ness PH, Bianco L, Rink A, Rubeck S, Ginter S, et al. Effect of cranberry capsules on bacteriuria plus pyuria among
older women in nursing homes: a randomized clinical trial. JAMA 2016;316(18):1879-87. [URL]
Antibiotic prophylaxis for recurrent UTI

For nonpregnant women with recurrent UTIs, antibiotic prophylaxis can decrease the incidence of UTI. However,
adverse effects (eg candidiasis) and the emergence of organisms resistant to the antibiotic used for prophylaxis is
common—see also Types of adverse effects of antimicrobials for further discussion about adverse effects
associated with antimicrobial use.
Consider antibiotic prophylaxis for women who have frequent symptomatic infections (ie two or more infections
within 6 months, or three or more infections within 12 months). Do not give antibiotic prophylaxis to patients with
asymptomatic bacteriuria. An alternative approach to antibiotic prophylaxis is patient-initiated treatment; see
Treatment of recurrent UTI in nonpregnant adults.
Antibiotic prophylaxis strategies for recurrent UTIs include continuous prophylaxis (see regimens below); and
intermittent postcoital prophylaxis (a single dose of one of the antibiotics listed below for continuous
prophylaxis taken within the 2-hour period after sexual intercourse).
For continuous prophylaxis of recurrent UTI in nonpregnant women, use:
1 trimethoprim 150 mg orally, at night
OR
2 cefalexin 250 mg orally, at night
OR
3 nitrofurantoin 50 mg orally, at night.
Typically, continuous prophylaxis is used for 6 months and then stopped. If UTIs recur despite prophylaxis, seek
expert advice.
Long-term use of nitrofurantoin has been associated with an increased risk of rare adverse effects, including
pulmonary toxicity, hepatotoxicity and peripheral polyneuropathy. Monitor for these adverse effects with regular
spirometry, liver function and kidney function tests. Polyneuropathy is more likely to occur in patients with
impaired kidney function.
Key references
Ahmed H, Davies F, Francis N, Farewell D, Butler C, Paranjothy S. Long-term antibiotics for prevention of recurrent
urinary tract infection in older adults: systematic review and meta-analysis of randomised trials. BMJ Open
2017;7(5):e015233. .
Albert X, Huertas I, Pereiró II, Sanfélix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract
infection in non-pregnant women. Cochrane Database Syst Rev 2004;(3):CD001209. .
Alexiou Z, Mouktaroudi M, Koratzanis G, Papadopoulos A, Kavatha D, Kanellakopoulou K, et al. The significance of

compliance for the success of antimicrobial prophylaxis in recurrent lower urinary tract infections: the Greek
experience. Int J Antimicrob Agents 2007;30(1):40–43 .
Barber AE, Norton JP, Spivak AM, Mulvey MA. Urinary tract infections: current and emerging management strategies.
Clin Infect Dis 2013;57(5):719–724 .
Dason S, Dason JT, Kapoor A. Guidelines for the diagnosis and management of recurrent urinary tract infection in
women. Can Urol Assoc J 2011;5(5):316–322 .
Gupta K, Trautner BW. Diagnosis and management of recurrent urinary tract infections in non-pregnant women. BMJ
2013;346:f3140. .
Hooton TM, Vecchio M, Iroz A, Tack I, Dornic Q, Seksek I, et al. Effect of Increased Daily Water Intake in
Premenopausal Women With Recurrent Urinary Tract Infections: A Randomized Clinical Trial. JAMA Intern Med
2018;178(11):1509–1515 .
Huttner A, Hatz C, van den Dobbelsteen G, Abbanat D, Hornacek A, Frölich R, et al. Safety, immunogenicity, and
preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of
recurrent urinary tract infection: a randomised, single-blind, placebo-controlled phase 1b trial. Lancet Infect Dis
2017;17(5):528–537 .
Juthani-Mehta M, Van Ness PH, Bianco L, Rink A, Rubeck S, Ginter S, et al. Effect of Cranberry Capsules on
Bacteriuria Plus Pyuria Among Older Women in Nursing Homes: A Randomized Clinical Trial. JAMA
2016;316(18):1879–1887 .
Leckie KJ. What is the evidence for the role of oestrogen in the prevention of recurrent urinary tract infections in
postmenopausal women? An evidence-based review. Journal of Clinical Gerontology and Geriatrics; 2010;1(2):31–
35. https://www.sciencedirect.com/science/article/pii/S2210833510000298.
Lee BS, Bhuta T, Simpson JM, Craig JC. Methenamine hippurate for preventing urinary tract infections. Cochrane
Database Syst Rev 2012;10:CD003265. .
Nicolle LE. Cranberry for Prevention of Urinary Tract Infection?: Time to Move On. JAMA 2016;316(18):1873–1874
.
Schwenger EM, Tejani AM, Loewen PS. Probiotics for preventing urinary tract infections in adults and children.
Urinary tract infection and bacteriuria in pregnancy
Asymptomatic bacteriuria in pregnancy
Untreated bacteriuria in pregnancy is associated with a 20 to 30% increased risk of developing pyelonephritis in
later pregnancy. This is likely due to physiological changes to the urinary tract during pregnancy. Untreated
bacteriuria may be associated with preterm birth and low birth weight. Antibiotic treatment of asymptomatic
bacteriuria reduces the risk of symptomatic urinary tract infection (UTI) during pregnancy.
Screen for asymptomatic bacteriuria during pregnancy by obtaining a urine sample for culture and susceptibility
testing at 12 to 16 weeks gestation (or at the first antenatal visit, if this occurs later). Confirm asymptomatic
bacteriuria with a second urine culture.
Treat pregnant women with confirmed asymptomatic bacteriuria; use susceptibility results to guide therapy—see
Acute cystitis in pregnancy for examples of suitable regimens.
Confirm the infection has resolved by repeating urine culture 1 to 2 weeks after treatment is completed. If
persistent bacteriuria is identified, see Recurrent UTI and bacteriuria in pregnancy.
If Streptococcus agalactiae (group B streptococcus [GBS]) is detected in urine at any stage of pregnancy,
intrapartum prophylaxis for GBS is usually indicated—see Prevention of neonatal Streptococcus agalactiae (group
B streptococcus) disease.
Acute cystitis in pregnancy

Obtain urine samples for culture and susceptibility testing before starting antibiotic therapy for pregnant women
with symptoms of cystitis (see Diagnosis of acute cystitis in adults for information about diagnosis).
When prescribing for pregnant women, consider the safety of the antimicrobial in the individual patient. For
empirical therapy of pregnant women with acute cystitis, while awaiting the results of urine culture, use:
1 nitrofurantoin 100 mg orally, 6-hourly for 5 days [Note 1] [Note 2]
OR
2 cefalexin 500 mg orally, 12-hourly for 5 days.
See Antibiotic choice for urinary tract infection in adults for a discussion of drug choice. Although trimethoprim
was traditionally avoided in pregnancy, evidence shows that it can be safely used in the second and third
trimesters. Use:
trimethoprim 300 mg orally, daily for 3 days [Note 3].
Modify empirical therapy if culture and susceptibility testing indicates the pathogen is resistant. If susceptibility is
confirmed, suitable alternatives are:
OR
Note 1: An alternative regimen is 100 mg 12-hourly for 5 days. This is from a study using Macrobid®, a
formulation unavailable in Australia. The Macrobid® product information states that urine concentrations from
this product are similar to those obtained with formulations available in Australia; however, no data are available
to confirm this claim.
Note 2: Avoid using nitrofurantoin close to delivery (after 37 weeks' gestation, or sooner if early delivery is
planned) because of the possible increased risk of neonatal jaundice and haemolytic anaemia.
Note 3: If the patient has been treated with trimethoprim in the previous 3 months, or had a trimethoprim-
resistant Escherichia coli isolate during this time, use an alternative antibiotic for empirical therapy.
Acute pyelonephritis in pregnancy

Treatment of acute pyelonephritis
Acute pyelonephritis in pregnancy has been associated with adverse maternal and fetal outcomes. For information
about diagnosis and appropriate investigations for suspected pyelonephritis, see Diagnosis of acute pyelonephritis
in adults.
For the treatment of patients with sepsis or septic shock (see Early recognition of sepsis or septic shock in
adults for definitions), see Sepsis and septic shock from a urinary tract source in adults.
When prescribing for pregnant women, consider the safety of the antimicrobial in the individual patient. For the
empirical therapy of pregnant women with pyelonephritis, while awaiting the results of investigations, use:
of use and see Modification and duration of therapy for acute pyelonephritis
PLUS EITHER

acute pyelonephritis
OR
1 ampicillin 2 g intravenously, 6-hourly; see Modification and duration of therapy for acute
pyelonephritis.
Pregnancy is not a contraindication for the use of gentamicin in the treatment of acute pyelonephritis.
Pregnancy is not a contraindication for the use of gentamicin in the treatment of acute pyelonephritis. If
gentamicin is contraindicated for another reason (see Box 2.42), as monotherapy, use:
1 ceftriaxone 1 g intravenously, daily; see Modification and duration of therapy for acute
pyelonephritis
OR
1 cefotaxime 1 g intravenously, 8-hourly; see Modification and duration of therapy for acute
pyelonephritis.
For patients with penicillin hypersensitivity, use gentamicin as a single drug (as above) for empirical therapy.
Modification and duration of therapy for acute pyelonephritis

and use ceftriaxone or cefotaxime as above.
Switch to oral therapy once the patient is clinically stable—see Guidance for antimicrobial intravenous to oral
switch. Oral therapy should be based on the results of culture and susceptibility testing. If susceptibility is
confirmed, suitable regimens include:
1 amoxicillin 500 mg orally, 8-hourly
OR
2 cefalexin 500 mg orally, 6-hourly
OR
3 amoxicillin+clavulanate 875+125 mg orally, 12-hourly.
See Antibiotic choice for urinary tract infection in adults for a discussion of drug choice. Although trimethoprim
has traditionally been avoided in pregnancy, evidence shows that it can be safely used in the second and third
trimesters. If susceptibility is confirmed, use:
trimethoprim 300 mg orally, daily.
The total duration of therapy (intravenous + oral) is 10 to 14 days, depending on clinical response.
Recurrent UTI and bacteriuria in pregnancy

Following the resolution of a urinary tract infection (UTI), recurrent bacteriuria occurs in up to one-third of
pregnant women. Perform repeat urine culture at antenatal visits to monitor for recurrent bacteriuria. Choose
treatment for recurrent bacteriuria based on the results of culture and susceptibility testing (see Acute cystitis in
pregnancy for examples of suitable regimens).
Treat an acute episode of recurrent UTI as for cystitis or pyelonephritis, as appropriate (see Acute cystitis in
pregnancy or Acute pyelonephritis in pregnancy).
Consider giving antibiotic prophylaxis to pregnant women with recurrent bacteriuria or bacteriuria and risk
factors for pyelonephritis (eg immune compromise, diabetes, neurogenic bladder). Use:
1 cefalexin 250 mg orally, at night for the remainder of the pregnancy
OR
2 nitrofurantoin 50 mg orally, at night for the remainder of the pregnancy [Note 4].
When prescribing for pregnant women, consider the safety of the antimicrobial in the individual patient.
Note 4: Avoid using nitrofurantoin close to delivery (after 37 weeks' gestation, or sooner if early delivery is
planned) because of the possible increased risk of neonatal jaundice and haemolytic anaemia.
Key references
Chean R, Garland SM, Leung L. Gentamicin in pregnancy: seeing past the drug categorisation in pregnancy. Intern
Med J 2017;47(1):124–125 .
Farkash E, Weintraub AY, Sergienko R, Wiznitzer A, Zlotnik A, Sheiner E. Acute antepartum pyelonephritis in
pregnancy: a critical analysis of risk factors and outcomes. Eur J Obstet Gynecol Reprod Biol 2012;162(1):24–27
.
Glaser AP, Schaeffer AJ. Urinary Tract Infection and Bacteriuria in Pregnancy. Urol Clin North Am 2015;42(4):547–560
.
Kazemier BM, Koningstein FN, Schneeberger C, Ott A, Bossuyt PM, de Miranda E, et al. Maternal and neonatal
consequences of treated and untreated asymptomatic bacteriuria in pregnancy: a prospective cohort study with an
embedded randomised controlled trial. Lancet Infect Dis 2015;15(11):1324–1333 .
Nicolle LE. Management of asymptomatic bacteriuria in pregnant women. Lancet Infect Dis 2015;15(11):1252–1254
.
Pfau A, Sacks TG. Effective prophylaxis for recurrent urinary tract infections during pregnancy. Clin Infect Dis
1992;14(4):810–814 .
Schneeberger C, Geerlings SE, Middleton P, Crowther CA. Interventions for preventing recurrent urinary tract infection
during pregnancy. Cochrane Database Syst Rev 2015;(7):CD009279. .
Smaill FM, Vazquez JC. Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev 2015;
(8):CD000490. .
Widmer M, Lopez I, Gülmezoglu AM, Mignini L, Roganti A. Duration of treatment for asymptomatic bacteriuria during
pregnancy. Cochrane Database Syst Rev 2015;(11):CD000491. .
Urinary tract infection in aged-care facility residents
Principles of antibiotic use for UTI and bacteriuria in aged-care
facility residents
Urinary tract infection (UTI) is a common indication for the use of antibiotics in aged-care facility residents.
Asymptomatic bacteriuria is common in aged-care facility residents; do not screen for or treat asymptomatic
bacteriuria, except in patients undergoing elective urological procedures—see Asymptomatic bacteriuria in
adults. Furthermore, recurrent asymptomatic bacteriuria is not a UTI and does not require antibiotic therapy.
Do not screen for or treat asymptomatic bacteriuria in aged-care facility residents, except in patients undergoing elective
urological procedures.
Overtreatment with antibiotics is common in aged-care facility residents and contributes to antimicrobial
resistance. Stop antibiotic therapy if there is no benefit.
Assessment of UTI and bacteriuria in aged-care facility residents

The diagnosis of symptomatic urinary tract infection (UTI) in aged-care facility residents can be difficult.
Validated criteria for diagnosing UTI in aged-care facility residents are lacking. Mental status change is often
inappropriately used to start antibiotics in elderly patients. Acute dysuria is the most specific genitourinary
symptom of symptomatic UTI in aged-care facility residents.
Aged-care facility residents have a high prevalence of bacteriuria, so urine culture is not helpful in evaluating
nonspecific symptoms. Cloudy or malodorous urine is not a reliable sign of UTI. Do not investigate (with
urinalysis or urine culture) or treat cloudy or malodorous urine in the absence of other signs or symptoms of
UTI.
Do not investigate or treat cloudy or malodorous urine in aged-care facility residents who do not have other signs or
symptoms of UTI.
Urinalysis demonstrating an absence of both leukocyte esterase and nitrite has a high negative predictive value
for the diagnosis of UTI. If urinalysis is negative, urine culture and antibiotic therapy are not required. A
positive urinalysis result has a low positive predictive value for UTI in this population, and is not an indication
for antibiotics.
Figure 2.13 is a general guide for the initial assessment and management of suspected UTI in aged-care facility
residents. If UTI is likely, obtain a urine sample for culture and susceptibility testing. There is a higher risk of
infection caused by multidrug-resistant bacteria in this group. A clean-catch or midstream urine sample may be
difficult to obtain. As an alternative, consider sampling urine with an in–out catheter for women or a new
condom catheter for men.
Assessment and treatment of aged-care facility residents with suspected urinary tract
infection (Figure 2.13)
Printable figure
NB1: Do not investigate or treat cloudy or malodorous urine in aged-care facility residents who do not have other signs or symptoms of UTI.
NB2: Consider whether an alternative diagnosis is likely. Consider both infective (eg pneumonia) and noninfective (eg medication-related adverse
events) causes.
NB3: Establish whether an advance care plan is in place as it may influence assessment and management (eg whether investigations are performed
or antibiotics given).
NB4: Fever is defined as a temperature higher than 38°C or an increase of more than 1.5°C above baseline temperature.
NB5: Acute mental status changes include new change in level of consciousness, periods of altered perception, disorganised speech and lethargy.
NB6: If the resident has an indwelling urinary catheter, see Box 2.33 for a guide to collecting urine samples in patients with indwelling urinary
catheters.
NB7: The duration of therapy does not need to be modified for this patient group and should always be stated on the prescription.
Treatment of UTI in aged-care facility residents

Establish whether an advance care plan is in place and if antibiotic treatment is consistent with the expressed
goals of the patient. Antibiotic therapy may not be inconsistent with a declared palliative treatment plan. For
information on advance care plans, see Advance care planning.
Before starting antibiotic therapy, correct dehydration. Delaying antibiotic therapy to assess for symptomatic
urinary tract infection (UTI) does not generally lead to adverse outcomes in aged-care facility residents. If
antibiotic therapy is indicated (see Figure 2.13), see Treatment of acute cystitis in adults or Treatment of acute
pyelonephritis in adults for regimens. Modify therapy based on the results of culture and susceptibility testing.
For selected patients with severe pyelonephritis, residential-care facility–based parenteral therapy (eg through a
Residential In-Reach Program) may be an appropriate alternative to hospital admission—see also Community-
Key references
D'Agata E, Loeb MB, Mitchell SL. Challenges in assessing nursing home residents with advanced dementia for
suspected urinary tract infections. J Am Geriatr Soc 2013;61(1):62–66 .
Juthani-Mehta M, Datunashvili A, Tinetti M. Tests for urinary tract infection in nursing home residents. JAMA
2014;312(16):1687–1688 .
Rowe TA, Juthani-Mehta M. Diagnosis and management of urinary tract infection in older adults. Infect Dis Clin
North Am 2014;28(1):75–89 .
Asymptomatic bacteriuria in adults
Asymptomatic bacteriuria in adults
Asymptomatic bacteriuria becomes more common with age. Antibiotic therapy for asymptomatic bacteriuria
does not reduce mortality, the incidence of symptomatic urinary tract infection (UTI), or UTI-related
complications, and significantly increases the risk of adverse events (including antimicrobial resistance; see
also Types of adverse effects of antimicrobials). Treatment of asymptomatic bacteriuria in healthy young
women may increase the risk of future symptomatic UTI.
Screening for and treatment of asymptomatic bacteriuria is not recommended, except for:
pregnant women; see Acute cystitis in pregnancy for treatment recommendations

patients undergoing elective urological procedures (except uncomplicated cystoscopic diagnostic
procedures); see Treatment of acute cystitis in adults for treatment recommendations.
Do not screen for or treat asymptomatic bacteriuria in patients undergoing joint replacement procedures.
Do not screen for or treat asymptomatic bacteriuria in patients undergoing joint replacement procedures.
Requesting a urine culture without a clear indication, or failing to correctly interpret and correlate the culture
result to the clinical situation, significantly contributes to antibiotic misuse.
Key references
Cai T, Mazzoli S, Mondaini N, Meacci F, Nesi G, D'Elia C, et al. The role of asymptomatic bacteriuria in young
women with recurrent urinary tract infections: to treat or not to treat?. Clin Infect Dis 2012;55(6):771–777
.
Cai T, Nesi G, Mazzoli S, Meacci F, Lanzafame P, Caciagli P, et al. Asymptomatic bacteriuria treatment is
associated with a higher prevalence of antibiotic resistant strains in women with urinary tract infections. Clin Infect
Dis 2015;61(11):1655–1661 .
Cordero-Ampuero J, González-Fernández E, Martínez-Vélez D, Esteban J. Are antibiotics necessary in hip

arthroplasty with asymptomatic bacteriuria? Seeding risk with/without treatment. Clin Orthop Relat Res
2013;471(12):3822–3829 .
Hartley S, Valley S, Kuhn L, Washer LL, Gandhi T, Meddings J. Overtreatment of asymptomatic bacteriuria:
identifying targets for improvement. Infect Control Hosp Epidemiol 2015;36(4):470–473 .
Leis JA, Gold WL, Daneman N, Shojania K, McGeer A. Downstream impact of urine cultures ordered without
indication at two acute care teaching hospitals. Infect Control Hosp Epidemiol 2013;34(10):1113–1114 .
Leis JA, Rebick GW, Daneman N, Gold WL, Poutanen SM, Lo P, et al. Reducing antimicrobial therapy for
asymptomatic bacteriuria among noncatheterized inpatients: a proof-of-concept study. Clin Infect Dis
2014;58(7):980–983 .
Mayne AI, Davies PS, Simpson JM. Screening for asymptomatic bacteriuria before total joint arthroplasty. BMJ
2016;354:i3569. .
National Institute for Health and Care Excellence (NICE). Urinary tract infections in adults: Quality standard
[QS90]. London: NICE; 2015. https://www.nice.org.uk/guidance/qs90.
Parvizi J, Gehrke T, Chen AF. Proceedings of the International Consensus on Periprosthetic Joint Infection. Bone
Joint J 2013;95-B(11):1450–1452 .
Sousa R, Muñoz-Mahamud E, Quayle J, Dias da Costa L, Casals C, Scott P. Is asymptomatic bacteriuria a risk
factor for prosthetic joint infection?. Clin Infect Dis 2014;59(1):41–47 .
Zalmanovici Trestioreanu A, Lador A, Sauerbrun-Cutler MT, Leibovici L. Antibiotics for asymptomatic bacteriuria.
Cochrane Database Syst Rev 2015;4:CD009534. .
Catheter-associated bacteriuria and urinary tract
infection in adults
Diagnosis of catheter-associated UTI in adults
Consider the diagnosis of catheter-associated urinary tract infection (CA-UTI) in catheterised patients with
signs and symptoms, including fever (38°C or higher), rigors, acute mental state change, flank pain, acute
haematuria, or pelvic discomfort.
Do not investigate (with urinalysis or urine culture) catheterised patients with nonspecific symptoms for CA-UTI.
Bacteriuria, pyuria, and cloudy or malodourous urine are not reliable signs of CA-UTI in the absence of
genitourinary symptoms. Inappropriate investigation (with urinalysis or urine culture) of asymptomatic
patients can result in the incorrect diagnosis and treatment of CA-UTI.
Urine samples for culture are often collected inappropriately as part of an evaluation of fever in patients with
a catheter who do not have genitourinary symptoms. The incidence of bacteriuria associated with an
indwelling urinary catheter is between 3 and 8% per day. Therefore, after a month, almost all patients with a
catheter will have bacteriuria. Asymptomatic catheter-associated bacteriuria rarely results in adverse
outcomes. Do not screen for or treat catheter-associated asymptomatic bacteriuria except in specific
circumstances—see Asymptomatic bacteriuria in adults.
The absence of pyuria in a symptomatic catheterised patient suggests a diagnosis other than UTI.
For patients with suspected CA-UTI, obtain a urine sample for culture and susceptibility testing before
starting antibiotic therapy. For a guide to collecting urine samples in patients with indwelling urinary
catheters, see Box 2.33.
Guide to collecting urine samples in patients with indwelling urinary catheters (Box 2.33)
Remove the indwelling catheter and obtain a midstream urine sample
OR (if ongoing catheterisation is required)
Replace the catheter [NB1], then collect a urine sample from the port in the drainage system, or if this is
not possible, by separating the catheter from the drainage system.
Do not collect a urine sample from the drainage bag for culture.
Ensure the pathology request clearly indicates that the urine sample provided for testing was obtained via a
catheter.
NB1: The catheter must be replaced before collecting the urine sample to avoid culture of bacteria present in the biofilm of the catheter but
not in the bladder.
Treatment of catheter-associated UTI in adults

Catheter-associated urinary tract infection (CA-UTI) is caused by similar organisms to those associated with
other UTIs (eg Escherichia coli, Klebsiella species). Other pathogens include Pseudomonas aeruginosa,
Enterococcus species, Staphylococcus species and Candida species.
Use the results of urine culture and susceptibility testing to guide choice of antimicrobial therapy. The
recommended duration of therapy is 7 days; if response to treatment is delayed, 10 to 14 days of therapy may
be required.
Antibiotic therapy for CA-UTI is often only transiently effective if the catheter is not removed or replaced,
because most antibiotics penetrate poorly into catheter biofilm. Treatment without catheter removal can lead
to superinfection with resistant organisms.
Prevention of catheter-associated UTI in adults

The most effective strategy to prevent catheter-associated urinary tract infection (CA-UTI) is to limit the use
of indwelling urinary catheters. Avoid using urinary catheters unless they are clearly indicated, and remove
them as soon as they are no longer required. Bladder ultrasound may avoid indwelling catheterisation.
To reduce the risk of infection in patients who require an indwelling urinary catheter, use sterile equipment
and aseptic technique, and ensure proper hygiene when maintaining and removing a catheter. A closed-
catheter drainage system, with ports in the distal catheter for needle aspiration of urine should be used.
Antiseptic or antimicrobial impregnated urinary catheters are expensive and more uncomfortable than
standard catheters, and do not reduce the incidence of CA-UTI to a clinically significant extent.
Do not give antibiotic prophylaxis to prevent CA-UTIs. Antibiotic prophylaxis is not indicated at the time of
catheter placement, removal or replacement.
Do not use instillations of antiseptic agents or irrigate the bladder with antimicrobial or antiseptic agents to
prevent CA-UTI.
Implementation of urinary catheter management programs (‘bundles’) reduces catheter use and therefore the
rate of CA-UTI.
Key references
Arnhem,NL: European Association of Urology; 2018. http://uroweb.org/guideline/urological-infections/ .
Chenoweth CE, Saint S. Urinary Tract Infections. Infect Dis Clin North Am 2016;30(4):869–885 .
Hooton TM, Bradley SF, Cardenas DD, Colgan R, Geerlings SE, Rice JC. Diagnosis, prevention, and treatment of
catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the
Infectious Diseases Society of America. Clin Infect Dis 2010;50(5):625–663 .
Kizilbash QF, Petersen NJ, Chen GJ, Naik AD, Trautner BW. Bacteremia and mortality with urinary catheter-
associated bacteriuria. Infect Control Hosp Epidemiol 2013;34(11):1153–1159 .
Lam TB, Omar MI, Fisher E, Gillies K, MacLennan S. Types of indwelling urethral catheters for short-term
catheterisation in hospitalised adults. Cochrane Database Syst Rev 2014;(9):CD004013. .
Lo E, Nicolle LE, Coffin SE, Gould C, Maragakis LL, Meddings J. Strategies to prevent catheter-associated
urinary tract infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014;35 Suppl 2:S32–
S47 .
Mody L, Meddings J, Edson BS, McNamara SE, Trautner BW, Stone ND. Enhancing Resident Safety by
Preventing Healthcare-Associated Infection: A National Initiative to Reduce Catheter-Associated Urinary Tract
Infections in Nursing Homes. Clin Infect Dis 2015;61(1):86–94 .
Saint S, Greene MT, Krein SL, Rogers MA, Ratz D, Fowler KE. A Program to Prevent Catheter-Associated
Urinary Tract Infection in Acute Care. N Engl J Med 2016;374(22):2111–2119 .
Bacteriuria and urinary tract infection in adults
with urinary stents
Bacteriuria and UTI in adults with urinary stents
The principles of management of bacteriuria and urinary tract infections (UTIs) in adults with urinary stents
are similar to Catheter-associated bacteriuria and urinary tract infection in adults.
Urinary stent colonisation eventually occurs in 100% of patients with a permanent urinary stent and 70% of
patients with a temporary urinary stent. Antibiotic prophylaxis does not prevent urinary stent colonisation. Do
not treat asymptomatic bacteriuria except in specific circumstances—see Asymptomatic bacteriuria in adults.
Diagnosis of UTI in patients with urinary stents is difficult—seek expert advice. In up to 80% of patients,
urinary stents cause symptoms similar to those associated with a UTI (eg frequency, dysuria, pain).
Antimicrobial therapy for a symptomatic UTI is often only transiently effective if the stent is not removed or
replaced, because most antibiotics penetrate poorly into biofilm.
For information about surgical prophylaxis for the insertion, removal or replacement of urinary stents see
here.
Key references
Miyaoka R, Monga M. Ureteral stent discomfort: Etiology and management. Indian J Urol 2009;25(4):455–460
.
Candiduria and candidal urinary tract infection in
adults
Asymptomatic candiduria in adults
Asymptomatic candiduria is common, particularly in patients with indwelling urinary catheters.
Asymptomatic candiduria almost always represents colonisation and rarely leads to disseminated candidiasis.
Pyuria in a patient with a urinary catheter or stent does not differentiate candidal infection from colonisation.
Most patients with asymptomatic candiduria do not require antifungal therapy (systemic or local). Only
patients with neutropenia or patients undergoing urological procedures require treatment, because these
patients have a high risk of developing disseminated candidiasis.
For adults with neutropenia and asymptomatic candiduria, treat as for symptomatic candidal pyelonephritis
(see regimen in Symptomatic candidal UTI in adults). Adults undergoing urological procedures should also
be treated with the regimen for symptomatic candidal pyelonephritis but for a shorter duration—for several
days before and after the procedure.
The risk of candiduria is increased by the continued use of urinary catheters, urinary stents or nephrostomy
tubes—remove these devices if possible.
Daily chlorhexidine baths may decrease the risk of candiduria in male patients in intensive care units.
Antifungal agents for candidal UTI

Fluconazole achieves a high urine concentration and is the drug of choice for treating candidal urinary tract
infection (UTI).
Amphotericin B deoxycholate achieves an adequate urine concentration and is active against most Candida
species; however, lipid formulations of amphotericin B may not achieve an adequate urine concentration.
Echinocandins are minimally excreted into the urine. Although there are reports of successful treatment, the
role of echinocandins in treating candidal UTI is uncertain.
Symptomatic candidal UTI in adults

Symptomatic candidal urinary tract infections (UTIs) are uncommon. In addition to antifungal therapy,
management requires relief of any urinary tract obstruction, and removal of urinary catheters, stents or
nephrostomy tubes if present.
Symptoms of acute candidal cystitis include acute dysuria, frequency, urgency and suprapubic tenderness.
For cystitis caused by fluconazole-susceptible Candida species in adults, use:
fluconazole 200 mg orally, daily for 14 days.
Symptoms of acute candidal pyelonephritis include flank pain and fever (38°C or higher); symptoms of
cystitis may be absent. For pyelonephritis caused by fluconazole-susceptible Candida species in adults, use:
fluconazole 400 mg orally, daily for 14 days.
For symptomatic UTI caused by fluconazole-resistant Candida species, treatment options include
amphotericin B deoxycholate and flucytosine—seek expert advice.
If symptomatic candidal UTI is associated with a fungus ball, endoscopic or surgical removal of the fungus
ball is required for successful treatment. Treat patients with the regimen for symptomatic candidal
pyelonephritis (see above). If a nephrostomy tube is present, seek expert advice; treatment options include an
irrigation of amphotericin B deoxycholate.
If disseminated candidiasis is suspected, treat as for Candida species sepsis (candidaemia).
Key references
Huang SS, Septimus E, Hayden MK, Kleinman K, Sturtevant J, Avery TR, et al. Effect of body surface
decolonisation on bacteriuria and candiduria in intensive care units: an analysis of a cluster-randomised trial.
Lancet Infect Dis 2016;16(1):70–79 .
Kauffman CA. Diagnosis and management of fungal urinary tract infection. Infect Dis Clin North Am
2014;28(1):61–74 .
Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical Practice Guideline
for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis
2016;62(4):e1–50 .
Prostatitis
Acute bacterial prostatitis
Diagnosis of acute bacterial prostatitis
Acute bacterial prostatitis usually presents with symptoms associated with urinary tract infection (UTI) (eg acute
dysuria, urinary frequency and urgency), and systemic features (eg fever [38°C or higher], chills, sweats).
Obstructive urinary symptoms (eg weak stream, dribbling, hesitancy or urinary retention) and symptoms
suggestive of prostatic involvement (eg pelvic or perineal pressure, or prostate tenderness on gentle digital rectal
examination) may also be present.
Acute bacterial prostatitis following genitourinary instrumentation (eg transrectal ultrasound-guided prostate
biopsy) is often associated with sepsis and multidrug-resistant Gram-negative bacteria—seek expert advice.
Obtain urine samples for culture and susceptibility testing for patients with acute bacterial prostatitis. For patients
in hospital, also collect blood samples for culture and susceptibility testing.
Prostatic abscess can complicate prostatitis. Imaging (eg transrectal ultrasound, CT scan, MRI) can identify
prostatic abscesses that may require drainage.
Treatment of acute bacterial prostatitis
Approach to treating acute bacterial prostatitis
Acute bacterial prostatitis is caused by similar organisms to those associated with other UTIs (eg Escherichia coli,
Proteus species, Klebsiella species). However, sexually transmitted pathogens (ie Chlamydia trachomatis,
Neisseria gonorrhoeae) may also cause acute bacterial prostatitis. Systemic pathogens (eg Burkholderia
pseudomallei; see Melioidosis) rarely cause infection, except in tropical regions of Australia [Note 1].
During acute infection, most antibiotics (except nitrofurantoin) have good penetration into the inflamed prostate.
Acute bacterial prostatitis is often painful—offer adequate analgesia as required; see Stepwise approach to acute
pain management.
Note 1: Tropical regions of Australia refer to regions north of 20°S latitude. This includes areas of Queensland north of Mackay, the Northern
Territory north of Tennant Creek, and Western Australia north of Port Hedland.
Empirical antibiotic therapy for nonsevere acute bacterial prostatitis
Acute bacterial prostatitis is considered nonsevere if the patient does not have fever (38°C or higher), systemic
features (eg chills, sweats), or sepsis or septic shock.
For empirical therapy of nonsevere acute bacterial prostatitis, while awaiting the results of culture and
susceptibility testing, use:
1 trimethoprim 300 mg orally, daily for 2 weeks [Note 2]
OR
2 cefalexin 500 mg orally, 6-hourly for 2 weeks.
See Antibiotic choice for urinary tract infection in adults for a discussion of drug choice. Modify empirical therapy
based on the results of culture and susceptibility testing.
If resistance to all of the above drugs is confirmed and the pathogen is susceptible, a suitable alternative is:
1 ciprofloxacin 500 mg orally, 12-hourly for 2 weeks

OR
2 norfloxacin 400 mg orally, 12-hourly for 2 weeks.
Fosfomycin is an option for the treatment of nonsevere acute bacterial prostatitis caused by some multidrug-
resistant bacteria—seek expert advice; evidence is limited and the dosage regimen is not well established.
Confirm the infection has resolved by repeating urine culture 1 week after treatment is completed.
Note 2: If the patient has been treated with trimethoprim in the previous 3 months, or had a trimethoprim-resistant E. coli isolate during this time, use
an alternative antibiotic for empirical therapy.
Empirical antibiotic therapy for severe acute bacterial prostatitis
Acute bacterial prostatitis is considered severe if the patient has fever (38°C or higher), systemic features (eg
chills, sweats), or sepsis or septic shock (see Early recognition of sepsis or septic shock in adults for definitions).
For the treatment of patients with sepsis or septic shock, see Sepsis and septic shock from a urinary tract source in
adults.
For empirical therapy of severe acute bacterial prostatitis, while awaiting the results of culture and susceptibility
testing, use:
of use
PLUS EITHER
OR
OR
For patients with penicillin hypersensitivity, use gentamicin as a single drug (as above) for empirical therapy.
and use ceftriaxone or cefotaxime as above. Switch to oral therapy (see regimens in Empirical antibiotic therapy
for nonsevere acute bacterial prostatitis) once the patient is clinically stable—see Guidance for antimicrobial
The total duration of therapy (intravenous + oral) is usually 4 weeks.
Confirm the infection has resolved by repeating urine culture 1 week after treatment is completed.
Chronic bacterial prostatitis

Diagnosis of chronic bacterial prostatitis
Chronic bacterial prostatitis is rare; less than 10% of men with symptoms of chronic prostatitis (eg chronic
prostatic pain, recurrent lower urinary tract symptoms) have a bacterial infection.
Chronic bacterial prostatitis is defined as recurrent UTI with culture of a recognised uropathogen from urine or
prostatic fluid. Patients with chronic bacterial prostatitis often have a history of intermittent symptomatic episodes
that resemble acute bacterial prostatitis, except fever is usually absent.
The diagnosis of chronic bacterial prostatitis is confirmed by comparing leucocyte count and the results of culture
of pre– with post–prostatic massage urine samples—the ‘two glass test’.
Patients without evidence of bacterial prostatitis have chronic (nonbacterial) prostatitis or chronic pelvic pain
syndrome and do not require antibiotic therapy. Treatment is symptomatic. Some patients benefit from
management by a specialist multidisciplinary team.
For patients who do not have genitourinary symptoms, the presence of leucocytes or bacteria (or both) in a prostate
biopsy, expressed prostatic secretion or semen indicates asymptomatic inflammatory prostatitis. Antibiotic
therapy is not indicated.
Treatment of chronic bacterial prostatitis
Chronic bacterial prostatitis is caused by similar organisms to those associated with other urinary tract infections
(eg Escherichia coli, Proteus species, Klebsiella species). However, sexually transmitted pathogens (ie Chlamydia
trachomatis, Neisseria gonorrhoeae) may also cause chronic bacterial prostatitis.
Prospective, head-to-head placebo-controlled trials to guide antibiotic choice for chronic bacterial prostatitis are
lacking. Ensure the antibiotic chosen achieves adequate penetration into the noninflamed prostate (eg quinolones,
trimethoprim, macrolides, tetracyclines).
Based on the results of culture and susceptibility testing, use:
1 ciprofloxacin 500 mg orally, 12-hourly for 4 weeks
OR
2 norfloxacin 400 mg orally, 12-hourly for 4 weeks
OR
2 trimethoprim 300 mg orally, daily for 4 weeks.
Recurrence of chronic bacterial prostatitis is common. Do not repeat courses of antibiotic therapy unless a
recognised uropathogen is found on culture from a symptomatic patient.
Fosfomycin is an option for treatment of chronic bacterial prostatitis caused by some multidrug-resistant bacteria
—seek expert advice; evidence is limited and the dosage regimen is not well established.
Key references
Gill BC, Shoskes DA. Bacterial prostatitis. Curr Opin Infect Dis 2016;29(1):86–91 .
Lipsky BA, Byren I, Hoey CT. Treatment of bacterial prostatitis. Clin Infect Dis 2010;50(12):1641–1652 .
Perletti G, Marras E, Wagenlehner FM, Magri V. Antimicrobial therapy for chronic bacterial prostatitis. Cochrane
Rees J, Abrahams M, Doble A, Cooper A. Diagnosis and treatment of chronic bacterial prostatitis and chronic
prostatitis/chronic pelvic pain syndrome: a consensus guideline. BJU Int 2015;116(4):509–525 .
Approach to managing urinary tract infection in
children
Diagnosis of UTI in children
In children, a urinary tract infection (UTI) is diagnosed by culture of a urine sample in the presence of
symptoms suggesting UTI. Symptoms of UTI include fever (38°C or higher), abdominal or loin pain and
acute dysuria or frequency. In young infants, additional features include jaundice, failure to thrive, poor
feeding, vomiting, irritability and strong-smelling urine.
Perform urinalysis, urine culture and susceptibility testing in children with suspected UTI before starting
antibiotic therapy. Several methods are used to obtain urine samples:
Suprapubic aspirate (SPA) is the definitive method for collecting urine samples for culture. Any
bacterial growth on urine culture of an SPA sample is diagnostic of UTI.
Clean-catch urine (CCU) [Note 1], midstream urine (MSU) or in–out catheter methods for collecting
urine samples are less invasive than SPA, but more likely to result in contaminated samples. For urine
samples taken by CCU or MSU, more than 108 colony forming units (CFU)/L on culture is diagnostic
of UTI. For urine samples taken from an in–out catheter, more than 106 CFU/L on culture is diagnostic
of UTI.
Although collecting urine samples from a bag is convenient, samples are frequently contaminated. Do
not perform culture of urine samples taken from a bag to confirm the diagnosis of UTI. However, UTI
can be excluded on the basis of negative urinalysis (absence of leucocyte esterase and nitrite).
For children in hospital, collect blood samples for culture and susceptibility testing before starting antibiotic
therapy.
While awaiting the results of culture and susceptibility testing, start empirical therapy for children with
symptoms of UTI if urinalysis (of samples taken by SPA, CCU, MSU or in–out catheter) is positive for
leucocyte esterase or nitrite, or bacteriuria is identified by microscopy.
UTI in children is commonly acute pyelonephritis; it is difficult to distinguish pyelonephritis from cystitis,
particularly in infants. If the child has bacteriuria and localising symptoms (such as dysuria, frequency,
urgency or lower abdominal discomfort), and does not have fever (38°C or higher) or loin pain or tenderness,
treat as acute cystitis. If the child has bacteriuria and either fever (38°C or higher) or loin pain or tenderness,
treat as acute pyelonephritis.
Do not screen for or treat asymptomatic bacteriuria in infants or children, except in some patients
undergoing elective urological procedures.
Note 1: A randomised controlled trial showed suprapubic stimulation hastened noninvasive urine collection (CCU) from infants. See Kaufman J,
Fitzpatrick P, Tosif S, Hopper SM, Bryant PA, Donath SM, et al. The QuickWee trial: protocol for a randomised controlled trial of gentle
suprapubic cutaneous stimulation to hasten non-invasive urine collection from infants. BMJ Open 2016;6(8):e011357. [URL]
Antibiotic choice for UTI in children

Recommendations for empirical antibiotic therapy for urinary tract infection (UTI) in children are based on
likely aetiology, convenience, cost, adverse effects, availability, rates of antimicrobial resistance and a
consideration of the risk of adverse outcomes from clinical failure. Published trials have not found one
antibiotic to be superior to others for the treatment of UTI in children.
In previously healthy children, over 75% of UTIs are caused by Escherichia coli. Staphylococcus
saprophyticus occasionally causes UTI in adolescent females. A wider range of organisms is found in patients
with anatomical or functional abnormalities of the urinary tract. If available, the susceptibility of organisms
recently identified in samples from the patient guides empirical antibiotic choice.
The recommendations for empirical oral antibiotic therapy for UTI in children are different to those for
adults. Antimicrobial resistance does not appear to affect bacteriological cure rates in children as much as in
adults. Trimethoprim continues to be recommended for empirical therapy for acute cystitis and acute
nonsevere pyelonephritis.
Amoxicillin+clavulanate has an unnecessarily broad spectrum of activity for empirical therapy of cystitis. The
use of broad-spectrum antibiotics selects for antibiotic-resistant organisms and increases the risk of
Clostridium difficile infection. Do not use norfloxacin to treat pyelonephritis; it does not achieve an adequate
concentration in kidney tissue.
The considerations for the choice of empirical intravenous antibiotic therapy for UTI are the same for
children as those for adults—see Empirical intravenous antibiotic therapy for UTI.
There is worldwide emergence of multidrug-resistant E. coli, particularly strains producing extended-

spectrum beta-lactamases (ESBLs). In Australia, UTIs caused by ESBL-producing strains remain uncommon
in children. Nevertheless, consider if the child has an increased risk of a multidrug-resistant infection.
Key references
Diagnosis of UTI in children
Gauthier M, Gouin S, Phan V, Gravel J. Association of malodorous urine with urinary tract infection in children
aged 1 to 36 months. Pediatrics 2012;129(5):885–890 .
Arnhem, NL: European Association of Urology; 2015. https://uroweb.org/wp-content/uploads/19-Urological-
infections_LR2.pdf.
Kaufman J, Fitzpatrick P, Tosif S, Hopper SM, Bryant PA, Donath SM, et al. The QuickWee trial: protocol for a
randomised controlled trial of gentle suprapubic cutaneous stimulation to hasten non-invasive urine collection from
infants. BMJ Open 2016;6(8):e011357. .
Lee SJ. Clinical guideline for childhood urinary tract infection (second revision). Child Kidney Dis 2015; 19(2):56–
64. http://chikd.org/journal/view.php?number=625.
McTaggart S, Danchin M, Ditchfield M, Hewitt I, Kausman J, Kennedy S, et al. KHA-CARI guideline: Diagnosis
and treatment of urinary tract infection in children. Nephrology (Carlton) 2015;20(2):55–60 .
Robinson JL, Finlay JC, Lang ME, Bortolussi R, Canadian Paediatric Society, Infectious Diseases Immunization
Committee, Community Paediatrics Committee. Urinary tract infections in infants and children: Diagnosis and
management. Paediatr Child Health 2014;19(6):315–325 .
Stein R, Dogan HS, Hoebeke P, Kočvara R, Nijman RJ, Radmayr C, et al. Urinary tract infections in children:
EAU/ESPU guidelines. Eur Urol 2015;67(3):546–558 .
Antibiotic choice for UTI in children
Alberici I, Bayazit AK, Drozdz D, Emre S, Fischbach M, Harambat J. Pathogens causing urinary tract infections in
infants: a European overview by the ESCAPE study group. Eur J Pediatr 2015;174(6):783–790 .
Bryce A, Hay AD, Lane IF, Thornton HV, Wootton M, Costelloe C. Global prevalence of antibiotic resistance in
paediatric urinary tract infections caused by Escherichia coli and association with routine use of antibiotics in
primary care: systematic review and meta-analysis. BMJ 2016;352:i939. .
Edlin RS, Shapiro DJ, Hersh AL, Copp HL. Antibiotic resistance patterns of outpatient pediatric urinary tract
infections. J Urol 2013;190(1):222–227 .
Gaspari RJ, Dickson E, Karlowsky J, Doern G. Antibiotic resistance trends in paediatric uropathogens. Int J
Antimicrob Agents 2005;26(4):267–271 .
Leazer R, Perkins AM, Shomaker K, Fine B. A Meta-analysis of the Rates of Listeria monocytogenes and
Enterococcus in Febrile Infants. Hosp Pediatr 2016;6(4):187–195 .
Robinson JL, Finlay JC, Lang ME, Bortolussi R, Canadian Paediatric Society, Infectious Diseases Immunization
Committee, Community Paediatrics Committee. Urinary tract infections in infants and children: Diagnosis and
management. Paediatr Child Health 2014;19(6):315–325 .
Strohmeier Y, Hodson EM, Willis NS, Webster AC, Craig JC. Antibiotics for acute pyelonephritis in children.
Acute cystitis in children
Treatment of acute cystitis in children
Treat neonates who have cystitis with intravenous antibiotic therapy in hospital; neonatal dosing is complex—seek
expert advice. Children older than 1 month who have cystitis can be treated with oral antibiotics.
For empirical therapy of acute cystitis in children, while awaiting the results of culture and susceptibility testing,
use:

OR (if a suitable trimethoprim formulation is available)
1 trimethoprim 4 mg/kg up to 150 mg orally, 12-hourly for 3 days [Note 1] [Note 2]
OR
2 cefalexin 12.5 mg/kg up to 500 mg orally, 6-hourly for 3 days.
See Antibiotic choice for UTI in children for a discussion of drug choice.
If culture and susceptibility testing indicate the pathogen is resistant to empirical therapy, do not modify therapy if
symptoms of cystitis are improving.
If the pathogen is resistant to empirical therapy and symptoms of cystitis are not improving, use the narrowest
spectrum antibiotic to which the pathogen is susceptible. If the pathogen is susceptible, suitable alternatives are:
1 amoxicillin 15 mg/kg up to 500 mg orally, 8-hourly for 3 days
OR
2 amoxicillin+clavulanate orally, for 3 days
infant younger than 2 months: 15+3.75 mg/kg, 8-hourly

child 2 months or older: 22.5+3.2 mg/kg up to 875+125 mg, 12-hourly.
If resistance to all of the above drugs is confirmed, provided the pathogen is susceptible, suitable alternatives are:
1 norfloxacin 10 mg/kg up to 400 mg orally, 12-hourly for 3 days [Note 3] [Note 4]
OR
2 ciprofloxacin 12.5 mg/kg up to 500 mg orally, 12-hourly for 3 days [Note 5] [Note 6].
Children with cystitis caused by Pseudomonas aeruginosa often have coexisting urological abnormalities. Treat
children who have cystitis caused by P. aeruginosa with norfloxacin or ciprofloxacin as above; however, a longer
treatment duration is often required—seek expert advice.
Do not perform post-treatment urine culture to confirm resolution of infection for asymptomatic children.
Note 1: If the child has been treated with trimethoprim or trimethoprim+sulfamethoxazole in the previous 6
months, or had a trimethoprim (or trimethoprim+sulfamethoxazole)-resistant Escherichia coli isolate during this
children with swallowing difficulties, see the Don’t Rush to Crush Handbook, published by the Society of
Hospital Pharmacists of Australia [URL].
Key references
Bitsori M, Maraki S, Koukouraki S, Galanakis E. Pseudomonas aeruginosa urinary tract infection in children: risk
factors and outcomes. J Urol 2012;187(1):260–264 .
paediatric urinary tract infections caused by Escherichia coli and association with routine use of antibiotics in primary
care: systematic review and meta-analysis. BMJ 2016;352:i939. .
Dis 2016;16(8):e139–e152 .
National Institute for Health and Care Excellence (NICE). Urinary tract infection (lower): antimicrobial prescribing
[NG109]. London: NICE; October 2018. https://www.nice.org.uk/guidance/ng109.
Schroeder AR, Ralston SL. Intravenous antibiotic durations for common bacterial infections in children: when is enough
enough?. J Hosp Med 2014;9(9):604–609 .
Acute pyelonephritis in children
Choice of empirical therapy for acute pyelonephritis in children
Initially, treat neonates who have pyelonephritis with intravenous antibiotic therapy in hospital; neonatal dosing is
Use intravenous antibiotic therapy (see Treatment of severe pyelonephritis in children) initially for children 1
month or older with acute pyelonephritis who have any of the following features:
risk factors for serious illness (eg immune compromise)

systemic symptoms (eg tachycardia, nausea, vomiting)
sepsis or septic shock (see Sepsis and septic shock from a urinary tract source in children)
inability to tolerate oral therapy.
For children 1 month or older who do not have any of these features, initial oral antibiotic therapy can be used; see
Treatment of nonsevere pyelonephritis in children.
Treatment of nonsevere pyelonephritis in children

Pyelonephritis is considered nonsevere if the child does not have systemic features (eg tachycardia, nausea,
vomiting), or sepsis or septic shock.
For empirical therapy of nonsevere pyelonephritis in children, use:

orally, 12-hourly for 10 days. If clinical response is rapid, stop therapy after 7 days [Note
1]
1 trimethoprim 4 mg/kg up to 150 mg orally, 12-hourly for 10 days. If clinical response is

rapid, stop therapy after 7 days [Note 1] [Note 2]
OR
2 cefalexin 12.5 mg/kg up to 500 mg orally, 6-hourly for 10 days. If clinical response is
rapid, stop therapy after 7 days
OR
3 amoxicillin+clavulanate orally, for 10 days; if clinical response is rapid, stop therapy after
7 days;
infant younger than 2 months: 15+3.75 mg/kg, 8-hourly
child 2 months or older: 22.5+3.2 mg/kg up to 875+125 mg, 12-hourly.
Modify empirical therapy based on the results of culture and susceptibility testing. Use the narrowest spectrum
antibiotic to which the pathogen is susceptible. If the pathogen is susceptible, a suitable alternative is:
amoxicillin 15 mg/kg up to 500 mg orally, 8-hourly for 7 days.
If resistance to all of the above drugs is confirmed, provided the pathogen is susceptible, use:
ciprofloxacin 12.5 mg/kg up to 500 mg orally, 12-hourly for 10 days [Note 3] [Note 4].
Children with pyelonephritis caused by Pseudomonas aeruginosa often have coexisting urological abnormalities.
Treat children who have pyelonephritis caused by P. aeruginosa with ciprofloxacin as above; however, a longer
treatment duration is often required—seek expert advice.
Assess the response to therapy within 24 to 48 hours; if the child has not improved and results of culture and
susceptibility testing are unavailable, reconsider the diagnosis, consider if the child is at risk of a UTI caused by a
multidrug-resistant bacterium (see Box 2.30) and consider switching to intravenous therapy—see Treatment of
severe pyelonephritis in children.
Treatment of severe pyelonephritis in children

Pyelonephritis is considered severe if the child has systemic symptoms (eg tachycardia, nausea, vomiting), or
sepsis or septic shock (see Early recognition of sepsis or septic shock in neonates, infants and children for
definitions).
For children with sepsis or septic shock, see Sepsis and septic shock from a urinary source in children for
management.
For empirical therapy of severe pyelonephritis in children, use:
of use
PLUS EITHER
1 amoxicillin 50 mg/kg up to 2 g intravenously, 6-hourly
OR
1 ampicillin 50 mg/kg up to 2 g intravenously, 6-hourly.
1 cefotaxime 50 mg/kg up to 1 g intravenously, 8-hourly
OR
1 ceftriaxone (child 1 month or older) 50 mg/kg up to 1 g intravenously, daily.
For children with penicillin hypersensitivity, use gentamicin as a single drug (as above) for empirical therapy.
and use either cefotaxime or ceftriaxone (as above).
Switch to oral therapy (see regimens in Treatment of nonsevere pyelonephritis in children) once the child is
clinically stable and can tolerate oral therapy (see Guidance for antimicrobial intravenous to oral switch for further
guidance).
The total duration of therapy (intravenous + oral) for acute pyelonephritis is 10 days; if clinical response is
rapid, stop therapy after 7 days.
Key references
Bitsori M, Maraki S, Koukouraki S, Galanakis E. Pseudomonas aeruginosa urinary tract infection in children: risk
factors and outcomes. J Urol 2012;187(1):260–264 .
Leazer R, Perkins AM, Shomaker K, Fine B. A Meta-analysis of the Rates of Listeria monocytogenes and
Enterococcus in Febrile Infants. Hosp Pediatr 2016;6(4):187–195 .
Dis 2016;16(8):e139–e152 .
McTaggart S, Danchin M, Ditchfield M, Hewitt I, Kausman J, Kennedy S, et al. KHA-CARI guideline: Diagnosis and
treatment of urinary tract infection in children. Nephrology (Carlton) 2015;20(2):55–60 .
Schroeder AR, Shen MW, Biondi EA, Bendel-Stenzel M, Chen CN, French J, et al. Bacteraemic urinary tract infection:
management and outcomes in young infants. Arch Dis Child 2016;101(2):125–130 .
Strohmeier Y, Hodson EM, Willis NS, Webster AC, Craig JC. Antibiotics for acute pyelonephritis in children. Cochrane
Sepsis and septic shock from a urinary tract source in
children
Empirical therapy for sepsis and septic shock from a urinary tract
source in children
For children with sepsis or septic shock from a urinary tract source (see Early recognition of sepsis or septic shock
in neonates, infants and children for definitions), start antibiotic therapy within 1 hour of presentation to medical
care or, for ward-based patients, development of sepsis or septic shock, immediately after taking blood samples for
culture. Take urine samples for culture as soon as possible, but do not delay antibiotic therapy to obtain urine
samples. For nonantibiotic management of sepsis or septic shock, see Early intervention for sepsis or septic shock.
Treatment of sepsis or septic shock from a urinary tract source in neonates is complex and should be based on local
protocols, or clinical microbiology or infectious diseases advice. If these are not immediately available, for
treatment of term neonates with early-onset infection (occurring within 72 hours of birth), see here; for treatment
of neonates with late-onset infection (occurring more than 72 hours after birth), see here. Prompt antibiotic
initiation in sepsis and septic shock improves outcomes.
For empirical therapy of sepsis or septic shock from a urinary tract source in infants 1 month to younger than 2
months, in whom meningitis has not been excluded, see here. For empirical therapy of sepsis or septic shock from
a urinary tract source in children 2 months or older , in whom meningitis has not been excluded, see here.
appropriateness of antibiotic therapy daily, with consideration given to the patient’s clinical status and the
For empirical treatment of sepsis or septic shock from a urinary tract source in children over the age of 1 month, in
whom meningitis has been excluded, use:

dosing [Note 3]
PLUS EITHER
1 amoxicillin 50 mg/kg up to 2 g intravenously, 6-hourly
OR
1 ampicillin 50 mg/kg up to 2 g intravenously, 6-hourly.
1 cefotaxime 50 mg/kg up to 1 g intravenously, 8-hourly; for children with septic shock or

requiring intensive care support, use cefotaxime 50 mg/kg up to 2 g intravenously, 8-
hourly
OR
1 ceftriaxone (child 1 month or older) 50 mg/kg up to 1 g intravenously, daily; for children

with septic shock or requiring intensive care support, use ceftriaxone (child 1 month or
older) 50 mg/kg up to 1 g intravenously, 12-hourly.
For children with penicillin hypersensitivity, use gentamicin as a single drug (as above) and then seek expert
advice.
Sepsis or septic shock caused by multidrug-resistant Gram-negative bacteria (eg extended-spectrum beta-lactamase
(ESBL)-producing bacteria) is an emerging problem, but remains uncommon in children in Australia. If infection
with these bacteria is strongly suspected (see Box 2.30), replace empirical therapy with:
meropenem 20 mg/kg up to 1 g intravenously, 8-hourly [Note 4] [Note 5].
Outcomes are inferior when piperacillin+tazobactam, rather than meropenem, is used to treat infection caused by
ESBL-producing bacteria.
Carbapenem resistance in Gram-negative bacteria is currently uncommon in Australia, but is emerging globally. If
infection with a carbapenem-resistant organism is suspected or confirmed, seek expert advice.
For patients presenting with sepsis or septic shock from an apparent urinary tract source, perform imaging to
exclude urinary obstruction or kidney stone disease.
treatment options.
Imaging to investigate urinary tract infection in
children
Imaging to investigate UTI in children
The role of routine imaging to investigate for anatomical abnormalities after the first episode of urinary tract
infection (UTI) in children is controversial. The current trend is to limit imaging—particularly the use of
dimercaptosuccinic acid (DMSA) scans, which are rarely indicated and result in a large radiation exposure.
Perform a renal ultrasound for children with:
UTI due to atypical organisms (eg Pseudomonas species)

concurrent bacteraemia
an age less than 3 months
kidney impairment
significant electrolyte abnormality
abdominal mass
poor urinary stream
failure to respond to appropriate antibiotics within 48 hours
a first UTI if the child did not have a normal second or third trimester antenatal ultrasound that included the
urinary tract
recurrent symptomatic UTIs.
If the renal ultrasound is normal, further imaging is not required.
Perform a micturating cystourethrogram (MCUG) to detect vesicoureteric reflux (VUR) for children with recurrent
pyelonephritis or boys with bilateral hydroureteronephrosis or bladder-wall thickening on ultrasound, to exclude
urethral pathology. Delay the micturating cystourethrogram until at least 2 weeks after the infection has resolved.
If micturating cystourethrogram is required, give oral antibiotic prophylaxis for 3 days, starting on the day before
the test. Suitable regimens are:

1 trimethoprim 4 mg/kg up to 150 mg orally, 12-hourly for 3 days [Note 1] [Note 2]
OR
2 cefalexin 12.5 mg/kg up to 500 mg orally, 6-hourly for 3 days.
These regimens will not prevent UTI caused by Pseudomonas species. Pseudomonal UTI following micturating
cystourethrogram is infrequent but more common in children with high-grade vesicoureteric reflux (grade IV to
V). For children with high-grade vesicoureteric reflux or other risk factors for infection by a multidrug-resistant
bacterium (see Box 2.30), follow local protocols or seek expert advice.
time, use an alternative antibiotic.
Key references
Kari JA, Tullus K. Controversy in urinary tract infection management in children: a review of new data and subsequent
changes in guidelines. J Trop Pediatr 2013;59(6):465–469 .
National Institute for Health and Care Excellence (NICE). Urinary tract infection in under 16s: diagnosis and
management [CG54]. London: NICE; Updated October 2018.
https://www.nice.org.uk/guidance/cg5https://www.nice.org.uk/guidance/cg54.
Pauchard JY, Chehade H, Kies CZ, Girardin E, Cachat F, Gehri M. Avoidance of voiding cystourethrography in infants
younger than 3 months with Escherichia coli urinary tract infection and normal renal ultrasound. Arch Dis Child
2017;102(9):804–808 .
Rachmiel M, Aladjem M, Starinsky R, Strauss S, Villa Y, Goldman M. Symptomatic urinary tract infections following
voiding cystourethrography. Pediatr Nephrol 2005;20(10):1449–1452 .
Riccabona M. Imaging in childhood urinary tract infection. Radiol Med 2016;121(5):391–401 .
Shaikh N, Craig JC, Rovers MM, Da Dalt L, Gardikis S, Hoberman A, et al. Identification of children and adolescents at
risk for renal scarring after a first urinary tract infection: a meta-analysis with individual patient data. JAMA Pediatr
2014;168(10):893–900 .
Shaikh N, Spingarn RB, Hum SW. Dimercaptosuccinic acid scan or ultrasound in screening for vesicoureteral reflux
among children with urinary tract infections. Cochrane Database Syst Rev 2016;7:CD010657. .
Sinha R, Saha S, Maji B, Tse Y. Antibiotics for performing voiding cystourethrogram: a randomised control trial. Arch
Dis Child 2018;103(3):230–234 .
Tullus K. Vesicoureteric reflux in children. Lancet 2015;385(9965):371–379 .
Prevention of urinary tract infection in children
Nonantibiotic strategies to prevent UTI in children
Evidence suggests that cranberry products may reduce the recurrence of urinary tract infection (UTI) in children.
However, further research is required to confirm efficacy and determine the optimal dose and frequency.
Male circumcision may reduce the childhood and lifetime risk of UTI, but risks of the procedure (eg those
associated with anaesthesia, surgical complications) must also be considered.
At the time of writing, there is insufficient evidence to determine if probiotics prevent UTI in children.
Antibiotic prophylaxis for UTI in children

Do not routinely give antibiotic prophylaxis to infants or children following the first episode of urinary tract
infection (UTI). Antibiotic prophylaxis is no longer routinely used for cases of vesicoureteric reflux (VUR).
Antibiotic prophylaxis for UTI in children increases the risk of infection with multidrug-resistant bacteria.
However, prophylaxis should be considered for infants and children with recurrent UTI or vesicoureteric reflux
grades III to V—seek expert advice.
If prophylaxis is indicated, use:

orally, at night
1 trimethoprim 2 mg/kg up to 150 mg orally, at night [Note 1]
OR
2 cefalexin 12.5 mg/kg up to 250 mg orally, at night
OR
2 nitrofurantoin (child 1 month or older) 1 mg/kg up to 50 mg orally, at night [Note 2].
Review the need for prophylaxis after 6 months.
Do not broaden the spectrum of antibiotic prophylaxis to target multidrug-resistant bacteria.
Long-term use of nitrofurantoin has been associated with an increased risk of rare adverse effects, including
pulmonary toxicity, hepatotoxicity and peripheral polyneuropathy.
Note 1: An oral liquid formulation of trimethoprim is not commercially available; for formulation options for children with swallowing difficulties, see
the Don’t Rush to Crush Handbook, published by the Society of Hospital Pharmacists of Australia [URL].
Note 2: An oral liquid formulation of nitrofurantoin is not commercially available; for formulation options for children with swallowing difficulties,
see the Don’t Rush to Crush Handbook, published by the Society of Hospital Pharmacists of Australia [URL].
Key references
Nonantibiotic strategies to prevent UTI in children
Durham SH, Stamm PL, Eiland LS. Cranberry Products for the Prophylaxis of Urinary Tract Infections in Pediatric
Patients. Ann Pharmacother 2015;49(12):1349–1356 .
Morris BJ, Kennedy SE, Wodak AD, Mindel A, Golovsky D, Schrieber L, et al. Early infant male circumcision:
Systematic review, risk-benefit analysis, and progress in policy. World J Clin Pediatr 2017;6(1):89–102 .
Morris BJ, Wiswell TE. Circumcision and lifetime risk of urinary tract infection: a systematic review and meta-analysis. J
Urol 2013;189(6):2118–2124 .
Schwenger EM, Tejani AM, Loewen PS. Probiotics for preventing urinary tract infections in adults and children.
Williams GJ, Craig JC, Carapetis JR. Preventing urinary tract infections in early childhood. Adv Exp Med Biol
2013;764:211–218 .
Antibiotic prophylaxis for UTI in children
Brandström P, Hansson S. Long-term, low-dose prophylaxis against urinary tract infections in young children. Pediatr
Nephrol 2015;30(3):425–432 .
Arnhem, NL: European Association of Urology; 2015. https://uroweb.org/wp-content/uploads/19-Urological-
infections_LR2.pdf.
Hari P, Hari S, Sinha A, Kumar R, Kapil A, Pandey RM, et al. Antibiotic prophylaxis in the management of
vesicoureteric reflux: a randomized double-blind placebo-controlled trial. Pediatr Nephrol 2015;30(3):479–486
.
Hewitt IK, Pennesi M, Morello W, Ronfani L, Montini G. Antibiotic Prophylaxis for Urinary Tract Infection-Related Renal
Scarring: A Systematic Review. Pediatrics 2017;139(5):[epub]. .
Kari JA, Tullus K. Controversy in urinary tract infection management in children: a review of new data and subsequent
changes in guidelines. J Trop Pediatr 2013;59(6):465–469 .
RIVUR Trial Investigators, Hoberman A, Greenfield SP, Mattoo TK, Keren R, Mathews R. Antimicrobial prophylaxis for
children with vesicoureteral reflux. N Engl J Med 2014;370(25):2367–2376 .
Robinson JL, Finlay JC, Lang ME, Bortolussi R, Canadian Paediatric Society, Community Paediatrics Committee,
Infectious Diseases and Immunization Committee. Prophylactic antibiotics for children with recurrent urinary tract
infections. Paediatr Child Health 2015;20(1):45–51 .
Selekman RE, Shapiro DJ, Boscardin J, Williams G, Craig JC, Brandström P, et al. Uropathogen Resistance and
Antibiotic Prophylaxis: A Meta-analysis. Pediatrics 2018;142(1): .
Shaikh N, Craig JC, Rovers MM, Da Dalt L, Gardikis S, Hoberman A, et al. Identification of children and adolescents at
risk for renal scarring after a first urinary tract infection: a meta-analysis with individual patient data. JAMA Pediatr
2014;168(10):893–900 .
Tullus K. Vesicoureteric reflux in children. Lancet 2015;385(9965):371–379 .
Catheter-associated bacteriuria and urinary tract
infection in children
Principles of management of catheter-associated bacteriuria and
UTI in children
Catheter-associated bacteriuria and urinary tract infection (UTI) occurs less commonly in children than in
adults, but the principles of management are similar—see Catheter-associated bacteriuria and urinary tract
infection in adults.
Candiduria and candidal urinary tract infection in
children
Candiduria and candidal UTI in children
The isolation of Candida from urine is common, particularly in children with indwelling urinary catheters;
this finding usually reflects colonisation and rarely leads to disseminated candidiasis.
Most children with asymptomatic candiduria do not require antifungal therapy (systemic or local). Only
patients at high risk of developing disseminated candidiasis require treatment.
Seek expert advice to treat candiduria in children. Consider treating candiduria in:
children with neutropenia

children undergoing urological procedures
infants of low birth weight
children with symptoms of a urinary tract infection (UTI).
Relapse after treatment is common; the risk of candiduria is increased by use of urinary catheters, urinary
stents or nephrostomy tubes—remove these devices if possible.
Consider renal imaging studies to exclude the presence of a fungus ball within the urinary tract in children
who have persistent candiduria or neonates with candiduria; if confirmed, surgical removal is strongly
recommended.
If disseminated candidiasis is suspected, treat as for Candida species sepsis (candidaemia).
Principles of antimicrobial use
Principles of appropriate antimicrobial prescribing
Appropriate antimicrobial prescribing
This topic outlines the principles of appropriate antimicrobial use for prophylactic, empirical and directed
therapy, in hospital and community practice. Appropriate antimicrobial therapy improves patient outcomes,
reduces unnecessary antimicrobial use and reduces adverse consequences for the patient and the community.
Appropriate antimicrobial prescribing includes the following steps:
decide whether antimicrobial therapy is indicated

when microbiological testing is indicated, collect samples for testing before the first dose of
antimicrobial
select an antimicrobial for the indication that is consistent with appropriate clinical guideline
recommendations, or based on advice from an infectious diseases physician or clinical microbiologist.
Consider the required spectrum of activity (use the narrowest spectrum therapy required), potential
adverse effects, drug interactions and cost, as well as patient factors such as history of antimicrobial
hypersensitivity, recent antimicrobial use, and pregnancy and breastfeeding
select an appropriate dose, frequency and route; use oral therapy when clinically appropriate
prescribe the shortest possible duration of therapy, consistent with the condition being treated and the
patient’s clinical response
document the antimicrobial therapy in the patient’s medical record or medication chart, including the
indication and the intended duration of therapy before further review or cessation.
Prophylactic, empirical and directed antimicrobial therapy
Antimicrobial use may be prophylactic, empirical, or directed against an identified pathogen.
Prophylactic antimicrobial therapy aims to prevent infection when there is a significant clinical risk of
infection developing. Prophylaxis is of proven benefit for many surgical procedures, open fractures, and in
other specific circumstances.
Empirical antimicrobial therapy is used to treat an established infection when the pathogen has not been
identified. Base antimicrobial choice on the clinical presentation and the expected antimicrobial susceptibility
of the most likely or important pathogen(s). Empirical therapy is reasonable in the following circumstances:
when treatment must be started before the results of culture or susceptibility testing are available
when the infection is not serious enough to warrant taking samples for culture
if a sample for culture cannot be obtained.
Review empirical therapy as soon as possible.
In hospital patients, review therapy daily.

If the diagnosis excludes infection, stop antimicrobial therapy.
If a pathogen is not identified, re-evaluate the clinical and microbiological justification for therapy. If
ongoing therapy is indicated, consider de-escalation (eg change parenteral therapy to oral therapy, or
change a broad-spectrum to a narrower-spectrum antimicrobial), for a defined duration.
If a pathogen is identified, follow the principles of directed therapy.
Directed antimicrobial therapy is used to treat an established infection when the pathogen has been
identified, and an antimicrobial with activity against the pathogen can be selected. Examples of the approach
to directed therapy can be found for pneumonia and bone and joint infections.
Preliminary microbiology results (eg Gram stain) may allow targeting of antimicrobial therapy before
definitive results are available; modify ongoing therapy once the pathogen and susceptibility are known.
Choosing the optimal route of administration for antimicrobials

Oral and enteral therapy
For the majority of infections, oral antimicrobial therapy is appropriate. Parenteral (eg intravenous,
intramuscular) therapy is required under specific circumstances—see Parenteral therapy below.
Oral therapy is usually associated with less serious adverse effects than parenteral therapy. It also has the
advantage of lower drug and administration costs.
The antimicrobials listed in Box 2.34 have good oral bioavailability and can often be given orally rather than
intravenously, provided they are appropriate for the indication, have adequate tissue penetration for the
infection being treated, and the patient can tolerate oral administration.
For children unable to swallow tablets, the availability of a suitable drug formulation can affect antimicrobial
choice.
If the oral route is unsuitable, the enteral route (eg nasogastric [NG], nasoenteric, percutaneous endoscopic
gastrostomy [PEG]) may be used.
Examples of antimicrobials with good oral bioavailability (Box 2.34)
The following antimicrobials have good oral bioavailability. They can often be given orally rather than
intravenously, provided the drug is appropriate for the indication, has adequate tissue penetration for the
infection being treated, and the patient can tolerate oral administration.
azithromycin [NB1]
ciprofloxacin
clindamycin
doxycycline
fluconazole
itraconazole (Lozanoc capsules)
linezolid
metronidazole
moxifloxacin
posaconazole modified-release tablets
rifampicin
trimethoprim+sulfamethoxazole
voriconazole
NB1: Despite lower bioavailability, oral azithromycin is extensively distributed and achieves high intracellular concentrations.
Parenteral therapy
Parenteral antimicrobial administration (usually intravenous, but occasionally intramuscular if intravenous
access is difficult) is required when:
oral administration is not tolerated or not possible

gastrointestinal absorption is likely to be significantly reduced (eg vomiting, gastrointestinal pathology),
or reduced absorption accentuates already poor bioavailability
an oral antimicrobial with a suitable spectrum of activity is not available
higher doses than can be easily administered orally are required to achieve an effective concentration at
the site of infection (eg meningitis, endocarditis)
urgent treatment is required for severe and rapidly progressing infection.
Other routes of administration

The use of nebulised antimicrobials is not recommended, except in specific circumstances (eg Pneumocystis
jirovecii pneumonia, cystic fibrosis).
Due to the risk of promoting resistance, topical antimicrobial therapy should be restricted to certain
indications (eg bacterial conjunctivitis). Antimicrobials used topically should preferably not be from classes
of drugs used for systemic therapy.
Guidance for antimicrobial intravenous to oral switch
Unless the infection is one that requires high tissue concentrations or prolonged parenteral therapy (eg
meningitis, endocarditis), reassess the need for ongoing intravenous therapy daily, and switch to oral or
enteral therapy once the patient is clinically stable. Guidance on when to switch from intravenous to oral
therapy is provided in Box 2.35.
If ongoing parenteral therapy is indicated, community-based parenteral antimicrobial therapy may be

considered for patients who are suitable.
Antimicrobial stewardship programs with a focus on intravenous to oral switch have demonstrated improved
patient care and reductions in length of hospital stay and antimicrobial costs.
Guidance for intravenous to oral switch (Box 2.35)
It is often appropriate to switch a patient’s therapy from the intravenous to oral route when all of the
following apply [NB1]:
clinical improvement
fever resolved or improving
no unexplained haemodynamic instability
tolerating oral intake with no concerns about malabsorption
a suitable oral antimicrobial with the same or similar spectrum, or an oral formulation of the same
drug, is available. For children, a suitable paediatric formulation is available.
NB1: Does not apply to infections that require high tissue concentrations or prolonged intravenous therapy (eg meningitis, endocarditis).
Tips for optimising antimicrobial dosage regimen

When selecting a dosage regimen for antimicrobial therapy, take into account patient factors, the
pharmacokinetic and pharmacodynamic properties of the drug, and potential drug interactions.
In certain patients with altered pharmacokinetics (eg altered drug clearance or volume of distribution),
dosing can be difficult and expert advice may be required. Examples include:
patients with septic shock or who require intensive care support

patients with severe burns
patients with fluid sequestration into a third space (eg severe pancreatitis, bleeding, ascites)
patients with cystic fibrosis
pregnant women
obese patients.
The use of extended or continuous infusions of antimicrobials may be considered in certain circumstances
to optimise the dosage regimen, for example in patients with septic shock or requiring intensive care support
(see Empirical regimens for sepsis and septic shock). Continuous infusions may also be appropriate for
community-based parenteral antimicrobial therapy.
Monitoring of antimicrobial blood concentration is used to improve efficacy and minimise dose-related
toxicity of drugs with a narrow therapeutic index, such as aminoglycosides, glycopeptides and azole
antifungals—see Monitoring antimicrobial blood concentrations. Monitoring may also be used to optimise
dosage regimens in other circumstances (eg patients with septic shock or who require intensive care support).
Choosing the duration of antimicrobial therapy

The duration of therapy for some indications is based on clinical practice because it is not clearly defined from
published studies. In general, use the shortest possible duration of therapy, consistent with the condition being
treated and the patient’s clinical response. Prolonged duration of antimicrobial therapy is associated with an
increased risk of adverse reactions, Clostridium difficile infection, candidiasis and selection of antibiotic-
resistant organisms, as well as increased costs.
Some examples of indications for which evidence supports a shorter duration of therapy (less than 7 days) are
shown in Box 2.36. However, there are certain indications that require prolonged therapy; for example,
endocarditis, osteomyelitis and Staphylococcus aureus bacteraemia.
As far as possible, advice on duration is included in the clinical topics in these guidelines.
Examples of indications for which shorter course therapy (less than 7 days) is often
appropriate (Box 2.36)
intra-abdominal infections when definitive surgical management has been undertaken

uncomplicated lower urinary tract infections
acute biliary infections when obstruction has been removed
acute bacterial rhinosinusitis
acute exacerbations of chronic obstructive pulmonary disease
community-acquired pneumonia
uncomplicated skin and soft tissue infections
Types of adverse effects of antimicrobials

Consider benefits versus harms of antimicrobial therapy
All antimicrobials can cause adverse effects, so consider the benefit–harm profile when deciding whether to
prescribe an antimicrobial. Adverse effects are usually minor or self-limiting but serious adverse effects,
including death, occur rarely. Adverse effects of antimicrobials can be classified as direct and indirect (see
below).
Discuss the benefits and harms of antimicrobial therapy with patients. The benefits vary depending on the
infection; Box 2.37 provides guidance on explaining the harms.
Explaining the harms of antibiotic therapy (Box 2.37)
Antibiotics disrupt the balance of bacteria in the body (the microbiome). While the consequences of this are
not fully understood, it can cause problems ranging from mild yeast infections (eg thrush) through to more
serious infections (eg Clostridium difficile).
Antibiotics can also cause bacteria to become resistant to treatment so that future infections are harder to
treat. Multidrug-resistant bacteria (known as ‘superbugs’) can spread between people, affecting other family
members and the community.
Direct adverse effects

Always check if a patient has a history of adverse drug reactions before prescribing an antimicrobial. Adverse
drug reactions to antimicrobials are most commonly non–immune-mediated, pharmacologically predictable
reactions (eg nausea, vomiting, diarrhoea) or immune-mediated nonsevere delayed reactions (eg
maculopapular rash), which do not necessarily preclude further use of the drug.
However, occasionally the reaction is a severe or life-threatening immune-mediated hypersensitivity reaction,

which can be immediate (eg anaphylaxis) or delayed (eg drug rash with eosinophilia and systemic symptoms
[DRESS], Stevens–Johnson syndrome / toxic epidermal necrolysis [SJS/TEN]), and subsequent exposure to
the drug could be fatal. For further discussion, see Types of antimicrobial hypersensitivity.
Always check if a patient has a history of hypersensitivity before prescribing an antimicrobial.
Indirect adverse effects
Indirect adverse effects of antimicrobials include effects on both commensal and environmental flora.
Clostridium difficile is a common cause of healthcare-associated and antibiotic-associated diarrhoea.
Impairment of the normal defence mechanisms (including the disruption of host gastrointestinal tract flora by
most antibiotics, proton pump inhibitors, or immunosuppressive drugs) may result in colonisation of the
gastrointestinal tract with C. difficile. A proportion of colonised patients progress to develop C. difficile
infection. Minimising exposure to antibiotics reduces the risk of developing C. difficile infection.
Candida species are normal flora in the gastrointestinal and genitourinary tracts, but antibiotic therapy
disrupts the normal flora, and infection caused by Candida species can develop (eg a local mucocutaneous
infection such as oropharyngeal or vulvovaginal candidiasis, or invasive infection in immunocompromised or
critically ill patients).
Antimicrobial use is associated with an increased risk of colonisation or infection with a drug-resistant
pathogen (see An overview of antimicrobial resistance). For example, acquisition of vancomycin-resistant
enterococci (VRE) has been associated with previous treatment with antimicrobials, particularly vancomycin
and cephalosporins. The risk of colonisation with methicillin-resistant Staphylococcus aureus (MRSA) has
been correlated with the frequency and duration of prior antibiotic therapy, particularly quinolones and
cephalosporins.
The microbiome is an ecological community of commensal, symbiotic and pathogenic organisms found in
(and on) all multicellular organisms, including humans. Emerging data on changes to the human microbiome
following antimicrobial use suggest that such changes may have implications for patient health that, while not
yet well understood, may be far-reaching. An intact microbiome is part of the body’s defence against
infection.
An overview of antimicrobial resistance

What is antimicrobial resistance?
Unlike other drugs, the use of antimicrobials in one patient can influence future efficacy in other patients. The
development and spread of resistance to antimicrobials is a major problem for society.
In the general sense, antimicrobial resistance means that an organism has either natural resistance (intrinsic
resistance) to an antibiotic, or has acquired a resistance mechanism (acquired resistance). Although the
mechanisms are complex, resistance usually develops due to selective pressure exerted by the widespread
presence of antimicrobial drugs in the environment, together with the facilitated transfer of organisms (or their
genetic material) within the environment, in both healthcare and community settings.
The concept of resistance also applies to laboratory antimicrobial susceptibility testing and reporting, where a
categorisation of ‘resistant’ implies ‘likely to fail treatment’ with the specified drug.
Categorisation of an organism as resistant or susceptible in the laboratory requires the application of

‘breakpoints’. A breakpoint is an agreed concentration (mg/L) of an antibiotic that is used to define whether a
species of bacteria is susceptible or resistant to that antibiotic. Breakpoints are usually set by international
organisations (eg European Committee on Antimicrobial Susceptibility Testing [EUCAST], Clinical and
Laboratory Standards Institute [CLSI]), and are developed based on a range of data including the in vitro
activity of the drug, its pharmacokinetic and pharmacodynamic properties, outcome data from clinical studies,
antimicrobial resistance mechanisms, and pharmacokinetic–pharmacodynamic modelling.
The minimum inhibitory concentration (MIC) is a measure of the lowest concentration of the drug required to
stop the visible growth of a specific organism in vitro. The breakpoint is compared to the MIC—if the MIC of
the tested organism is less than or equal to the predetermined breakpoint, the organism is considered
susceptible to the antibiotic; if the MIC is greater than this value, the organism is considered resistant to the
antibiotic.
In some circumstances, even if reported as resistant, an organism with an acquired resistance mechanism may
remain susceptible to treatment if exposure to the drug is increased by using higher-dose regimens or
changing the mode of administration. Standard doses of the drug may be effective if the antimicrobial is
naturally concentrated at the site of infection (eg the urinary tract).
Organisms of concern
Antimicrobial resistance is increasing in many pathogens. Problem organisms include Streptococcus
pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA) in both healthcare and community settings,
vancomycin-resistant enterococci (VRE), strains of Klebsiella and Escherichia coli that produce extended-
spectrum beta-lactamase (ESBL) enzymes, Neisseria gonorrhoeae, and multidrug-resistant Acinetobacter and
Pseudomonas aeruginosa. The emergence of carbapenemase-producing Enterobacteriaceae (CPE) is
particularly concerning, and has placed greater emphasis on the need for ‘one health’ antimicrobial
stewardship programs. A ‘one health’ approach recognises that the health of humans, animals and the
environment are closely linked, and that in order to reduce the threat of antimicrobial resistance, action is
required in all sectors where antimicrobials are used (see the National Centre for Antimicrobial Stewardship
website).
Emergence of resistance to ‘reserve’ antibiotics—such as quinolones, carbapenems, vancomycin,

colistimethate sodium (colistin)—is a major public health challenge.
Antimicrobial use and emergence of resistance

Appropriate antimicrobial use delays the emergence of resistance and minimises the prevalence of resistance
after it has emerged.
To ensure that antimicrobials remain effective for treating important infections, it is crucial to reduce
inappropriate antimicrobial prescribing, particularly of cephalosporins, quinolones, carbapenems, beta-
lactamase inhibitor combinations, and vancomycin.
Useful resources about antimicrobial resistance are available from:
Australian Commission for Safety and Quality in Health Care [URL]

NPS MedicineWise [URL]
Centers for Disease Control and Prevention [URL].
An introduction to antimicrobial stewardship

What is antimicrobial stewardship?
Antimicrobial stewardship (AMS) promotes optimal antimicrobial prescribing. The aim of an antimicrobial
stewardship program is to improve patient outcomes and reduce adverse consequences associated with
antimicrobial use, including antimicrobial resistance, toxicity and unnecessary costs. Antimicrobial
stewardship is an important strategy for preserving the effectiveness of the antimicrobials that are currently
available, in the face of rising antimicrobial resistance. Evidence shows that antimicrobial stewardship
activities can reduce inappropriate antimicrobial use, which is associated with improved patient care.
The Australian Antimicrobial Stewardship Clinical Care Standard describes standards for safe, high-quality
care of any person who receives antimicrobial therapy. These standards apply to prescribing in community
and hospital settings.
For more information about antimicrobial stewardship, see the Australian Commission on Safety and Quality
in Health Care publication Antimicrobial Stewardship in Australian Health Care 2018.
Antimicrobial stewardship in hospitals

In Australia, national safety and quality standards require all health service organisations to have an effective
antimicrobial stewardship (AMS) program in place, which is assessed for accreditation. An antimicrobial
stewardship program encompasses all the activities that promote and monitor safe and appropriate prescribing
and use of antimicrobials in an organisation. The program should be part of the organisation’s quality
improvement and patient safety governance structure; it is generally managed by a committee.
Dedicated staff resources are required to carry out antimicrobial stewardship activities in a health service
organisation. Ideally this work is done by a multidisciplinary team, often including at least a lead doctor and
pharmacist. In smaller facilities, if a team is not available, the staff responsible for antimicrobial stewardship
may be supported by offsite clinicians with relevant expertise. Part of the role of an antimicrobial stewardship
service is to ensure that ongoing education and training about infection management, antimicrobial resistance
and optimal antimicrobial use is provided for health professionals and consumers. Antimicrobial stewardship
services also provide resources to prescribers to promote optimal antimicrobial use, and monitor prescribing
practices to identify problems and document improvement.
The Australian Commission on Safety and Quality in Health Care recommends six essential strategies for
effective antimicrobial stewardship in hospitals [Note 1].
Providing access to and implementing clinical guidelines consistent with Therapeutic Guidelines:
Antibiotic that take into account local microbiology and antimicrobial susceptibility data [Note 2].
Implementing formulary restriction and approval systems that include restricting broad-spectrum and
later-generation antimicrobials to patients in whom their use is clinically justified [Note 3].
Reviewing antimicrobial prescribing, with intervention and direct feedback to the prescriber.
Implementing point-of-care interventions (including directed therapy, intravenous to oral switch and
dose optimisation).
Ensuring that the clinical microbiology service:
provides guidance and support for optimal sample collection
targets reporting of clinically meaningful pathogens and their susceptibilities
uses selective reporting of susceptibility test results
generates location-specific antimicrobial susceptibility reports (antibiograms) annually.
Monitoring antimicrobial use and outcomes, and reporting to clinicians and management.
Measuring the appropriateness of antimicrobial prescribing is a key focus of antimicrobial stewardship

programs. The National Centre for Antimicrobial Stewardship (NCAS) coordinates and delivers the National
Antimicrobial Prescribing Survey (NAPS), a standardised auditing tool to assess the appropriateness of local
antimicrobial prescribing.
Ongoing review of antimicrobial stewardship programs should be undertaken to assess the impact of
interventions.
Note 1: Australian Commission on Safety and Quality in Health Care (ACSQHC). Antimicrobial Stewardship in Australian Health Care 2018.
Sydney: ACSQHC; 2018. [URL]
Note 2: Guidelines include clinical pathways and care bundles.
Note 3: Refers to institutional formularies; in the community, the Pharmaceutical Benefits Scheme and the Repatriation Pharmaceutical Benefits
Scheme act as the formulary.
Antimicrobial stewardship in the community setting

Most antimicrobial use occurs in the community setting, so general practice is an important focus for
antimicrobial stewardship (AMS).
Community-based practitioners can use many strategies to optimise antimicrobial prescribing. Efforts to avoid
antibiotic use for infections when the likelihood of benefit is low (eg upper respiratory tract infections), or
selection of narrow-spectrum antibiotics rather than broad-spectrum antibiotics (where possible), can have a
major impact on population-wide antimicrobial consumption. Continued improvements in this area are likely
to positively impact antimicrobial resistance over time.
Importantly, community-based practitioners can also have a positive influence on the beliefs of individual
patients and the broader community about antimicrobial use and antimicrobial resistance. For patient
resources, see Patient resources to promote appropriate use of antimicrobials.
The Australian Commission on Safety and Quality in Health Care is developing antimicrobial stewardship
strategies for general practice, including strategies for Primary Health Networks, general practices, general
practitioners and other staff—for examples, see Table 2.64.
Antimicrobial stewardship strategies for general practice (Table 2.64)
Component of general Strategies for antimicrobial stewardship (AMS)

practice
Promote Antibiotic Awareness Week.
Establish a local antimicrobial stewardship advisory group.

Primary Health Networks
Promote antimicrobial stewardship through education, information
resources and tools for schools, childcare centres and community groups.
Promote the Antimicrobial Stewardship Clinical Care Standard [NB1].
Provide staff with access to Therapeutic Guidelines: Antibiotic.

General practice owners
Encourage participation in audit and feedback on antimicrobial prescribing
at a practice level.
Participate in online learning modules on antimicrobial stewardship.
Demonstrate commitment to antimicrobial stewardship using a

‘commitment poster’.
Prescribe according to Therapeutic Guidelines: Antibiotic.
Configure clinical software to default to zero repeats for antimicrobials.
General practitioners Specify the duration of antimicrobial therapy on the prescription.
Use shared decision making with consumers for antimicrobial decisions,

when appropriate.
Use delayed antimicrobial prescriptions in selective situations for

management of upper respiratory tract infections.
Participate in audit and feedback activities for prescribing of antimicrobials.
Discuss vaccination to minimise need for antibiotics.

Implement infection control and prevention strategies according to national
guidelines.
General practice staff
Provide displays (eg posters, videos, information pamphlets) for consumers.
Promote up-to-date immunisation.

NB1: See the Australian Commission on Safety and Quality in Health Care website.
There are often high rates of antibiotic use in residential aged-care facilities. Care providers can implement
organisation-wide antimicrobial stewardship activities to promote safe and effective use of antimicrobials for
residents. These activities should complement good infection prevention and control strategies, and support
the efforts of general practitioners who care for residents.
Examples of antimicrobial stewardship activities in residential aged-care facilities include:
educating staff about antibiotic resistance and antimicrobial stewardship, viral versus bacterial
infections, and recognition of suspected infection
providing information for residents and families about infection prevention and antibiotic use
participating in audit activities such as the Aged Care National Antimicrobial Prescribing Survey
[URL].
Antimicrobial drug shortages

There have been problems with the supply of antimicrobial drugs in Australia. The National Centre for
Antimicrobial Stewardship has developed a set of fact sheets about shortages of antimicrobials, outlining
patient management and the use of alternative antimicrobials when a particular drug is not available—see
their website.
Patient resources to promote appropriate use of antimicrobials

NPS MedicineWise has developed patient information about the appropriate use of antibiotics and antibiotic
resistance—see Antibiotics, explained and Antibiotic resistance: the facts.
Discuss the benefits and harms of antimicrobial therapy with patients. The benefits vary depending on the
infection; Box 2.37 provides guidance on explaining the harms.
Key references
Choosing the optimal route of administration for antimicrobials
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Antimicrobial drug shortages
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Antimicrobial hypersensitivity
Introduction to antimicrobial hypersensitivity
‘Hypersensitivity’ is a broad term for unpredictable adverse drug reactions, which can be caused by immune-
mediated or other mechanisms. ‘Allergy’ refers to an immune-mediated mechanism. In this topic, ‘immune-
mediated hypersensitivity’ and ‘allergy’ are used interchangeably.
It is common for patients to report a history of allergy to an antimicrobial—usually penicillin—and this can
present a clinical dilemma. If the antimicrobial is administered to an allergic patient, a severe reaction can
occur; however, it is known that many patients who report an allergy tolerate the drug if it is administered
again. A patient history of antimicrobial allergy often dates back to a reaction that occurred in childhood; it is
commonly described as a rash, with vague features not typical of an immediate immune-mediated (IgE)
hypersensitivity reaction. In fact, few childhood reactions are reproducible in adulthood, and over 90% of
reported penicillin allergies can be excluded by skin testing and oral provocation.
Over 90% of reported penicillin allergies can be excluded by antibiotic allergy testing.
Careful assessment and confirmation of antimicrobial hypersensitivity ensures that patients with serious
infections are not unnecessarily denied the most effective treatment, or treated unnecessarily with broad-
spectrum antibiotics. Recent studies (including Australian data) found that when an antimicrobial allergy was
recorded on a medication chart, patients were more likely to receive inappropriate antibiotic therapy and have
inferior clinical and microbiological outcomes.
Accurate and detailed information about antimicrobial hypersensitivity must be documented in the patient’s
medical record. If a reported allergy is subsequently excluded, update the medical record and, to avoid
relabelling, include information about how the allergy has been excluded.
If a reported allergy is subsequently excluded, update the patient’s medical record accordingly.
Advise patients to wear a medical alert bracelet or necklace following a confirmed severe hypersensitivity
reaction (eg drug rash with eosinophilia and systemic symptoms [DRESS], Stevens–Johnson syndrome / toxic
epidermal necrolysis [SJS/TEN]), or after allergy is confirmed on testing.
For information on anaphylaxis, see Anaphylaxis.
Common misconceptions about antimicrobial allergy are clarified in Box 2.38.

Common misconceptions about antimicrobial allergy (Box 2.38)
Misconception: Antimicrobial allergy is lifelong.
Antimicrobial allergy is likely to wane over time and many people who report an allergic reaction in
childhood are able to tolerate the drug as an adult.
Misconception: All childhood rashes associated with beta-lactam antibiotics are due to allergy.
Childhood rashes are commonly caused by a viral infection or a drug–virus interaction rather than drug
allergy, and are often not reproducible upon a supervised challenge when the patient is well.
Misconception: Documented antimicrobial allergies are always true allergies.
In an Australian review of antimicrobial prescribing, up to 20% of documented ‘allergies’ were

pharmacologically predictable non–immune-mediated adverse reactions (eg gastrointestinal intolerance).
Misconception: Cephalosporin cross-reactivity in patients allergic to penicillin is around 10%.
Recent reviews have found that overall, only 1 to 2% of patients with a confirmed penicillin allergy have a
cephalosporin allergy (see Cross-reactivity between beta lactams).
Types of antimicrobial hypersensitivity

Type A versus Type B reactions
Type A adverse drug reactions are pharmacologically predictable reactions (eg gastrointestinal intolerance).
Type B reactions are unpredictable reactions mediated by immunological or other mechanisms. The most
common types of immune-mediated reactions are immediate IgE-mediated (Type B-I) and delayed T-cell
mediated (Type B-IV) reactions.
Immediate or acute reactions that do not involve an IgE-mediated mechanism can also occur; for example,
vancomycin infusion-related ‘red-man’ syndrome. These are usually caused by direct mast-cell degranulation,
and may be ameliorated by prophylactic antihistamines and slowing the infusion rate.
Immediate immune-mediated (IgE) hypersensitivity reactions

Immediate IgE-mediated (allergic) hypersensitivity is characterised by a reaction ranging in severity from
mild urticaria or immediate rash to more severe reactions including extensive urticaria, compromised airway,
angioedema, hypotension, collapse or anaphylaxis. The reaction occurs soon after exposure to a drug,
typically within minutes to 2 hours. Anaphylaxis is more likely with parenteral rather than oral administration.
For penicillins, anaphylaxis occurs at an estimated rate of 1 to 4 cases per 10 000 courses. A clear history of
an IgE-mediated reaction means the drug (and sometimes related drugs) should not be administered again
unless appropriate precautions can be taken (eg according to a desensitisation protocol), or after specialist
advice on the basis of relevant skin testing followed by oral provocation.
Not all immediate hypersensitivity reactions are severe.
Delayed immune-mediated (T-cell) hypersensitivity reactions

Delayed immune-mediated hypersensitivity reactions are usually the result of T-cell (not IgE) mediated
mechanisms, and produce a range of syndromes commonly characterised by maculopapular rash (exanthem).
These reactions typically occur after more than one dose of a drug, with an onset days after starting treatment.
However, delayed immune-mediated hypersensitivity can occur more rapidly on rechallenge (within 6 hours).
Delayed hypersensitivity reactions are far more common than immediate reactions; the majority are not severe.
Delayed hypersensitivity reactions are far more common than immediate reactions. They often occur in
patients with a viral infection and can be due to the infection or a drug–virus interaction; consequently, such
reactions may not be reproducible upon a supervised challenge when the patient is well. In particular, a mild
maculopapular rash caused by a penicillin, especially amoxicillin or ampicillin, is not strongly predictive of a
future reaction and many patients tolerate the drug if it is administered at a later time.
Delayed severe reactions are uncommon but serious. They include severe cutaneous adverse reactions
(SCAR), a group of T-cell mediated hypersensitivities with cutaneous plus internal organ or mucous
membrane involvement.
Examples of delayed severe reactions:
Drug rash with eosinophilia and systemic symptoms (DRESS)—typically characterised by fever,
eosinophilia, desquamative dermatitis and liver or kidney dysfunction.
Stevens–Johnson syndrome / toxic epidermal necrolysis (SJS/TEN)—a rare, acute and potentially fatal
skin reaction caused by acute keratinocyte death, resulting in fulminant epidermal skin and epithelial
mucosal loss similar to burn injuries.
Acute generalised exanthematous pustulosis (AGEP)—characterised by dozens to hundreds of pin-sized
pustules on a background of erythema, often with fever and leucocytosis, and rarely, organ
involvement; can have a quick onset following drug administration (eg 1 day).
Acute interstitial nephritis (AIN)—a T-cell mediated hypersensitivity reaction most commonly
associated with penicillins; causes kidney dysfunction and can include eosinophilia, fever and
exanthematous rash.
Serum sickness—characterised by vasculitic or urticarial rash, arthralgia/arthritis, fever,
hypocomplementaemia and sometimes proteinuria. Serum sickness is triggered more commonly by
cefaclor than other cephalosporins, and also by sulfonamides; the onset is typically several days after
starting treatment.
Drug-induced liver disease.
A delayed severe hypersensitivity reaction is a contraindication to further drug exposure—including

desensitisation—because this can be fatal.
Further drug exposure—including desensitisation—is contraindicated following a delayed severe reaction.
Diagnosis of antimicrobial hypersensitivity

Clinical history
The clinical history is critically important in the diagnosis of antimicrobial hypersensitivity. If hypersensitivity
is reported, ask about the nature and severity of the reaction, timing, how it was managed, and whether the
patient knows if other antibiotics have been tolerated since the reaction (see Box 2.39).
Common pharmacologically predictable antimicrobial adverse reactions include gastrointestinal (eg nausea,
vomiting, diarrhoea), neurological (eg headache, dizziness) and skin effects (eg pruritus without rash, fever or
internal organ involvement); in many cases these reactions do not justify avoiding the antimicrobial in future.
A family history of antimicrobial allergy does not justify avoidance of the implicated drug.
Questions to ask in an antibiotic allergy assessment (Box 2.39)
Severity and type of reaction
1.
Do you remember the details of the reaction?
2.
How was the reaction managed? Did it require treatment or hospitalisation?
Timing
3.
How long after taking the antibiotic did the reaction occur?
4.
How many years ago did the reaction occur?
Antibiotic use since reaction
5.
Are there other antibiotics that have you taken without problems since the reaction?
Specific tests
When to do allergy testing
The role of allergy testing is largely limited to assessing patients with a history of immune-mediated
hypersensitivity. Seek expert advice if considering allergy testing.
Allergy testing is most accurate when performed as early as possible after the patient has recovered from the
acute reaction (usually at least 6 weeks after the reaction), because results may become negative over time.
Allergy tests can be negative even in patients who have true allergy; a negative test result in the presence of a
strong history can be a false negative result and requires specialist interpretation.
Skin testing
Skin testing, including skin-prick and intradermal testing with immediate reading, is the standard method used
in specialised centres to test for immediate (IgE-mediated) hypersensitivity. These tests have good sensitivity
and specificity if performed soon after the reaction, especially for phenoxymethylpenicillin, benzylpenicillin,
amoxicillin and ampicillin. Intradermal tests have better diagnostic sensitivity than skin-prick tests, but there
is a higher risk of adverse reactions.
Intradermal tests with readings after 48 to 72 hours can be used to diagnose delayed (T-cell mediated)
hypersensitivity; these tests have lower sensitivity than for immediate reactions.
Skin tests for penicillin hypersensitivity should be performed by specialists, using both the penicillin major
and minor determinants—these increase the sensitivity of testing.
In vitro tests
In the context of immediate reactions, a significant elevation of mast-cell tryptase concentration detected in a
blood sample collected 1 to 4 hours after a reaction may be helpful to identify mast-cell degranulation.
Other in vitro tests for IgE-mediated hypersensitivity are available for benzylpenicillin,
phenoxymethylpenicillin, amoxicillin and cefaclor through commercial laboratories; however, such testing is
of limited utility, with concerns about false-positive and false-negative results.
Drug provocation testing
Drug provocation testing, also called drug challenge, graded challenge or test dosing, is the controlled
administration of a drug in order to diagnose hypersensitivity. It is often used to confirm tolerance to an
antimicrobial when skin-prick or intradermal tests are negative or equivocal.
Drug provocation testing should only be performed under medical supervision, after consultation with a
specialist, in a safe environment where severe allergic reactions such as anaphylaxis can be managed, and
after obtaining informed consent from the patient.
In carefully selected patients (eg those with a history of benign rash in childhood or other delayed nonsevere
skin reaction) and with specialist advice, direct oral challenge without prior skin testing can be considered
when therapy with phenoxymethylpenicillin or amoxicillin is required. In patients with delayed nonsevere
hypersensitivity, prolonged oral provocation (5 to 7 days) following a supervised single-dose provocation is
often used to ensure true delayed hypersensitivity is not missed. Do not perform direct oral challenge without
prior skin testing in patients with a history of severe (immediate or delayed) antimicrobial allergy.
The International Consensus on Drug Allergy provides detailed information about drug provocation testing
[Note 1].
Note 1: Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International Consensus on drug allergy. Allergy
2014;69(4):420-37. [URL]
Management of patients reporting hypersensitivity to penicillins

Managing a patient who reports hypersensitivity to penicillins depends on many factors. Consider whether
antimicrobial therapy is necessary, and the balance of benefits and harms.
If the details of the reaction are not clear, take a clinical history to determine the nature and severity of the
reaction, how it was managed, and whether the patient knows if other antibiotics have been tolerated since—
see Box 2.39. A quick guide to assessing patients with reported penicillin allergy is available as a PDF to
print: Penicillin allergy assessment guide (best printed in colour).
One common scenario is a patient reporting a childhood history of penicillin allergy that is unclear. In this
situation, keep in mind that many childhood rashes associated with beta-lactam antibiotics are caused by a
viral infection or a drug–virus interaction, rather than true antibiotic allergy. These reactions are rarely severe
and patients can potentially be rechallenged under specialist guidance.
Although it is not possible to give clear guidance to cover all situations, Figure 2.14 provides a guide for
generalists to manage some common penicillin hypersensitivity scenarios. This is a simplified summary of a
complex field; the Antibiotic Expert Groups recognise that there are regional variations in how penicillin
hypersensitivity is managed, and that specialists may choose to manage their patients differently after
weighing up the benefits and harms in an individual.
When selecting an antimicrobial in a patient with penicillin hypersensitivity, it is important to understand how
R1 side-chains affect the risk of cross-reactivity between beta lactams—see Cross-reactivity between beta
lactams below.
In patients known or strongly suspected to have immediate hypersensitivity to the preferred drug for therapy,
desensitisation can be attempted in some cases to enable safe administration—see Antimicrobial
desensitisation protocols.
For management of patients with a history of cephalosporin hypersensitivity, seek expert advice.
Suggested management of patients reporting hypersensitivity to penicillins in whom a beta-

lactam antibiotic is the preferred drug (Figure 2.14)
Printable figure
NB1: In a critical situation, a cephalosporin can be considered in this group after undertaking a risk–benefit analysis and assessment of potential
side-chain cross-reactivity (see Cross-reactivity between beta lactams). Seek expert advice.
NB2: In patients with penicillin hypersensitivity, the rate of immune-mediated cross-reactivity with carbapenems is approximately 1%;
therefore, carbapenems can be considered in supervised settings. However, in patients with a history of a severe cutaneous adverse reaction (eg
drug rash with eosinophilia and systemic symptoms [DRESS], Stevens–Johnson syndrome / toxic epidermal necrolysis [SJS/TEN], acute
generalised exanthematous pustulosis [AGEP]), consider a carbapenem only in a critical situation when there are limited treatment options.
NB3: For example DRESS, SJS/TEN, AGEP.
NB4: There is limited evidence on the safety of cephalosporins in patients with a history of penicillin-associated acute interstitial nephritis
(AIN). In a critical situation, directed therapy with a cephalosporin can be considered.
NB5: In patients who have had a recent reaction, consider avoiding cephalosporins with the same or similar R1 side-chain as the implicated
penicillin (see Cross-reactivity between beta lactams).
NB6: However, avoid aztreonam in patients hypersensitive to ceftazidime; these drugs have the same R1 side-chain, so there is a risk of cross-
reactivity.
Cross-reactivity between beta lactams

Immune-mediated penicillin hypersensitivity was historically thought to be due solely to the beta-lactam ring
structure that is common to all beta-lactam antibiotics (penicillins, cephalosporins, carbapenems and
monobactams). However, recent evidence and clinical experience suggests that most reactions occur in
response to antigenic molecules in the R1 side-chain that distinguishes individual penicillins and
cephalosporins from one another. Drugs with the same or similar R1 side-chains are more likely to cross-react
(see Figure 2.15).
The prevalence of cross-reactivity between beta lactams is not known precisely. It is a common misconception
that cephalosporin allergy occurs in approximately 10% of patients who are allergic to a penicillin. However,
recent reviews show that overall, only 1 to 2% of patients with a confirmed penicillin allergy have a
cephalosporin allergy. Cross-reactivity is more likely in patients with an amoxicillin or ampicillin allergy who
receive cefalexin or cefaclor, due to their similar R1 side-chains.
Beta-lactam cross-reactivity is more likely in patients with amoxicillin or ampicillin allergy who receive cefalexin or
cefaclor, due to their similar R1 side-chains.
Cefazolin has no common side-chains with other beta lactams so is often tolerated in patients with a penicillin
or cephalosporin allergy.
Cefazolin has no common side-chains with other beta lactams so is often tolerated in penicillin or cephalosporin allergy.
In patients with penicillin allergy confirmed on testing, the rate of immune-mediated cross-reactivity with
carbapenems is approximately 1%. There is no cross-reactivity between penicillins and monobactams.
Cross-reactivity between penicillins and carbapenems is approximately 1%.
There is no cross-reactivity between penicillins and monobactams.
In settings where allergy testing is not available and a beta-lactam antibiotic is the preferred drug,
antimicrobials to avoid based on potential cross-reactivity due to identical or similar R1 side-chains are:
amoxicillin or ampicillin allergy—avoid cefalexin and cefaclor (except in delayed nonsevere

hypersensitivity; see Figure 2.14 for guidance)
ceftriaxone allergy—avoid cefotaxime, cefepime and cefuroxime
ceftazidime allergy—avoid aztreonam.
In patients with immediate severe penicillin hypersensitivity (eg anaphylaxis, angioedema), avoid penicillins
and cephalosporins in most situations; however, in a critical situation when a beta lactam is the preferred drug,
a cephalosporin can be considered after undertaking a risk–benefit analysis and assessment of potential side-
chain cross-reactivity (eg for sepsis, meningitis, endocarditis). Seek expert advice.
In patients with delayed severe penicillin hypersensitivity (eg drug rash with eosinophilia and systemic
symptoms [DRESS], Stevens–Johnson syndrome / toxic epidermal necrolysis [SJS/TEN]), do not use cross-
reactivity to guide treatment and avoid all penicillins and cephalosporins—see Figure 2.14 for guidance.
In patients with delayed severe penicillin hypersensitivity, do not use cross-reactivity to guide treatment.
Beta-lactam structure and side-chain similarity (Figure 2.15)

NB1: Penicillins have one side-chain (R1), while cephalosporins have two side-chains (R1, R2). Similarity between the R1 side-chains can
cause cross-reactivity.
Cross-reactivity between sulfonamides

Antibiotic sulfonamides (eg sulfamethoxazole, sulfadiazine, dapsone [a sulfone antibiotic closely resembling
sulfonamide antibiotics]) are often avoided in patients who are allergic to nonantibiotic sulfonamides (eg
frusemide). However, this is usually not necessary because, with one exception, there is no cross-reactivity
between antibiotic and nonantibiotic sulfonamides. (The exception is sulfasalazine, a nonantibiotic
sulfonamide that is structurally similar to sulfonamide antibiotics; avoid sulfasalazine in patients with
antibiotic sulfonamide allergy, and vice versa.)
Furthermore, evidence shows that the rate of immune-mediated cross-reactivity within the antibiotic
sulfonamide group (eg between sulfamethoxazole and dapsone) is lower (9 to 12%) than previously thought
(20%), and therefore these antibiotics could be used in a patient with a history of nonsevere allergy to another
antibiotic sulfonamide. However, this does not apply in patients with anaphylaxis or a severe cutaneous
adverse reaction such as drug rash with eosinophilia and systemic symptoms (DRESS) or Stevens–Johnson
syndrome / toxic epidermal necrolysis (SJS/TEN).
For more information about allergy to sulfonamides, including a patient information sheet, see the
Australasian Society of Clinical Immunology and Allergy (ASCIA) website.
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crucial for pseudo-allergic drug reactions. Nature 2015;519(7542):237–41.
Diagnosis of antimicrobial hypersensitivity
Bousquet PJ, Co-Minh HB, Arnoux B, Daures JP, Demoly P. Importance of mixture of minor determinants and
benzylpenicilloyl poly-L-lysine skin testing in the diagnosis of beta-lactam allergy. J Allergy Clin Immunol
2005;115(6):1314–6.
Confino-Cohen R, Rosman Y, Meir-Shafrir K, Stauber T, Lachover-Roth I, Hershko A, et al. Oral challenge without
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Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International Consensus on
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Johansson SG, Adedoyin J, van Hage M, Gronneberg R, Nopp A. False-positive penicillin immunoassay: an
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Kosnik M, Zidarn M, Korosec P. Over-reliance on assays for specific IgE in diagnostics of penicillin allergy?
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Matheu V, Perez-Rodriguez E, Sanchez-Machin I, de la Torre F, Garcia-Robaina JC. Major and minor

determinants are high-performance skin tests in beta-lactam allergy diagnosis. J Allergy Clin Immunol
2005;116(5):1167–8; author reply 8-9.
Sellaturay P, Nasser S, Ewan P. The incidence and features of systemic reactions to skin prick tests. Ann Allergy
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Tucker MH, Lomas CM, Ramchandar N, Waldram JD. Amoxicillin challenge without penicillin skin testing in
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Management of patients reporting hypersensitivity to penicillins
Blumenthal KG, Shenoy ES, Varughese CA, Hurwitz S, Hooper DC, Banerji A. Impact of a clinical guideline for
prescribing antibiotics to inpatients reporting penicillin or cephalosporin allergy. Ann Allergy Asthma Immunol
2015;115(4):294–300 e2.
Blumenthal KG, Youngster I, Shenoy ES, Banerji A, Nelson SB. Tolerability of cefazolin after immune-mediated
hypersensitivity reactions to nafcillin in the outpatient setting. Antimicrob Agents Chemother 2014;58(6):3137–43.
Confino-Cohen R, Rosman Y, Meir-Shafrir K, Stauber T, Lachover-Roth I, Hershko A, et al. Oral challenge without
skin testing safely excludes clinically significant delayed-onset penicillin hypersensitivity. J Allergy Clin Immunol
Pract 2017;5(3):669–75.
Kula B, Djordjevic G, Robinson JL. A systematic review: can one prescribe carbapenems to patients with IgE-
mediated allergy to penicillins or cephalosporins? Clin Infect Dis 2014;59(8):1113–22.
Pipet A, Veyrac G, Wessel F, Jolliet P, Magnan A, Demoly P, et al. A statement on cefazolin immediate
hypersensitivity: data from a large database, and focus on the cross-reactivities. Clin Exp Allergy
2011;41(11):1602–8.
2016;27(1):50–4.
Cross-reactivity between beta lactams
Buonomo A, Pascolini L, Rizzi A, Aruanno A, Pecora V, Ricci AG, et al. Cross-reactivity and tolerability of
ertapenem in patients with IgE-mediated hypersensitivity to beta-lactams. J Investig Allergol Clin Immunol
2016;26(2):100–5.
Campagna JD, Bond MC, Schabelman E, Hayes BD. The use of cephalosporins in penicillin-allergic patients: a
literature review. J Emerg Med 2012;42(5):612–20.
Gaeta F, Valluzzi RL, Alonzi C, Maggioletti M, Caruso C, Romano A. Tolerability of aztreonam and carbapenems
in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol 2015;135(4):972–6.
Kula B, Djordjevic G, Robinson JL. A systematic review: can one prescribe carbapenems to patients with IgE-
mediated allergy to penicillins or cephalosporins? Clin Infect Dis 2014;59(8):1113–22.
Madaan A, Li JT. Cephalosporin allergy. Immunol Allergy Clin North Am 2004;24(3):463–76, vi–vii.
Miranda A, Blanca M, Vega JM, Moreno F, Carmona MJ, Garcia JJ, et al. Cross-reactivity between a penicillin
and a cephalosporin with the same side chain. J Allergy Clin Immunol 1996;98(3):671–7.
Pichichero ME, Casey JR. Safe use of selected cephalosporins in penicillin-allergic patients: a meta-analysis.
Otolaryngol Head Neck Surg 2007;136(3):340–7.
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hypersensitivity: data from a large database, and focus on the cross-reactivities. Clin Exp Allergy
2011;41(11):1602–8.
Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Caruso C, Quaratino D. Cross-reactivity and tolerability of
aztreonam and cephalosporins in subjects with a T cell-mediated hypersensitivity to penicillins. J Allergy Clin
Immunol 2016;138(1):179–86.
Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Zaffiro A, Caruso C, et al. IgE-mediated hypersensitivity to
cephalosporins: Cross-reactivity and tolerability of alternative cephalosporins. J Allergy Clin Immunol
2015;136(3):685–91 e3.
Romano A, Gaeta F, Arribas Poves MF, Valluzzi RL. Cross-Reactivity among Beta-Lactams. Curr Allergy Asthma
Rep 2016;16(3):24.
Saxon A, Hassner A, Swabb EA, Wheeler B, Adkinson NF, Jr. Lack of cross-reactivity between aztreonam, a
monobactam antibiotic, and penicillin in penicillin-allergic subjects. J Infect Dis 1984;149(1):16–22.
Trubiano JA, Thursky KA, Stewardson AJ, Urbancic K, Worth LJ, Jackson C, et al. Impact of an Integrated
Antibiotic Allergy Testing Program on Antimicrobial Stewardship: A Multicenter Evaluation. Clin Infect Dis 2017.
Uyttebroek AP, Decuyper, II, Bridts CH, Romano A, Hagendorens MM, Ebo DG, et al. Cefazolin Hypersensitivity:
Toward Optimized Diagnosis. J Allergy Clin Immunol Pract 2016;4(6):1232–6.
Wall GC, Nayima VA, Neumeister KM. Assessment of hypersensitivity reactions in patients receiving carbapenem
antibiotics who report a history of penicillin allergy. J Chemother 2014;26(3):150–3.
Cross-reactivity between sulfonamides

Australasian Society of Clinical Immunology and Allergy (ASCIA). Sulfonamide antibiotic allergy. Sydney: ASCIA;
2016. https://www.allergy.org.au/patients/drug-allergy/sulfonamide-antibiotic-allergy.
Beumont MG, Graziani A, Ubel PA, MacGregor RR. Safety of dapsone as Pneumocystis carinii pneumonia
prophylaxis in human immunodeficiency virus-infected patients with allergy to trimethoprim/sulfamethoxazole. Am
J Med 1996;100(6):611–6.
Carr A, Penny R, Cooper DA. Efficacy and safety of rechallenge with low-dose trimethoprim-sulphamethoxazole
in previously hypersensitive HIV-infected patients. AIDS 1993;7(1):65–71.
Depta JP, Altznauer F, Gamerdinger K, Burkhart C, Weltzien HU, Pichler WJ. Drug interaction with T-cell
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Strom BL, Schinnar R, Apter AJ, Margolis DJ, Lautenbach E, Hennessy S, et al. Absence of cross-reactivity
between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med 2003;349(17):1628–35.
Pneumocystis jirovecii pneumonia prophylaxis in hematology malignancy and transplant recipients. Transpl Infect
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Zawodniak A, Lochmatter P, Beeler A, Pichler WJ. Cross-reactivity in drug hypersensitivity reactions to

sulfasalazine and sulfamethoxazole. Int Arch Allergy Immunol 2010;153(2):152–6.
Antimicrobial desensitisation protocols
Introduction to antimicrobial desensitisation protocols
Drug desensitisation renders mast cells temporarily unresponsive so that a patient with a history of
antimicrobial hypersensitivity can receive the drug. Desensitisation remains effective while the patient is
continuously exposed to the drug; hypersensitivity returns soon after the drug is cleared from the body
(typically after five drug half-lives).
Desensitisation remains effective while the patient is continuously exposed to the drug—hypersensitivity returns soon after
the drug is cleared from the body.
Drug desensitisation is predominantly used in patients with a history of IgE-mediated immediate

hypersensitivity (see Types of antimicrobial hypersensitivity) for whom there are no appropriate alternative
antimicrobials, or when a particular antimicrobial is the preferred drug (eg benzylpenicillin for streptococcal
endocarditis). Desensitisation has also been used to induce drug tolerance in patients with other types of
reactions (eg nonsevere T-cell mediated reactions such as rash related to trimethoprim+sulfamethoxazole).
Desensitisation has been best validated for penicillins, but it has also been described for other antimicrobials.
This topic includes desensitisation protocols for adults for:
phenoxymethylpenicillin
benzylpenicillin
amoxicillin
trimethoprim+sulfamethoxazole
a generic beta-lactam desensitisation protocol that can be adapted for different beta-lactam antibiotics.
Protocols for other antimicrobials (eg quinolones, macrolides, vancomycin, clindamycin, pentamidine,
antituberculosis drugs) have undergone limited clinical testing. Consult a specialist in immunology or drug
allergy to discuss any desensitisation protocol that has not been clinically validated.
Desensitisation is usually performed using the drug that is needed for treatment.
Desensitisation is usually performed using the drug that is needed for treatment; however,
phenoxymethylpenicillin can be used to desensitise to benzylpenicillin, and amoxicillin can be used to
desensitise to ampicillin.
Drug desensitisation can be carried out in children—seek expert advice.
Precautions for antimicrobial desensitisation

Type of hypersensitivity
Desensitisation is contraindicated in patients with a history of delayed severe immune-mediated

hypersensitivity, including:
drug rash with eosinophilia and systemic symptoms (DRESS)

Stevens–Johnson syndrome / toxic epidermal necrolysis (SJS/TEN)
acute generalised exanthematous pustulosis (AGEP)
acute interstitial nephritis
drug-induced liver injury
haemolytic anaemia.
Desensitisation is contraindicated in patients with a history of delayed severe immune-mediated hypersensitivity.

Setting of desensitisation
Desensitisation should be performed in a hospital setting, where the patient can be closely monitored and
resources to manage anaphylaxis and threatened airway are available, including experienced staff, intravenous
access, medications and equipment.
In patients with a history of life-threatening drug hypersensitivity, including anaphylaxis during

previous desensitisation, consider performing desensitisation in the intensive care unit.
In patients with non–life-threatening drug hypersensitivity (eg delayed rash associated with
trimethoprim+sulfamethoxazole), oral desensitisation may be performed in an outpatient setting with
regular observation and specialist oversight, provided resuscitation facilities are available.
Role of premedication
The role of premedication with an antihistamine or corticosteroid is unclear. Although premedication reduces
the risk of a hypersensitivity reaction during desensitisation, it can mask early signs of a reaction and delay
management. Consider premedication (eg a single dose of prednis(ol)one 0.25 to 0.5 mg/kg orally) in higher-
risk cases, such as a person who has had an anaphylactic reaction during desensitisation in the past.
Management of reactions during desensitisation

Specialist advice is required for management of hypersensitivity reactions that occur during desensitisation.
Minor reactions (eg itch, urticaria, rash or rhinorrhoea)—suspend the desensitisation protocol and discuss
with the medical team. The same dose can be repeated until it is tolerated, or the dose can be escalated more
slowly. Supportive treatment (eg antihistamine, oral corticosteroid, salbutamol) may be required.
Life-threatening reactions (eg anaphylaxis, bronchospasm, angioedema, hypotension)—stop the

desensitisation protocol and reconsider alternative antimicrobial therapy. If an alternative is not available,
resume desensitisation once the patient has been treated and is clinically stable, starting at one-tenth the
previous dose and increasing at one-half the previous rate.
Maintenance dosing
Once the therapeutic antimicrobial dosage has been attained, do not interrupt treatment. Hypersensitivity will
return soon after the drug is cleared from the body (typically after five drug half-lives).
Patient counselling
Ensure patients who have received antimicrobial desensitisation and finished their course of therapy
understand that the effect of desensitisation is temporary and that they are still allergic to the drug. It is also
important to communicate this to the patient’s general practitioner. Counsel the patient to avoid the drug in
future, and that repeat desensitisation must be performed if the drug is required again.
Ensure patients understand that the effect of desensitisation is temporary.
Phenoxymethylpenicillin desensitisation protocol for adults (oral)

A rapid oral phenoxymethylpenicillin desensitisation protocol is shown in Table 2.65. Use this protocol when
the drug required for treatment is phenoxymethylpenicillin or benzylpenicillin.
Oral desensitisation with phenoxymethylpenicillin can be used even if subsequent therapy will be with
parenteral benzylpenicillin, and is recommended because it is considered safer than intravenous
desensitisation.
Before starting desensitisation, see Precautions for antimicrobial desensitisation.
Rapid oral phenoxymethylpenicillin desensitisation protocol for adults (Table 2.65)
Step (at 15-minute Phenoxymethyl- Volume (mL) Dose (mg) Cumulative dose
intervals) penicillin (mg)
suspension
(mg/mL)
1 0.5 0.1 0.05 0.05
2 0.5 0.2 0.1 0.15
3 0.5 0.4 0.2 0.35
4 0.5 0.8 0.4 0.75
5 0.5 1.6 0.8 1.55
6 0.5 3.2 1.6 3.15
7 0.5 6.4 3.2 6.35
8 5.0 1.2 6 12.35
9 5.0 2.4 12 24.35
10 5.0 4.8 24 48.35
11 50 1 50 98.35
12 50 2 100 198.35
13 50 4 200 398.35
14 50 8 400 798.35
Observe for 30 minutes; if no reaction occurs, administer phenoxymethylpenicillin 500
15 mg orally or benzylpenicillin 1.2 g intravenously. Start therapy with the required drug
at the standard dosage for the indication.
Benzylpenicillin desensitisation protocol for adults (intravenous)

A rapid intravenous benzylpenicillin desensitisation protocol is shown in Table 2.66.
When benzylpenicillin treatment is required, desensitisation can be performed with either

phenoxymethylpenicillin or benzylpenicillin. Intravenous desensitisation is more likely to cause anaphylaxis
than oral desensitisation, so oral phenoxymethylpenicillin desensitisation is preferred.
Rapid intravenous benzylpenicillin desensitisation protocol for adults (Table 2.66)
Step (at 15-minute Benzylpenicillin Volume (mL) Dose (mg) Cumulative dose
intervals) solution (mg/mL) (mg)
[NB1]
1 0.1 0.1 0.01 0.01
2 0.1 0.2 0.02 0.03
3 0.1 0.4 0.04 0.07
4 0.1 0.8 0.08 0.15
5 1 0.16 0.16 0.31
6 1 0.32 0.32 0.63
7 1 0.64 0.64 1.27
8 10 0.12 1.2 2.47
9 10 0.24 2.4 4.87
10 10 0.48 4.8 10
11 100 0.1 10 20
12 100 0.2 20 40
13 100 0.4 40 80
14 100 0.8 80 160
15 100 1.6 160 320
16 100 3.2 320 640
17 100 6.4 640 1280
Observe for 30 minutes; if no reaction occurs, administer benzylpenicillin 1.2 g
18
intravenously. Start therapy at the standard dosage for the indication.
NB1: Dilute reconstituted solution in sodium chloride 0.9%.
Amoxicillin desensitisation protocol for adults (oral)

A rapid oral amoxicillin desensitisation protocol is shown in Table 2.67. Use this protocol when the drug
required for treatment is amoxicillin or ampicillin.
Oral desensitisation with amoxicillin can be used even if subsequent therapy will be with parenteral
amoxicillin or ampicillin, and is recommended because it is safer than intravenous desensitisation.
Rapid oral amoxicillin desensitisation protocol for adults (Table 2.67)
Step (at 15-minute Amoxicillin Volume (mL) Dose (mg) Cumulative dose
intervals) suspension (mg)
(mg/mL)
1 0.5 0.1 0.05 0.05
2 0.5 0.2 0.1 0.15
3 0.5 0.4 0.2 0.35
4 0.5 0.8 0.4 0.75
5 0.5 1.6 0.8 1.55
6 0.5 3.2 1.6 3.15
7 0.5 6.4 3.2 6.35
8 5 1.2 6 12.35
9 5 2.4 12 24.35
10 5 4.8 24 48.35
11 50 1 50 98.35
12 50 2 100 198.35
13 50 4 200 398.35
14 50 8 400 798.35
Observe for 30 minutes; if no reaction occurs, administer amoxicillin 1 g orally or
15 intravenously, or ampicillin 1 g intravenously. Start therapy with the required drug at
the standard dosage for the indication.
Trimethoprim+sulfamethoxazole desensitisation protocol for adults

(oral)
The most common hypersensitivity reaction to sulfonamides is a delayed skin reaction characterised by
erythema, maculopapular or morbilliform rash, urticaria and pruritus. In most cases the immunological
mechanism involved is unknown, but it is not thought to be IgE-mediated.
Pneumocystis jirovecii pneumonia is the most common infection for which sulfonamide therapy is required
despite a history of sulfonamide allergy.
Keep in mind that allergy to most nonantibiotic sulfonamides (eg frusemide) does not imply allergy to
antibiotic sulfonamides (eg sulfamethoxazole). In patients who are allergic to a nonantibiotic sulfonamide
(with the exception of sulfasalazine), an antibiotic sulfonamide can be used without the need for
desensitisation (see Cross-reactivity between sulfonamides for more detail).
An oral trimethoprim+sulfamethoxazole desensitisation protocol is shown in Table 2.68. Oral desensitisation

with trimethoprim+sulfamethoxazole can be used even if subsequent therapy will be parenteral, and is
recommended because it is safer than intravenous desensitisation.
Rapid oral trimethoprim+sulfamethoxazole desensitisation protocol for adults (Table 2.68)
Step (at 1-hour Trimethoprim+sulfamethoxazole Amount Sulfamethoxazole Cumulative

intervals) preparation dose (mg) sulfamethoxazole
dose (mg)
suspension [NB1] diluted 1:2000
1 (at 0 hours) 1 mL 0.02 0.02
(0.004+0.02 mg/mL)
2 (at 1 hour) 1 mL 0.2 0.22
(0.04+0.2 mg/mL)
3 (at 2 hours) suspension [NB1] diluted 1:20 1 mL 2 2.22
(0.4+2 mg/mL)
4 (at 3 hours) 1 mL 20 22.22
(4+20 mg/mL)
undiluted suspension (8+40
5 (at 4 hours) 5 mL 200 222.22
mg/mL)
6 (at 5 hours)
tablet (160+800 mg) 1 tablet 800 1022.22
[NB2]
7 (at 6 hours)
tablet (160+800 mg) 2 tablets 1600 2622.22
[NB3]
NB1: Use trimethoprim+sulfamethoxazole 40+200 mg per 5 mL suspension.
NB2: If the therapeutic dose will be 1 tablet (160+800 mg strength), stop at step 6. Two hours later, administer 1 tablet and then continue
therapy at the usual dosing interval. For prophylaxis of Pneumocystis jirovecii pneumonia or Toxoplasma gondii encephalitis in
immunocompromised patients, use one of the daily treatment regimens rather than the 3 times weekly regimen (see Opportunistic and co-
infections in adults with HIV infection and Primary prophylaxis in immunocompromised adults without HIV infection).
NB3: If the therapeutic dose will be 2 tablets (160+800 mg strength), stop at step 7. Two hours later, administer 2 tablets and then continue
therapy at the usual dosing interval.
Generic desensitisation protocol for beta-lactam antibiotics in adults

(intravenous)
While the commonly used drugs for desensitisation are phenoxymethylpenicillin, benzylpenicillin,
amoxicillin and trimethoprim+sulfamethoxazole, desensitisation can also be undertaken with other drugs (eg
flucloxacillin), using protocols based on local clinical experience.
An example of a generic intravenous desensitisation protocol culminating in a 1 g or 2 g therapeutic dose is

given in Table 2.69; drug doses are administered as short infusions. This protocol can be used for beta-lactam
antibiotic desensitisation in adults. Consult a specialist in immunology or drug allergy to discuss any protocol
that has not been clinically validated.
Example of a generic intravenous desensitisation protocol for beta-lactam antibiotics in

adults (Table 2.69)
Step [NB1] Solution for infusion [NB2] Total volume and Dose (mg) Cumulative
infusion time dose (mg)
Stock solution A: 4 mg/mL of drug
0.25 mL stock solution A and
1 30 mL over 15 minutes 1 1
29.75 mL diluent
0.5 mL stock solution A and
29.5 mL diluent
1 mL stock solution A and 29
mL diluent
mL diluent
mL diluent
mL diluent
mL diluent
mL diluent
Stock solution B: 100 mg/mL of drug
2.5 mL stock solution B and
47.5 mL diluent
5 mL stock solution B and 45
10 50 mL over 15 minutes 500 1005
mL diluent
10 mL stock solution B and 40 50 mL over 30 minutes
11 1000 2005
mL diluent [NB3]
12 [NB4] 20 mL stock solution B and 30 50 mL over 30 minutes 2000 4005
mL diluent [NB3]
Observe for 30 minutes; if no reaction occurs, start therapy with the standard dosage for the
13
indication.
NB1: Drug doses are administered as short infusions. Perform patient observations at the end of each infusion; if stable, proceed with the next step.
NB2: Mix stock solution with diluent (sodium chloride 0.9% injection or glucose 5% injection, depending on drug compatibility), in a 50 mL
syringe.
NB3: Administer over 30 minutes unless the Product Information for the drug recommends administration over a longer period for therapeutic
doses.
NB4: Step 12 is only required if the therapeutic dose will be more than 2 g (eg piperacillin+tazobactam 4+0.5 g).
Key references
Candela L. Caring for a patient with Listeria endocarditis: use of antibiotic desensitization. Crit Care Nurse
2002;22(5):38–43.
Castells M. Rapid desensitization for hypersensitivity reactions to medications. Immunol Allergy Clin North Am
2009;29(3):585–606.
Cernadas JR, Brockow K, Romano A, Aberer W, Torres MJ, Bircher A, et al. General considerations on rapid
desensitization for drug hypersensitivity - a consensus statement. Allergy 2010;65(11):1357–66.
Legendre DP, Muzny CA, Marshall GD, Swiatlo E. Antibiotic hypersensitivity reactions and approaches to
desensitization. Clin Infect Dis 2014;58(8):1140–8.
Legere HJ, 3rd, Palis RI, Rodriguez Bouza T, Uluer AZ, Castells MC. A safe protocol for rapid desensitization in
patients with cystic fibrosis and antibiotic hypersensitivity. J Cyst Fibros 2009;8(6):418–24.
O'Donovan WJ, Klorfajn I. Sensitivity to penicillin; anaphylaxis and desensitisation. Lancet 1946;2(6422):444–6.
Pyle RC, Butterfield JH, Volcheck GW, Podjasek JC, Rank MA, Li JT, et al. Successful outpatient graded
administration of trimethoprim-sulfamethoxazole in patients without HIV and with a history of sulfonamide adverse
drug reaction. J Allergy Clin Immunol Pract 2014;2(1):52–8.
Strom BL, Schinnar R, Apter AJ, Margolis DJ, Lautenbach E, Hennessy S, et al. Absence of cross-reactivity
between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med 2003;349(17):1628–35.
Sullivan TJ, Yecies LD, Shatz GS, Parker CW, Wedner HJ. Desensitization of patients allergic to penicillin using
orally administered beta-lactam antibiotics. J Allergy Clin Immunol 1982;69(3):275–82.
Urbancic KF, Ierino F, Phillips E, Mount PF, Mahony A, Trubiano JA. Taking the challenge: A protocolized
approach to optimize Pneumocystis pneumonia prophylaxis in renal transplant recipients. Am J Transplant
2018;18(2):462–6.
Practical information on using antibacterial drugs
This topic covers practical information on using the antibacterial drugs recommended in these guidelines. For
comprehensive drug information, including precautions, contraindications, adverse effects and drug
interactions, consult an appropriate drug information resource. If prescribing an antibacterial drug, consider
the benefit–harm profile of the drug in the individual patient.
Practical information on using aminoglycosides

Aminoglycosides are rapidly bactericidal and are used to treat infections caused by aerobic Gram-negative
bacteria. For information on the role of aminoglycosides in treating infection, and aminoglycoside dosing and
monitoring, see Principles of aminoglycoside use.
Gentamicin is active against most aerobic Gram-negative bacteria, including Pseudomonas aeruginosa—
approximately 95% of aerobic Gram-negative isolates remain susceptible to gentamicin. Gentamicin is
preferred for most infections for which a parenteral aminoglycoside is indicated.
Tobramycin is marginally more active than gentamicin against P. aeruginosa, but not against other aerobic
Gram-negative bacteria. It is inactivated by a similar range of bacterial enzymes as gentamicin.
Amikacin is more resistant to bacterial enzymatic inactivation than gentamicin or tobramycin, so it should
generally be reserved for treating infections resistant to other aminoglycosides.
Kanamycin, along with amikacin, has largely replaced streptomycin in the treatment of resistant
mycobacterial infections, because of higher rates of susceptibility and better availability. However, kanamycin
is inferior to other aminoglycosides against aerobic Gram-negative bacteria. Capreomycin has also been used
for multidrug-resistant tuberculosis.
For information on paromomycin, see Practical information on using paromomycin.
Framycetin is used topically for superficial ear infections (in combination with other drugs) and eye
infections. Framycetin eye drops can cause can cause contact hypersensitivity reactions, which can be severe.
Neomycin is used topically for superficial ear infections (in combination with other drugs). It may be used, in
combination with other interventions, as an oral nonabsorbable antibiotic for surgical prophylaxis for elective
colorectal resections.
If possible, avoid ear drops containing an aminoglycoside (eg framycetin, neomycin) in patients with a
perforated tympanic membrane or a tympanostomy tube in situ because of the risk of inner ear damage;
however, this complication appears to be rare. It is also preferable to avoid aminoglycosides if the tympanic
membrane cannot be visualised, in case it is perforated.
Practical information on using beta lactams: introduction

The beta-lactam antibiotics are penicillins, cephalosporins, carbapenems and aztreonam—these antibiotics
have a beta-lactam ring in their structure.
Beta lactams have a wide therapeutic index. In the majority of patients, beta lactams do not cause significant
adverse effects; however, some patients are hypersensitive to one or more beta lactams (see Antimicrobial
hypersensitivity).
For information on monitoring beta-lactam plasma concentrations, see Monitoring beta lactams.
Practical information on using beta lactams: aztreonam

Aztreonam is a monobactam that is active against the majority of aerobic Gram-negative bacteria, including
beta-lactamase–producing Haemophilus influenzae, Enterobacteriaceae (enteric Gram-negative bacilli) and
Pseudomonas aeruginosa. It is sensitive to inactivation by extended-spectrum beta-lactamase enzymes
(ESBLs), but resistant to metallo-carbapenemase enzymes. Aztreonam is inactive against anaerobic Gram-
negative bacteria, and all Gram-positive bacteria.
Practical information on using beta lactams: carbapenems

Carbapenems are broad-spectrum antibacterial drugs with activity against many strains of Gram-negative
bacteria that are resistant to other drug classes. However, widespread use of carbapenems is linked to an
increasing prevalence of infections caused by methicillin-resistant Staphylococcus aureus (MRSA),
vancomycin-resistant enterococci (VRE), multidrug-resistant Gram-negative bacteria and Clostridium
difficile. Furthermore, carbapenem resistance is emerging worldwide, often due to the production of various
carbapenemase enzymes, which also confer resistance to other antibiotics. Therefore, the use of carbapenems
should be reserved.
Imipenem and meropenem have broad activity against Enterobacteriaceae (enteric Gram-negative bacilli),
including isolates that produce extended-spectrum beta-lactamase enzymes (ESBLs), and Pseudomonas
aeruginosa; this activity is comparable to that of aminoglycosides. They also have excellent activity against
anaerobic Gram-negative bacteria (including Bacteroides fragilis), and many Gram-positive bacteria
(including Nocardia species). Imipenem has activity against Enterococcus faecalis, which meropenem lacks.
Imipenem is formulated in combination with the renal dipeptidase enzyme inhibitor, cilastatin, to prevent
inactivation. High-dose meropenem achieves adequate concentrations in the cerebrospinal fluid and has a
lower incidence of seizures than imipenem.
Ertapenem has a similar spectrum of activity to the other carbapenems, but has poor activity against P.
aeruginosa, E. faecalis and Acinetobacter species.
Carbapenems are inactive against MRSA, VRE, Enterococcus faecium, Mycoplasma species, Chlamydia
species and Stenotrophomonas maltophilia.
Practical information on using beta lactams: cephalosporins

Introduction to cephalosporins
Widespread use of cephalosporins is linked to an increasing prevalence of infections caused by methicillin-
resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), multidrug-resistant
Gram-negative bacteria and Clostridium difficile.
Moderate-spectrum cephalosporins: cefalexin, cefalotin and cefazolin
Cefalexin, cefalotin and cefazolin have a similar spectrum of antibacterial activity. In terms of Gram-positive
activity, they are active against streptococci and staphylococci, including beta-lactamase–producing
(penicillin-resistant) staphylococci, but inactive against methicillin-resistant Staphylococcus aureus (MRSA),
enterococci and Listeria monocytogenes. They are active against a narrow range of aerobic Gram-negative
bacteria, including wild-type Escherichia coli and some Klebsiella species, but have no activity against
anaerobic Gram-negative bacteria, including Bacteroides fragilis.
Clinical failures with cefazolin for S. aureus infections have been reported. These failures may be due to
cefazolin hydrolysis caused by S. aureus isolates that produce beta-lactamase enzyme subtypes that hydrolyse
cefazolin, but not cefalotin or antistaphylococcal penicillins (eg flucloxacillin). Cefazolin hydrolysis has been
observed in vitro when using a high bacterial inoculum of S. aureus (which theoretically correlates to
infection with a high bacterial burden). For these reasons, cefalotin has been preferred for severe
staphylococcal infections. However, increased rates of clinical failure with cefazolin have not been observed
in large cohort studies and the prevalence of S. aureus isolates that hydrolyse cefazolin in Australia is
unknown.
Cefazolin has replaced cefalotin in these guidelines because cefazolin is no less effective than cefalotin and
the short half-life of cefalotin makes it inadequate for the treatment of Gram-negative infections.
Moderate-spectrum cephalosporins with anti-Haemophilus activity: cefuroxime and

cefaclor
Cefuroxime and cefaclor have marginally broader Gram-negative activity than cephalexin, cefalotin and
cefazolin.
Cefuroxime has replaced cefaclor in these guidelines because cefaclor has inferior activity against
Streptococcus pneumoniae and is more likely to cause serum sickness–like syndrome, particularly in children.
For oral treatment of respiratory tract infections, cefuroxime is preferred to cefalexin because of its superior
activity against S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis.
Moderate-spectrum cephalosporin with antianaerobic activity: cefoxitin
Cefoxitin has significant activity against anaerobic bacteria—more than 80% of Bacteroides species are
susceptible. However, cefoxitin is rarely recommended in these guidelines because metronidazole provides
superior activity against most anaerobic bacteria.
Broad-spectrum cephalosporins: cefotaxime and ceftriaxone
Cefotaxime and ceftriaxone are broad-spectrum antibacterial drugs with activity against the majority of
community-associated Enterobacteriaceae (enteric Gram-negative bacilli); they are not active against
Pseudomonas aeruginosa. Cefotaxime and ceftriaxone are less active against staphylococci than cefazolin and
cefalotin, and are inactive against methicillin-resistant Staphylococcus aureus (MRSA). Although cefotaxime
has better intrinsic activity against staphylococci than ceftriaxone, the antistaphylococcal activity of both
drugs is dose dependent; at lower doses or for serious infections, co-administration with flucloxacillin for
empirical therapy of staphylococcal infections may be recommended. Cefotaxime and ceftriaxone do not have
clinically useful activity against enterococci.
Some Gram-negative bacteria (eg Serratia, Citrobacter and Enterobacter species) have innate chromosomal
resistance in the form of cephalosporinase enzymes. These enzymes may be constitutively expressed (always
produced), or be inducible (increased production on exposure), in which case resistance can develop during
treatment. Plasmid-mediated extended-spectrum beta-lactamase enzymes (ESBLs) acquired by some Gram-
negative bacteria (commonly strains of Escherichia coli or Klebsiella pneumoniae) also inactivate cefotaxime
and ceftriaxone.
Unlike cefazolin and cefalotin, cefotaxime and ceftriaxone are effective for meningitis because (in the
presence of meningeal inflammation) they achieve therapeutic concentrations in the cerebrospinal fluid.
There is a risk of harm associated with using ceftriaxone in neonates—it is highly protein bound and can
displace bilirubin from albumin, increasing the risk of bilirubin encephalopathy. If using ceftriaxone in
neonates, this potential harm must be balanced against the potential benefit of therapy.
To avoid precipitation, do not mix ceftriaxone with calcium-containing intravenous solutions. Ceftriaxone is
contraindicated in neonates (up to 28 days old) who are receiving intravenous calcium-containing solutions
because this has caused fatalities. In other age groups, ceftriaxone must not be administered simultaneously
with intravenous calcium-containing preparations, but can be administered sequentially, provided the infusion
lines are thoroughly flushed with a compatible fluid between infusions.
Broad-spectrum cephalosporins with antipseudomonal activity: ceftazidime and

cefepime
Ceftazidime and cefepime have an extended spectrum of activity, which includes activity against the majority
of Enterobacteriaceae (enteric Gram-negative bacilli) and Pseudomonas aeruginosa. Both drugs are
inactivated by extended-spectrum beta-lactamase enzymes (ESBLs), and ceftazidime may be inactivated by
cephalosporinase enzymes (see Broad-spectrum cephalosporins: cefotaxime and ceftriaxone for examples of
bacteria that produce these enzymes). Cefepime is more active than ceftazidime against Gram-positive
bacteria.
Broad-spectrum cephalosporin with anti-MRSA activity: ceftaroline
Ceftaroline has good activity against Gram-positive aerobic bacteria and is the only cephalosporin active
against methicillin-resistant Staphylococcus aureus (MRSA). Ceftaroline has variable activity against Gram-
negative aerobic bacteria and Gram-positive and Gram-negative anaerobic bacteria.
Practical information on using beta lactams: penicillins

Narrow-spectrum penicillins: benzylpenicillin, benzathine benzylpenicillin, procaine
benzylpenicillin and phenoxymethylpenicillin
Narrow-spectrum penicillins are mainly active against Gram-positive bacteria, but are inactivated by beta-
lactamase enzymes. Most Staphylococcus aureus strains produce beta-lactamase enzymes, and isolates should
only be considered penicillin-susceptible (ie susceptible to the narrow-spectrum penicillins, benzylpenicillin
and phenoxymethylpenicillin) if susceptibility is confirmed by a clinical microbiologist.
Benzylpenicillin (penicillin G) remains the treatment of choice for susceptible infections in which parenteral
therapy is required (such as pneumococcal pneumonia) because of its narrow spectrum of activity.
Benzathine benzylpenicillin and procaine benzylpenicillin are given intramuscularly. A dose of benzathine
benzylpenicillin provides low blood concentrations of benzylpenicillin for up to 4 weeks. A dose of procaine
benzylpenicillin maintains an effective blood concentration of benzylpenicillin for up to 24 hours.
Phenoxymethylpenicillin (penicillin V) is given orally; food impairs absorption. It is intrinsically less active
than benzylpenicillin.
Narrow-spectrum penicillins with antistaphylococcal activity: dicloxacillin and

flucloxacillin
Dicloxacillin and flucloxacillin are stable to beta-lactamase enzymes produced by staphylococci, including
penicillin-resistant, methicillin-susceptible Staphylococcus aureus (MSSA). They are also active against
streptococci, so are recommended as first-line treatment for many skin and soft tissue infections.
Food impairs the absorption of of dicloxacillin and flucloxacillin. Ideally, they should be dosed at 6-hourly
intervals, but for practical purposes (eg in children) four-times-daily dosing, evenly spaced during waking
hours, is often used.
Flucloxacillin is usually well tolerated; rarely, it is associated with cholestatic jaundice, particularly in older
patients on prolonged therapy. Cholestatic jaundice can occur after oral or intravenous administration, and up
to 6 weeks after treatment. Dicloxacillin appears to cause less irreversible hepatotoxicity, but causes more
interstitial nephritis. Dicloxacillin may be preferable to flucloxacillin for patients requiring prolonged oral
therapy.
Moderate-spectrum penicillins: amoxicillin and ampicillin
The aminopenicillins, amoxicillin and ampicillin, have better activity than benzylpenicillin against some
Gram-negative bacteria (eg Escherichia coli, Haemophilus influenzae), but are inactivated by strains that
produce beta-lactamase enzymes. They are the drugs of choice for enterococcal infections. Amoxicillin is
preferred to phenoxymethylpenicillin for oral treatment of Streptococcus pneumoniae infections because
amoxicillin has a longer half-life, leading to higher overall drug exposure.
When given orally, amoxicillin is better absorbed, less affected by food, and requires fewer daily doses than
ampicillin. When given parenterally, they are equivalent.
Broad-spectrum penicillins (beta-lactamase inhibitor combinations):

amoxicillin+clavulanate and piperacillin+tazobactam
The beta-lactamase enzyme inhibitors, clavulanate and tazobactam, have little inherent antibacterial activity;
they inhibit the beta-lactamase enzymes produced by Staphylococcus aureus, Bacteroides fragilis and
Haemophilus influenzae, and some of the beta-lactamase enzymes produced by Escherichia coli and
Klebsiella species. They are used in combination with amoxicillin (clavulanate) or piperacillin
(tazobactam) to significantly broaden the spectrum of activity of these antibiotics.
Beta-lactamase inhibitor combinations should be reserved for infections caused by bacteria that produce beta-
lactamase enzymes. Additional treatment for anaerobic bacteria (eg metronidazole) is usually not required
with beta-lactamase inhibitor combinations.
Piperacillin is only available in combination with tazobactam. Piperacillin is the only penicillin that has
activity against Pseudomonas aeruginosa; when used to treat P. aeruginosa, it must be dosed 6-hourly.
For some indications, there is limited clinical evidence to support the commonly used dose of oral
amoxicillin+clavulanate (875+125 mg orally, 12-hourly); despite this, it is widely used in practice without
notable clinical failures. However, pharmacokinetic/pharmacodynamic modelling suggests a higher dose of
amoxicillin is required to achieve adequate time above the minimum inhibitory concentration (MIC) for
pathogens with an MIC above 1 mg/L. If a higher dose of amoxicillin is desired, seek expert advice for an
appropriate regimen.
Intravenous amoxicillin+clavulanate has an emerging role in Australia and is recommended for a limited
number of infections in the guidelines.
Practical information on using chloramphenicol

Chloramphenicol is a broad-spectrum antibiotic active against many Gram-positive and Gram-negative
bacteria.
Systemic chloramphenicol is rarely used because it can cause bone marrow suppression, and is not widely
available. Chloramphenicol is available as a topical preparation for eye or ear infections, but should not be
used if infection with Pseudomonas aeruginosa is suspected because it is ineffective against this organism.
Chloramphenicol eye drops can cause contact hypersensitivity reactions, which may be severe.
Practical information on using colistimethate sodium

Colistimethate sodium (colistin) is a polymyxin antibiotic with bactericidal activity against many strains
of Gram-negative bacteria that are resistant to other drug classes, including strains of Pseudomonas
aeruginosa and Acinetobacter baumannii.
Colistimethate sodium should only be used with expert supervision. Dosing of intravenous colistimethate
sodium is complex and dosing recommended in the product information is not appropriate [Note 1].
Note 1: Suggested dosing for critically ill patients is described in: Nation RL, Garonzik SM, Thamlikitkul V, Giamarellos-Bourboulis EJ, Forrest
A, Paterson DL, et al. Dosing guidance for intravenous colistin in critically-ill patients. Clin Infect Dis 2017;64(5):565-71. [URL]
Practical information on using daptomycin

Daptomycin is only active against Gram-positive bacteria, including most strains of methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). It has a similar spectrum of
activity to the glycopeptides.
Daptomycin is not recommended for the treatment of pneumonia because it is inactivated by pulmonary
surfactant.
Myopathy is an adverse effect of daptomycin. In patients treated with daptomycin, measure plasma creatine
kinase concentration at least once weekly, or more frequently if the patient has renal impairment (creatinine
clearance less than 30 mL/minute) or is receiving concomitant drugs associated with myopathy (eg statins).
Practical information on using fidaxomicin

Fidaxomicin is a macrocyclic antibiotic used for recurrent or refractory Clostridium difficile infection.
Fidaxomicin is not systemically absorbed and adverse effects are usually limited to the gastrointestinal tract.
Practical information on using folic acid antagonists: trimethoprim

and sulfamethoxazole
Trimethoprim and sulfamethoxazole (a sulfonamide) act by inhibiting bacterial folate production.
The combination of trimethoprim+sulfamethoxazole (cotrimoxazole) should be restricted to indications for

which the combination is more effective than trimethoprim alone. This includes treatment and prophylaxis of
Pneumocystis jirovecii pneumonia (PJP), and treatment of community-associated methicillin-resistant
Staphylococcus aureus (CA-MRSA), Burkholderia pseudomallei, Listeria monocytogenes and Nocardia
infections. For treatment and prophylaxis of some infections (eg uncomplicated urinary tract infection),
trimethoprim alone is as effective as trimethoprim+sulfamethoxazole.
Avoid trimethoprim+sulfamethoxazole in neonates (up to 1 month old) because of the risk of kernicterus
(precipitated by the displacement of bilirubin from albumin by sulfonamides).
Some patients are hypersensitive to sulfonamide antibiotics (see Antimicrobial hypersensitivity).

Trimethoprim inhibits tubular secretion of creatinine, which can elevate serum creatinine without any true
decrease in glomerular filtration rate. Trimethoprim also inhibits tubular excretion of potassium and can cause
hyperkalaemia. Monitor serum potassium after 3 days of treatment with trimethoprim in patients at increased
risk of hyperkalaemia (eg patients with renal impairment, patients who are taking a high dose of trimethoprim
or other drugs that can cause hyperkalaemia).
Dapsone is also a folic acid antagonist; see Practical information on using antimycobacterial drugs for
information on dapsone.
Practical information on using fosfomycin

Fosfomycin has activity against many strains of multidrug-resistant Gram-negative bacteria, including isolates
that produce extended-spectrum beta-lactamase enzymes (ESBLs), but is inactive against Pseudomonas
aeruginosa.
In these guidelines, oral fosfomycin is reserved for the treatment of multidrug-resistant urinary tract infections
to reduce the risk of resistance to fosfomycin developing. Oral fosfomycin is not suitable for the treatment of
pyelonephritis because it does not achieve adequate concentrations in kidney tissue.
Practical information on using fusidate sodium

Fusidate sodium (fusidic acid, sodium fusidate) is a narrow-spectrum antibacterial drug, mainly active against
Staphylococcus aureus.
Fusidate sodium should always be used concomitantly with other antibiotics because resistance develops
readily. It should not be used topically.
Practical information on using glycopeptides

The glycopeptides, teicoplanin and vancomycin, are active against a wide range of Gram-positive bacteria;
Gram-negative bacteria are not susceptible.
The primary indication for parenteral glycopeptides is treatment of infection with methicillin-resistant
Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (eg Staphylococcus
epidermidis) and Enterococcus faecium. Glycopeptides are sometimes used for prophylaxis of these
infections. They also have a role in the treatment and prophylaxis of infection in patients hypersensitive to
penicillins (see Management of patients reporting hypersensitivity to penicillins).
Teicoplanin and vancomycin are associated with selection of glycopeptide-resistant bacteria (eg vancomycin-
resistant enterococci [VRE], vancomycin-intermediate S. aureus [VISA]). If a glycopeptide is indicated,
vancomycin is preferred to teicoplanin because of greater clinical experience with its use and lower likelihood
of resistance developing. In some centres, teicoplanin is used as an alternative to vancomycin because, unlike
vancomycin, it does not require a long infusion.
Oral vancomycin is used to treat Clostridium difficile infection. In patients with severe disease, particularly in
the presence of ileus, vancomycin can be given as a retention enema in addition to oral therapy. Intravenous
vancomycin is not effective against C. difficile infection because of inadequate penetration of the drug into the
lumen of the colon.
For information on vancomycin dosing and monitoring, see Principles of vancomycin use.
For information on monitoring teicoplanin plasma concentration, see Monitoring teicoplanin.
Practical information on using lincosamides

The lincosamides, clindamycin and lincomycin, are active against most Gram-positive aerobic bacteria (but
not Enterococcus species) and most Gram-positive and Gram-negative anaerobic bacteria. Clindamycin may
be active against Cutibacterium acnes (formerly Propionibacterium acnes). Despite limited clinical evidence,
lincosamides are used to reduce bacterial toxin production in necrotising skin and soft tissue infections and
toxic shock syndromes.
Although clindamycin is inherently more active than lincomycin, for most indications the same dosage is
appropriate. In these guidelines, clindamycin is ranked preferentially to lincomycin because there are more
clinical data to support its use.
Clindamycin and lincomycin have similar adverse effects; they can both cause antibiotic-associated diarrhoea.
Practical information on using linezolid

Linezolid is active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus
(MRSA), methicillin-resistant coagulase-negative staphylococci, vancomycin-resistant enterococci (VRE),
and penicillin-resistant strains of Streptococcus pneumoniae. Linezolid should be reserved for infections
caused by multidrug-resistant bacteria.
Bone marrow suppression and peripheral neuropathy can occur in patients taking linezolid for longer than 14
days, so haematological and neurological monitoring is required. A protocol for monitoring patients for
linezolid toxicity has been proposed [Note 2].
Linezolid is a weak monoamine oxidase inhibitor, so it significantly interacts with some foods and drugs.
Consult an appropriate resource on drug interactions if starting or stopping linezolid in patients taking other
drugs.
For information on monitoring linezolid plasma concentration, see Monitoring linezolid.
Note 2: Bishop E, Melvani S, Howden BP, Charles PG, Grayson ML. Good clinical outcomes but high rates of adverse reactions during
linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients. Antimicrob Agents Chemother
2006;50(4):1599-602. [URL]
Practical information on using macrolides

The macrolides, azithromycin, clarithromycin, erythromycin and roxithromycin, have a broad spectrum of
activity, including activity against Gram-positive cocci, Corynebacterium species, Gram-negative cocci,
and Legionella, Mycoplasma and Chlamydia species, as well as some Gram-positive and Gram-negative
anaerobic bacteria. Erythromycin, azithromycin and clarithromycin are also active against Bordetella
pertussis.
Unlike other macrolides, clarithromycin has a microbiologically active metabolite. Clarithromycin is active
against nontuberculous mycobacteria, including Mycobacterium avium complex (MAC), and is used in
combination with other drugs for this indication. It is also used in combination with other drugs for
eradication of Helicobacter pylori.
Azithromycin is less active than erythromycin against Gram-positive bacteria, but has a broader range of
Gram-negative activity (eg Salmonella species). Azithromycin is also active against nontuberculous
mycobacteria (including MAC), Rickettsia species and some parasites (eg Toxoplasma gondii).
Macrolides attain high intracellular concentrations, which are theoretically beneficial for the treatment of
infections caused by intracellular bacteria.
Oral formulations of erythromycin have variable absorption and are poorly tolerated because of
gastrointestinal adverse effects. Furthermore, poor adherence is likely because of the four-times-daily dosing
regimen. These factors limit the use of erythromycin in practice. Erythromycin is not recommended for
neonates (up to 1 month old) because of the risk of pyloric stenosis.
Erythromycin and clarithromycin are potent inhibitors of the cytochrome P450 enzyme CYP3A4, so they
have many clinically significant drug interactions. Consult an appropriate resource on drug interactions if
starting or stopping these drugs in patients taking other drugs.
Azithromycin, erythromycin and clarithromycin can prolong the QT interval. For more information on drugs
that prolong the QT interval, see the CredibleMeds website.
Practical information on using mupirocin

Topical mupirocin has a limited role in treatment of infection. It is also used intranasally for eradication of
staphylococcal carriage (decolonisation).
Prolonged or widespread use causes high-level mupirocin resistance in methicillin-resistant Staphylococcus

aureus (MRSA).
Practical information on using nitrofurantoin
Nitrofurantoin is active against bacteria that commonly cause cystitis, including many Gram-negative bacilli
(eg Escherichia coli) and Gram-positive cocci (eg Enterococcus faecalis).
Nitrofurantoin is predominantly eliminated by glomerular filtration. Effective treatment of urinary tract

infection depends on achieving an adequate concentration of nitrofurantoin in the urine, so treatment is less
effective in patients with reduced glomerular filtration rate.
Practical information on using nitroimidazoles

The nitroimidazoles, metronidazole and tinidazole, have activity against almost all Gram-negative anaerobic
bacteria (eg Bacteroides fragilis) and most Gram-positive anaerobic bacteria (eg Clostridium species, but not
Cutibacterium acnes [formerly Propionibacterium acnes]). It is also active against protozoa, including
Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Helicobacter pylori resistance to
metronidazole is common in Australia (about 50% of H. pylori infections, reflecting high community
exposure to nitroimidazole drugs).
Metronidazole and tinidazole can cause nausea, vomiting, flushing, headache and palpitations if taken
concomitantly with alcohol; it is similar to the reaction that occurs when alcohol is taken with disulfiram.
Advise patients to avoid alcohol during treatment and for at least 24 hours after completing the course of
metronidazole or at least 72 hours after completing the course of tinidazole.
For the treatment of mixed aerobic and anaerobic infections in these guidelines, the recommended dosage of
metronidazole is 400 mg orally or 500 mg intravenously, 12-hourly. The 12-hourly dosing regimen is based
on pharmacokinetic data and minimum inhibitory concentrations of the pathogens involved, in addition to
limited clinical studies and extensive clinical experience with its use.
Practical information on using quinolones

The quinolones should generally be reserved for treatment of infections resistant to other drugs or when
alternative antibiotics are contraindicated. Resistance to quinolones is now widespread, particularly in
Enterobacteriaceae (enteric Gram-negative bacilli), Pseudomonas aeruginosa, Campylobacter species and
Neisseria gonorrhoeae.
Ciprofloxacin has a broad spectrum of activity, which includes activity against aerobic Gram-negative
bacteria (including Haemophilus influenzae, Enterobacteriaceae [enteric Gram-negative bacilli], P.
aeruginosa and Gram-negative cocci) and some aerobic Gram-positive cocci. It is also active against
intracellular bacteria, including Legionella species and some mycobacteria. Ciprofloxacin has poor activity
against anaerobic bacteria and streptococci.
Moxifloxacin, an extended-spectrum quinolone, has increased activity against Gram-positive aerobic bacteria
(including staphylococci and streptococci) compared to ciprofloxacin. Susceptibility among strains of
methicillin-resistant Staphylococcus aureus (MRSA) is variable. Moxifloxacin is active against many Gram-
negative aerobic bacteria, but has poor activity against P. aeruginosa. Moxifloxacin has good activity against
anaerobic bacteria and most atypical bacteria that cause pneumonia. It is also used for the management of
some mycobacterial infections.
Norfloxacin is reserved mainly for multidrug-resistant cystitis, provided the pathogen is susceptible, and
acute infectious diarrhoea (eg traveller’s diarrhoea, cholera).
Ofloxacin is used topically to treat eye infections.
Quinolones are not licensed for use in children on the basis of animal studies that showed an adverse effect on
cartilage development; however, there are few data from human trials to support this finding. A quinolone can
be used in children if it is the drug of choice.
Tendinitis caused by quinolones commonly involves the Achilles tendon, though other tendons can be
affected. Risk factors for developing tendinitis are concomitant corticosteroid use, advanced age, renal
impairment and prolonged therapy.
Quinolones have many clinically significant drug interactions. Consult an appropriate resource on drug
interactions if starting or stopping quinolones in patients taking other drugs.
Quinolones can prolong the QT interval. For more information on drugs that prolong the QT interval, see the
CredibleMeds website.
For information on monitoring quinolone plasma concentrations, see Monitoring quinolones.
Practical information on using rifamycins

The rifamycins include rifampicin, rifabutin, rifaximin and rifapentine.
Rifampicin and rifabutin are active against Gram-positive bacteria (including staphylococci), Gram-negative
bacteria and mycobacteria. These drugs must always be used in combination with antimicrobials from a
different class because of the rapid emergence of resistance.
Rifabutin is used for the treatment and prophylaxis of Mycobacterium avium complex (MAC) infection.
Rifampicin is mainly used for the treatment of tuberculosis, nontuberculous mycobacteria (including MAC)
and methicillin-resistant Staphylococcus aureus (MRSA) infection. Rifampicin is also used as prophylaxis in
contacts of patients with Haemophilus influenzae type b infection and meningococcal disease.
Rifaximin is not systemically absorbed, so is concentrated in the faeces. Rifaximin is active against Gram-
positive and Gram-negative aerobic and anaerobic bacteria. It is mainly used for hepatic encephalopathy. The
potential benefits of rifaximin must be balanced against the potential adverse effects, including the
development of resistant bacteria.
Rifampicin can cause hepatitis, so check liver biochemistry before starting and during treatment. Warn
patients that rifamycins can cause orange discolouration of bodily fluids, including urine, sweat and tears, and
that soft contact lenses can become stained.
Rifampicin and rifabutin have many clinically significant drug interactions. Consult an appropriate resource
on drug interactions if starting or stopping these drugs in patients taking other drugs. Useful information about
interactions between rifamycins and antiretroviral drugs can be accessed at the US Centers for Disease
Control and Prevention website.
Practical information on using tetracyclines

Tetracyclines have a broad spectrum of activity, which includes activity against Gram-positive and Gram-
negative bacteria, Chlamydia species, Rickettsia species, Mycoplasma species, spirochaetes, some
nontuberculous mycobacteria and some protozoa (eg Plasmodium species causing malaria).
Doxycycline is the preferred tetracycline in most situations. Doxycycline has not been associated with tooth
discolouration, enamel hypoplasia or bone deposition, even in children younger than 8 years, so is
increasingly used in this age group. However, use is limited by the lack of a suitable commercially available
formulation (eg an oral liquid formulation).
Minocycline is active against some bacteria that are resistant to other tetracyclines, including strains of
staphylococci. However, adverse effects limit its use (eg benign intracranial hypertension, vestibular adverse
effects, skin pigmentation).
Oesophagitis can occur with oral doxycycline and, less commonly, oral minocycline. Oral tetracyclines should
be taken with food and a large glass of water, and the patient should be instructed to remain upright after
administration. Photosensitivity reactions can occur with tetracyclines; warn patients to avoid sun exposure.
Tigecycline is a broad-spectrum antibiotic given intravenously, with activity against aerobic Gram-positive
bacteria (eg methicillin-resistant Staphylococcus aureus [MRSA], vancomycin-resistant enterococci [VRE]),
aerobic Gram-negative bacteria (but not Pseudomonas aeruginosa), anaerobic bacteria and rapidly growing
nontuberculous mycobacteria. However, data show that outcomes are worse with tigecycline compared with
other antimicrobials, so its use is limited.
Practical information on using antimycobacterial drugs

Dapsone
Dapsone is a sulfone antibiotic closely resembling sulfonamide antibiotics. It is used to treat and prevent
Pneumocystis jirovecii pneumonia (PJP), to prevent toxoplasmosis, and to treat leprosy.
Exclude glucose-6-phosphate dehydrogenase (G6PD) deficiency before starting treatment, because patients
who are deficient are at risk of developing severe haemolysis. Peripheral neuropathy can occur, particularly
with daily doses exceeding 200 mg.
For discussion of cross-reactivity between dapsone and sulfonamide antibiotics, see Cross-reactivity between
sulfonamides.
Ethambutol
Ethambutol is used to treat tuberculosis and nontuberculous mycobacterial infections, including

Mycobacterium avium complex (MAC). Ethambutol can cause optic neuritis; check visual acuity and colour
vision before starting treatment, and instruct patients to report any changes in vision. Ethambutol must be
stopped immediately if visual symptoms occur.
For discussion on monitoring ethambutol therapy for tuberculosis, see Monitoring tuberculosis therapy.
Isoniazid
Isoniazid is used as part of combination treatment for active Mycobacterium tuberculosis infection and other
mycobacterial infections. It is also used to treat latent tuberculosis as monotherapy or in combination with
other tuberculosis drugs.
Although peripheral neuropathy can occur, the risk is minimised by co-administration with pyridoxine. Severe
hepatitis has been reported with isoniazid; the risk is greater in females, and increases with age, hazardous
alcohol consumption and pre-existing liver disease.
Pyrazinamide
Pyrazinamide is used exclusively as part of combination treatment of Mycobacterium tuberculosis. It is not

effective for treating other mycobacterial infections.
Rifamycins
See Practical information on using rifamycins.
Practical information on using antifungal drugs
Introduction to antifungal drugs
This topic covers practical information on using the antifungal drugs recommended in these guidelines. For
interactions, consult an appropriate drug information resource. If prescribing an antifungal drug, consider the
benefit–harm profile of the drug in the individual patient.
Useful information on antifungal drug interactions is available on the Aspergillus website.
Practical information on using azoles

The azoles are used systemically for fungal infections; their spectrums of activity vary:
Fluconazole is active against yeasts, including Candida species and Cryptococcus species.
Itraconazole is active against yeasts, Sporothrix schenckii and some Aspergillus species.
Isavuconazole is active against Aspergillus species; some Scedosporium, Lomentospora and Fusarium
species; zygomycetes and phaeohyphomycetes.
Voriconazole is active against yeasts, Aspergillus species, and some Scedosporium, Lomentospora and
Fusarium species.
Posaconazole is active against yeasts; Aspergillus species; some Scedosporium, Lomentospora and
Fusarium species; zygomycetes and phaeohyphomycetes.
Fluconazole has good tissue and central nervous system penetration.
Oral preparations of itraconazole are not bioequivalent; appropriate dosing and administration depends on the
preparation. In these guidelines, the Lozanoc formulation of itraconazole capsules is recommended in
preference to conventional itraconazole formulations due to superior bioavailability and because it is not
affected by pH.
Itraconazole from the Sporanox capsule formulation (and bioequivalent brands of the capsule formulation)
requires an acidic environment for absorption, so absorption is reduced in patients taking proton pump
inhibitors or histamine H2-receptor antagonists. Absorption of itraconazole from the Sporanox oral liquid
formulation is not affected by pH, but food impairs absorption.
Absorption of posaconazole is more variable from the oral liquid formulation than the modified-release
tablets. Absorption of posaconazole oral liquid requires an acidic environment, so absorption is reduced in
patients taking proton pump inhibitors or histamine H2-receptor antagonists. The oral liquid should be taken
with a fatty meal for best absorption, or with an acidic beverage. Absorption of posaconazole modified-
release tablets are not affected by the presence of food. Posaconazole can be given intravenously if oral
therapy is not possible.
Azoles have many clinically significant drug interactions. Consult an appropriate resource on drug
interactions if starting or stopping azoles in patients taking other drugs.
QT-interval prolongation has been reported with voriconazole; other azoles may also prolong the QT interval
under certain conditions (eg when administered with other drugs that prolong the QT interval). For more
information on drugs that prolong the QT interval, see the CredibleMeds website.
For information on monitoring azole plasma concentrations, see Monitoring systemic antifungals.
Practical information on using echinocandins

Anidulafungin, caspofungin and micafungin are active against Candida species, and are used for treatment
of severe candidal infection.
Practical information on using flucytosine

Flucytosine is used in combination with amphotericin B for synergistic activity against Cryptococcus
neoformans and Cryptococcus gattii.
Bone marrow toxicity is associated with high plasma concentrations of flucytosine, which often occur in
patients with renal impairment. Therefore, plasma concentration monitoring is necessary (see Monitoring
systemic antifungals). Perform a full blood count regularly in all patients receiving flucytosine to detect bone
marrow suppression.
Practical information on using pentamidine

Pentamidine is active against Pneumocystis jirovecii.
Pentamidine is administered intravenously or via a jet nebuliser. It should be used with caution in patients
with lung disease (eg asthma, chronic obstructive pulmonary disease [COPD]) because nebulised
pentamidine may cause cough and bronchospasm.
Adverse effects include nephrotoxicity, elevated liver enzyme concentrations, hypoglycaemia, blood
disorders and arrhythmias. These are more common with intravenous use.
Practical information on using polyenes

Amphotericin B
Amphotericin B is active against a wide range of yeasts (including Candida and Cryptococcus species) and
other fungi (including most Aspergillus species, but not A. terreus or A. nidulans), some Fusarium species,
zygomycetes and phaeohyphomycetes, and Leishmania species.
Amphotericin B is associated with significant toxicity, including infusion-related adverse effects,

nephrotoxicity, electrolyte abnormalities (especially hypokalaemia and hypomagnesaemia) and anaemia;
monitoring is essential. In particular, adverse reactions are common with amphotericin B desoxycholate (the
‘conventional’ form of amphotericin B). To minimise amphotericin B desoxycholate toxicity, prehydrate the
patient with sodium chloride 0.9% (0.5 to 1 L intravenously, before amphotericin B infusion) and consider
pretreatment with hydrocortisone, an antihistamine, an antiemetic, an analgesic or an antipyretic. If
nephrotoxicity or severe infusion reactions occur with amphotericin B desoxycholate, consider switching
to the lipid complex or liposomal formulation of amphotericin B, which are usually better tolerated.
The dosage and infusion rates for each amphotericin B formulation (conventional, lipid complex or
liposomal) are significantly different—exercise caution if prescribing and administering amphotericin B
because errors have caused fatalities.
Nystatin
Nystatin is mainly active against Candida species. It is poorly absorbed orally and is not absorbed through
skin or mucous membranes when applied topically.
Practical information on using antiviral drugs
Introduction to antiviral drugs
This topic covers practical information on using the antiviral drugs recommended in these guidelines. For
interactions, consult an appropriate drug information resource. If prescribing an antiviral drug, consider the
benefit–harm profile of the drug in the individual patient.
For practical information on using antiretrovirals, see Human immunodeficiency virus infection.
Practical information on using cidofovir

Cidofovir is active against cytomegalovirus (CMV). It does not penetrate the central nervous system and
should not be used to treat CMV encephalitis.
The risk of nephrotoxicity from cidofovir is reduced by co-administration with probenecid (before and after
the cidofovir infusion) and fluid (before and, if tolerated, during the cidofovir infusion). Instruct patients to
drink plenty of fluids while being treated with cidofovir.
Practical information on using foscarnet

Foscarnet is active against herpesviruses (eg cytomegalovirus [CMV]). It is usually used intravenously. For
immediate sight-threatening CMV retinitis, foscarnet may be used intravitreally in combination with systemic
antiviral therapy.
The risk of nephrotoxicity with intravenous foscarnet is reduced by co-administration with fluid before and
during treatment.
Practical information on using guanine analogues

The guanine analogues, aciclovir, famciclovir and valaciclovir, are active against herpes simplex and
varicella-zoster viruses. Aciclovir is poorly and erratically absorbed from the gut, and even less so through
the skin. Valaciclovir, a prodrug of aciclovir, and famciclovir are well absorbed after oral administration; they
are dosed less frequently than aciclovir.
In Australia, valaciclovir is not licensed for use in children younger than 12 years; however, it is licensed
internationally for use in younger children (older than 2 years). Famciclovir is not used in children.
Ganciclovir is used intravenously for the treatment of cytomegalovirus (CMV) infection. It causes bone
marrow suppression, which is dose dependent. For immediate sight-threatening CMV retinitis, ganciclovir
may be used intravitreally in combination with systemic antiviral therapy.
Valganciclovir, a prodrug of ganciclovir, is well absorbed when taken orally; it is then hydrolysed to
ganciclovir. Oral valganciclovir has been shown to be equally effective to intravenous ganciclovir in some
settings, but has not been studied in all situations. Valganciclovir is also used for CMV prophylaxis in
For information on monitoring plasma concentrations of guanine analogues, see Monitoring guanine
analogue antivirals.
Practical information on using neuraminidase inhibitors

Oseltamivir (oral), zanamivir (inhaled or intravenous) and peramivir (intravenous) inhibit influenza virus A
and B neuraminidase (an enzyme required for viral replication). In selected patient groups, they are used for
the treatment (all drugs and formulations) and prevention (only oral oseltamivir and inhaled zanamivir) of
influenza.
Neuropsychiatric adverse effects have been reported rarely in children and adolescents taking neuraminidase
inhibitors.
Practical information on using antiprotozoal drugs
Introduction to antiprotozoal drugs
This topic covers practical information on using the antiprotozoal drugs recommended in these guidelines.
For comprehensive drug information, including precautions, contraindications, adverse effects and drug
interactions, consult an appropriate drug information resource. If prescribing an antiprotozoal drug, consider
Practical information on using artemisinin derivatives

Artemisinin (qinghaosu) derivatives, artesunate and artemether, have potent activity against all human
malaria parasites. Artemether is used in combination with lumefantrine, which also has antimalarial activity.
Artesunate is used to treat severe malaria.
Artemether+lumefantrine is used to treat acute uncomplicated malaria. It should be taken with fatty food or
full-fat milk to ensure adequate absorption of lumefantrine.
Practical information on using atovaquone and

atovaquone+proguanil
Atovaquone+proguanil is used to prevent and treat malaria.
Atovaquone, as a single drug, is used to prevent and treat Pneumocystis jirovecii pneumonia (PJP) in patients
who do not tolerate other therapies.
Atovaquone (with or without proguanil) should be taken with fatty food or full-fat milk to ensure adequate
absorption. Consider alternative therapy for patients with severe chronic diarrhoea because absorption can be
significantly reduced.
Practical information on using chloroquine

Chloroquine-resistant Plasmodium falciparum has spread to most malaria-endemic areas of the world, and
high-grade chloroquine-resistant Plasmodium vivax now occurs in several areas of the Asia–Pacific region.
The role of chloroquine in the management of malaria is limited to recurrence of Plasmodium malariae
infection after treatment with artemether+lumefantrine.
Practical information on using mefloquine

Mefloquine is used to prevent malaria. Mefloquine is not approved for use in children in Australia (though it
has been widely used).
Neuropsychiatric disturbances (eg headache, nightmares, depression, psychosis) occur infrequently, usually
within the first 4 weeks of treatment, and can continue for many months after stopping therapy.
Mefloquine can prolong the QT interval, so it should not be used with other drugs that prolong the QT
interval or in patients with a cardiac conduction abnormality. For more information on drugs that prolong the
QT interval, see the CredibleMeds website.
Practical information on using nitazoxanide

Nitazoxanide is an oral antiprotozoal drug with activity against Cryptosporidium species, Cyclospora
cayetanensis and Giardia intestinalis. It is also used to treat liver fluke (Fasciola hepatica), and Clostridium
difficile infection in children with second and subsequent recurrences or ongoing refractory disease.
Adverse effects are usually mild and can include nausea, abdominal pain, diarrhoea and headache.
Practical information on using paromomycin

Paromomycin is an aminoglycoside that is not systemically absorbed. It is active against protozoa, including
Entamoeba histolytica and Giardia intestinalis. It is used to eradicate cysts in the gut to prevent relapse after
the initial treatment of invasive amoebiasis or amoebic liver abscess, and for treatment of giardiasis. It is also
used to treat asymptomatic carriage of E. histolytica to minimise transmission and the risk of developing
invasive disease.
Adverse effects are limited to gastrointestinal intolerance, particularly diarrhoea.
Practical information on using primaquine and tafenoquine

Primaquine is essential for the treatment of malaria caused by Plasmodium vivax and Plasmodium ovale
because it eradicates dormant parasites (hypnozoites) in the liver that can reactivate to cause relapsed malaria.
Primaquine is also used to eliminate the transmissible stages of Plasmodium falciparum, preventing the
transfer of parasites from human hosts to mosquitoes.
Exclude glucose-6-phosphate dehydrogenase (G6PD) deficiency before starting treatment with primaquine
because patients who are deficient are at risk of developing severe haemolysis. Adverse effects of primaquine
include gastrointestinal disturbances and methaemoglobinaemia.
Tafenoquine is registered in Australia for radical cure of P. vivax malaria and for malaria prophylaxis. While
currently available G6PD tests can be used to assess the safety of primaquine, they do not reliably identify
the level of G6PD activity required for safe use of tafenoquine.
Practical information on using pyrimethamine

Pyrimethamine is used in combination with another drug (eg sulfadiazine) for the prevention and treatment of
toxoplasmosis.
Co-administration of calcium folinate reduces the incidence of bone marrow suppression.
Practical information on using quinine

Quinine is used orally to treat uncomplicated malaria and intravenously to treat severe malaria.
Hypersensitivity or drug accumulation may lead to cinchonism (tinnitus, impaired hearing, headache,
gastrointestinal disturbances, visual disturbances). Other adverse effects include urticaria, fever, rash,
dyspnoea, and, in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, haemolytic anaemia.
Practical information on using anthelmintic drugs
Introduction to anthelmintic drugs
This topic covers practical information on using the anthelmintic drugs recommended in these guidelines. For
interactions, consult an appropriate drug information resource. If prescribing an anthelmintic drug, consider
Practical information on using benzimidazoles

The benzimidazoles, albendazole and mebendazole, are predominantly used to treat intestinal worm
infections, such as roundworm (Ascaris lumbricoides), threadworm (or pinworm) (Enterobius vermicularis),
hookworm (Ancylostoma duodenale and Necator americanus), dog hookworm (Ancylostoma caninum),
whipworm (Trichuris trichiura) and strongyloidiasis (Strongyloides stercoralis). Albendazole is also used for
community deworming programs.
Albendazole has some specific uses; for example, it is used to treat hydatid disease (Echinococcus species of
tapeworm) in conjunction with surgery or percutaneous drainage, and neurocysticercosis (in those with active
cysts) in conjunction with corticosteroids. It is also used as an alternative to ivermectin to treat cutaneous
larva migrans.
For treating systemic infections and intestinal worm infections that can cause invasive disease, albendazole
should be taken with a fatty meal to improve absorption. In contrast, for treating other intestinal worm
infections, albendazole should be taken on an empty stomach to limit systemic absorption.
The main adverse effects of both albendazole and mebendazole are elevated liver transaminases,
gastrointestinal symptoms and haematological abnormalities (eg leucopenia). Avoid albendazole in children
6 months or younger.
Triclabendazole is used to treat liver fluke (Fasciola hepatica).
Practical information on using ivermectin

Ivermectin is used to treat filariasis, strongyloidiasis, crusted (Norwegian) scabies, head lice and cutaneous
larva migrans. It is also used for prophylaxis of strongyloidiasis in immunocompromised adults without HIV
infection.
It is not recommended for children who weigh less than 15 kg. Absorption of oral ivermectin is improved
when taken with food. A veterinary formulation of ivermectin injection, given subcutaneously, has
occasionally been used for patients with strongyloidiasis who have hyperinfection or disseminated disease
and who do not respond to oral ivermectin.
Ivermectin can cause hypersensitivity reactions when used for filarial infections. These reactions are usually
transient and respond to analgesics and antihistamines.
Practical information on using niclosamide

Niclosamide is used to treat tapeworm (Taenia species) infection.
The most common adverse effect is gastrointestinal disturbances.
Practical information on using praziquantel

Praziquantel is used to treat tapeworm (Taenia species) and fluke infections, such as cysticercosis,
schistosomiasis and liver flukes (Clonorchis sinensis and Opisthorchis viverrini). It is sometimes used as
adjunctive therapy for hydatid disease.
Adverse effects are transient and include gastrointestinal disturbances, headache, dizziness and drowsiness.
Practical information on using pyrantel

Pyrantel is effective against roundworm (Ascaris lumbricoides), hookworm (Ancylostoma duodenale and
Necator americanus), and threadworm (or pinworm) (Enterobius vermicularis).
Adverse effects are uncommon.
Community-based parenteral antimicrobial
therapy
Introduction to community-based parenteral antimicrobial therapy
In this topic, community-based parenteral antimicrobial therapy refers to the use of parenteral antimicrobial
drugs in a community setting, as an alternative to care in hospital. There are a variety of models of care,
including outpatient parenteral antimicrobial therapy (OPAT) programs and antimicrobials administered
through hospital in the home (HITH) services. Moreover, there are differences across Australian states in
funding and governance requirements for these programs. The aim of this topic is to set a standard of care that
applies to all patients receiving community-based parenteral antimicrobial therapy, regardless of the way it is
delivered.
Community-based parenteral antimicrobial therapy programs increase patient satisfaction, reduce the risk of
hospital-acquired infections, and can reduce costs for hospitals. Expansion of these services has been enabled
by the increasing availability of suitable antimicrobial preparations, and advances in vascular access and
infusion device technology.
The quality and safety of care provided by community-based parenteral antimicrobial therapy programs should not be
inferior to hospital care.
The quality and safety of care provided to patients receiving community-based parenteral antimicrobial
therapy should be at least equal to that which they would receive if managed in hospital; if this is not possible,
the patient should be managed in hospital. Governance is an important element of a community-based
parenteral antimicrobial therapy program—see Box 2.40.
For children, community-based parenteral antimicrobial therapy is administered by specialist paediatric

programs, though usually not for children younger than 4 weeks of age. Most of the information in this topic
also applies to children; however, there are some key differences in a paediatric program.
Vascular access devices: Peripheral intravenous cannulae are generally not appropriate to use for
community-based parenteral antimicrobial therapy in children. General anaesthetic is usually required
for insertion of central venous catheters, including peripherally inserted central catheter (PICC) lines.
Antimicrobial regimens: Due to differences in pharmacokinetics, the use of adult once-daily antibiotic
regimens is sometimes not appropriate for children younger than 12 years of age.
Further information on state-based hospital in the home (HITH) programs is available for Victoria
[URL], New South Wales [URL] and Queensland [URL].
Governance of community-based parenteral antimicrobial therapy programs (Box 2.40)
A community-based parenteral antimicrobial therapy program should be part of a hospital’s clinical

governance structure. Key requirements are:
an accountable senior medical officer with overall responsibility for each episode of care
regular medical review of patients (usually at least once a week)
an effective monitoring system to detect and respond to clinical deterioration and complications in a
timely manner
clear clinical endpoints of therapy for each patient, and medical follow-up at the end of therapy.
Antimicrobial stewardship is a key feature of community-based parenteral antimicrobial therapy programs.

Patients entering a program should have their antimicrobial plan reviewed to assess whether:
oral therapy would suffice

a narrower-spectrum antimicrobial is appropriate
the shortest duration of both intravenous and oral therapy is prescribed, consistent with the condition
being treated and the patient’s clinical response.
Delivery of care in community-based parenteral antimicrobial

therapy programs
The majority of community-based parenteral antimicrobial therapy programs deliver care in one of three
ways, each with its own advantages and disadvantages.
Visiting clinician: administration of parenteral antimicrobial therapy by a nurse or other healthcare

professional in the patient’s home. This is the most common model in Australia.
Self-administration or carer administration: administration of parenteral antimicrobial therapy by the
patient or carer in the community, after a period of training. Written information must be provided, and
the patient or carer must be linked with a hospital unit or health service for clinical monitoring and
access to 24-hour support (see Information for patients receiving community-based parenteral
antimicrobial therapy). This option is particularly useful for patients in remote or regional areas of
Australia.
Healthcare setting: includes administration of parenteral antimicrobial therapy in a hospital outpatient
or general practitioner’s clinic, residential aged-care facility, or dialysis centre.
Most patients receive community-based parenteral antimicrobial therapy after discharge from hospital.
However, some patients receive community-based therapy without having been admitted to hospital.
Team and service structure of community-based parenteral

antimicrobial therapy programs
Important members of a community-based parenteral antimicrobial therapy team include:
a medically qualified clinician (eg infectious diseases physician, general physician or other doctor with
expertise in the management of infection and community-based parenteral antimicrobial therapy)
a specialist nurse (hospital- or community-based) with expertise in parenteral drug administration and
intravascular device management
a clinical pharmacist with community-based parenteral antimicrobial therapy expertise.
Effective communication between the community-based parenteral antimicrobial therapy team and other
healthcare professionals involved in the patient’s care, including the general practitioner, is essential. The
team should maintain contact with the medical team that referred the patient for community-based therapy.
Medical responsibility for ongoing care of patients receiving parenteral antimicrobials in the community lies
with the treating doctor, who must be clearly identified in the patient’s records.
Medical responsibility for ongoing care of patients receiving parenteral antimicrobials in the community lies with the
treating doctor.
Patient selection for community-based parenteral antimicrobial
therapy
Careful patient selection for community-based parenteral antimicrobial therapy is crucial for positive clinical
outcomes. Selection criteria must include all of the following:
the patient must be medically stable

the patient has an infection that can only be treated with parenteral (usually intravenous) antimicrobials
(see Principles of antimicrobial use)
an appropriate intravenous antimicrobial regimen amenable to administration in a community setting is
available, and is consistent with the principles of appropriate antimicrobial prescribing
the patient must be assessed initially by at least one member of the community-based parenteral
antimicrobial therapy team, but ideally by both doctor and nurse
medical responsibility must be established and documented, and ongoing review arranged
the home or other treatment environment must be suitable (includes running water, light and heat,
refrigeration and a working telephone) and safe for the patient and visiting staff.
Patients with drug or alcohol misuse problems should be assessed for suitability on a case-by-case basis.
Careful counselling about the hazards of vascular access manipulation is recommended.
Indications for community-based parenteral antimicrobial therapy

The clinical diagnosis should be established before the patient is admitted to a community-based parenteral
antimicrobial therapy service; this may require additional investigations. Other relevant components of
infection management, such as surgical debridement, are usually performed before admission for community-
based therapy.
Infections that are commonly treated with community-based parenteral antimicrobial therapy include skin and
soft tissue infections, bone and joint infections and endocarditis. Patients with misdiagnosed cellulitis are
commonly referred for community-based parenteral antimicrobial therapy—for information on diagnosis of
cellulitis, see Clinical presentation of cellulitis and erysipelas. A range of other infections can also be
managed with community-based parenteral antimicrobial therapy, as long as patient selection criteria are met.
An increasing number of patients with multidrug-resistant infections (eg urinary tract infection) and
nontuberculous mycobacterial infections are managed with community-based parenteral antimicrobial therapy
—consultation with a specialist is required.
Some infections are not suitable for management via community-based parenteral antimicrobial therapy.
These include infections that are severe, can deteriorate rapidly, or can have severe complications that are
difficult to manage outside hospital (eg septic emboli from left-sided infective endocarditis). Community-
based parenteral antimicrobial therapy can be considered for such infections in selected patients after a period
of stabilisation in hospital.
Patients with moderate- or high-severity community-acquired pneumonia or severe pyelonephritis are at risk
of deterioration, and should generally be managed in hospital while receiving parenteral antibiotics. When the
patient is well enough to go home, a switch to oral therapy is usually appropriate. If there are no options for
oral therapy (eg due to antibiotic resistance or drug intolerance), community-based parenteral antimicrobial
therapy may be suitable.
In certain circumstances it may be appropriate to treat patients with parenteral antibiotics in the community
who do not meet the usual criteria; for example, a patient with moderate- to high-severity pneumonia in an
aged-care facility, when management in hospital does not fit with the patient’s goals of care—see Parenteral
therapy for CAP in residents of aged-care facilities.
Antimicrobial choice and administration in community-based

parenteral antimicrobial therapy
Antimicrobial choice and treatment plan
The principles of appropriate antimicrobial prescribing and antimicrobial stewardship apply in community-
based parenteral antimicrobial therapy programs.
Choose the antimicrobial regimen according to prescribing guidelines.

Do not use parenteral antimicrobial therapy when oral therapy is available and appropriate. Some
antimicrobials have good oral bioavailability and can often be given orally rather than intravenously
(see Box 2.34).
Do not use parenteral antimicrobial therapy for longer than necessary—switch to oral therapy as soon as
it is clinically appropriate to do so (see Guidance for antimicrobial intravenous to oral switch).
Document the infection treatment plan in the patient’s records before admission to a community-based
parenteral antimicrobial therapy service, including the expected duration of intravenous therapy and the
plan for follow-up after completing therapy.
Do not use parenteral antimicrobial therapy in the community when oral therapy is available and appropriate.
Drug delivery
Parenteral antimicrobial therapy in community-based programs is usually administered intravenously, but is

occasionally given intramuscularly or subcutaneously.
Antimicrobial therapy can be administered by a specialist nurse trained in community-based parenteral

antimicrobial therapy, another health professional, or by the patient or carer, depending on the program. When
patients or carers are responsible for giving the intravenous therapy, they must be trained and competent
before the patient is admitted to the service.
Due to the risk of anaphylaxis, the first dose of a parenteral antimicrobial should be given in a setting with
appropriately trained staff and equipment—preferably in a hospital or, in carefully selected patients, in
another setting supervised by staff trained in community-based parenteral antimicrobial therapy. Patients with
a history of immune-mediated antimicrobial hypersensitivity (see Antimicrobial hypersensitivity), idiopathic
anaphylaxis, or chronic idiopathic urticaria should always receive the first dose of parenteral antimicrobial
therapy in hospital.
Community-based parenteral antimicrobial therapy services should have an anaphylaxis management policy
that includes procedures for administration of intramuscular adrenaline, and staff should be appropriately
trained. For information about managing anaphylaxis, see the Australian Prescriber anaphylaxis wallchart.
Devices for drug delivery and intravascular access
The community-based parenteral antimicrobial therapy team is responsible for the choice of drug delivery
device and intravascular access device. Factors to consider are:
duration of treatment
concentration and potential for vascular irritation of the drug
ease of vascular access
number of drugs to be administered
patient acceptability
cost
potential for complications, particularly sepsis.
In patients with chronic kidney disease who may need fistula formation in future for haemodialysis, the
position of the vascular access device requires careful consideration and discussion with the nephrologist or
vascular surgeon. Upper limb peripherally inserted central catheters (PICCs) are particularly problematic in
this situation, and tunnelled central venous catheters (CVCs) are a better option in some patients.
Drug delivery devices used in community-based parenteral antimicrobial therapy include elastomeric infusor
devices, programmable infusion pumps and syringe infusion pumps. Drugs can also be delivered by
intravenous injection or short intermittent infusion, without a pump.
Intravascular access devices used for drug administration in community-based parenteral antimicrobial
therapy include central intravascular access devices, midline catheters, and peripheral intravenous cannulae—
each has advantages and disadvantages.
Central intravascular access devices include PICCs, tunnelled CVCs and implanted ports. Nontunnelled CVCs
(eg subclavian CVCs) are not recommended for community-based parenteral antimicrobial therapy because
they are associated with a higher complication rate than tunnelled CVCs. Central intravascular access devices
are used for intermittent dosing or continuous infusion. They can be left in place for weeks to months when
there are no complications, with duration dependent on the device.
Midline catheters are peripherally inserted catheters. The tip is located at or below the axillary vein. They can
remain in place for up to 4 weeks and are an alternative to PICC lines. They are used for intermittent dosing
or continuous infusion of drugs that do not cause vascular irritation.
Peripheral intravenous cannulae (PIVC) are usually only suitable for a short duration (up to 7 days) of
community-based parenteral antimicrobial therapy, with drugs that do not cause vascular irritation. Patients
must have adequate vascular access. PIVCs can be used for intravenous injection or intermittent infusion.
They are generally not recommended for continuous infusion because of the risk of failure of the device
(‘tissuing’) and associated problems (eg extravasation, interruption of drug therapy). PIVCs should be
changed at least every 3 days. For therapy longer than 7 days, a central line or midline catheter should be used
instead.
For information on managing and monitoring intravenous access devices, see Box 2.41. Each type of device
has a recognisable risk of catheter-related adverse events, most commonly local infection, sepsis or deep vein
thrombosis. The rate of device complications should be regularly audited by the service. A complication rate
of less than 1 per 1000 catheter-days is usually considered acceptable.
Key points for managing and monitoring intravenous access devices (Box 2.41)
For CVCs (including PICCs), the position of the catheter tip should be checked when it is inserted and
regularly during use to make sure it is in the superior vena cava.
Lines should be flushed regularly to ensure patency, generally once daily or after each infusion if
administered more frequently.
Insertion sites of intravascular access devices should be visible through a clear dressing.
Dressings over CVC sites (including PICCs) should be changed at least weekly if stable or more frequently
if there is blood at the site, which is more common after recent insertion.
PIVCs should be changed at least every 3 days.
Fever in a patient receiving community-based parenteral antimicrobial therapy should prompt early review
of the intravascular access device (see Monitoring patients receiving community-based parenteral
antimicrobial therapy).
CVC = central venous catheter; PICC = peripherally inserted central catheter; PIVC = peripheral intravenous cannula
Antimicrobial stability and preparation in community-based

parenteral antimicrobial therapy
Antimicrobial preparations for infusion can be made either on-site or by a manufacturing pharmacy, or
purchased from a licensed manufacturer. Antimicrobials given as an intravenous injection or intermittent
infusion are usually prepared immediately before administration. To ensure sterility, preparations made in
advance of administration (more than 24 hours) should be prepared under aseptic conditions, in an
appropriately maintained clean room using suitable equipment (eg laminar flow hood, clean room garments),
by trained staff. Quality control measures, such as appropriate environmental monitoring, are essential.
The antimicrobial drug preparation should be sufficiently stable for the duration of the infusion, and for
extended periods if prepared in advance. Stability is usually defined as more than 90% of the original
concentration remaining at the end of the infusion, and is dependent on drug concentration, temperature of the
preparation, and, in some cases, the buffer and diluent fluid used. The presence of degradation products may
also affect shelf life.
Infusions prepared in advance should generally be stored at 2 to 8°C until use. Patients should be advised how
to store the infusions both before and during use (see Information for patients receiving community-based
parenteral antimicrobial therapy).
Table 2.70 lists the stability of antimicrobial drugs commonly used in community-based parenteral
antimicrobial therapy on refrigeration and at elevated temperatures. However, there are limitations in the
available data. Most of the stability data are based on studies performed at fixed temperatures (usually
refrigerated and room temperature [typically less than 25°C]), whereas research shows there is significant
temperature fluctuation in practice, and that infusions placed close to the patient’s body often reach high
temperatures (up to 35°C). The information presented in the table therefore represents a conservative
interpretation of the available data, to minimise the risk of patients receiving substandard care. The table is not
intended to replace local protocols; drug administration practices in community-based parenteral antimicrobial
therapy programs vary across Australia, largely as a consequence of the way the program is delivered (eg
once- or twice-daily visits) and local experience. Local patient outcome data is sometimes used to inform
protocols, but is usually unpublished.
Some antimicrobials (eg many beta lactams) are pharmacokinetically and pharmacodynamically suited to
continuous infusion via delivery devices. In some cases, antimicrobials not stable in solution for 24 hours out
of the fridge can be given by continuous infusion provided the daily dose is split into two preparations that are
changed every 12 hours. The patient should be encouraged to place such infusions away from the bed (eg on a
bedside table) overnight, since significantly higher temperatures occur when infusions are stored under the
blankets. Alternatively, freezer packs can be used to reduce temperatures and improve stability, provided they
are replaced regularly.
The rate of drug delivery through elastomeric infusors may be affected by temperature—low temperatures can
reduce the flow rate and high temperatures can increase it. Consider the effect of temperature if the flow rate is
unexpectedly low or high.
Drugs not recommended for use in community-based parenteral antimicrobial therapy due to inadequate
stability are listed in Table 2.71.
Drugs commonly used for community-based parenteral antimicrobial therapy in adults

(Table 2.70) [NB1] [NB2]
Antibiotic Stability on Stability at Usual maximum adult Notes

refrigeration elevated total daily dose and
at 2 to 8°C temperature intravenous dosing
[NB3] [NB4] [NB3] [NB6] schedule for community-
[NB5] [NB7] based parenteral
antimicrobial therapy
[NB8] [NB9] [NB10]
See Principles of
aminoglycoside use for
information on dosage and
monitoring requirements.
dosage, preparation and
amikacin – – administration as for Ideally, doses given by
inpatient management intravenous injection or
intermittent infusion should
be reconstituted
immediately before
administration.
Ideally, doses given by
be reconstituted
5 mg/kg by intermittent
amphotericin B more than 7 immediately before
24 hours infusion over 30 to 60
liposomal days administration.
minutes
Reconstitution requires use
of a filter; see product
information for details.
benzylpenicillin For buffer, add 8.5 mL of
more than 7 10.8 to 14.4 g by 24-hour
(buffered 24 hours at 37°C 4% sodium citrate to each 3
days continuous infusion
solution) g vial of benzylpenicillin.
For cellulitis, dosages of 2 g
2 to 4 g daily, by once- or daily plus oral probenecid 1
twice-daily intravenous g daily OR 2 g 12-hourly
72 hours at 21 to injection or intermittent have been used [NB13].
more than 7 25°C infusion
cefazolin Ideally, doses given by
days 24 hours at 37°C 6 to 8 g by 24-hour intravenous injection or
[NB12] continuous infusion or intermittent infusion should
intermittent injection via be reconstituted
programmable pump immediately before
administration.
6 g daily by intermittent
injection or continuous
24 hours at 25°C infusion
14 hours at 30°C due to instability at elevated

Stability data for
more than 7 (120 mg/mL) temperatures, consider
cefepime temperatures between 25°C
days giving 50% of the daily
less than 10 hours dose over 12 hours, then and 37°C are limited.
at 37°C (120 attaching new refrigerated
mg/mL) bag and giving the
remaining 50% of the dose
over the next 12 hours
[NB11]
12 g daily by continuous
infusion
due to lack of stability data

at elevated temperatures,
more than 7 consider giving 50% of the Stability data for
cefoxitin 24 hours at 25°C temperatures between 25°C
days daily dose over 12 hours,
and 37°C are limited.
then attaching new
refrigerated bag and giving
the remaining 50% of the
dose over the next 12 hours
[NB11]
6 g daily
Consider using an
dosing schedule dependent alternative antibiotic with
24 hours at 25°C on shelf life of product, better stability.
ceftazidime 5 days which varies between
8 hours at 37°C manufacturers; consult Stability data for
local protocols and temperatures between 25°C
manufacturer’s advice and 37°C are lacking.
[NB11]
Stability data for
temperatures above 25°C
are lacking.
once-daily intravenous
more than 7 injection (doses up to 1 g) Ideally, doses given by
ceftriaxone 24 hours at 25°C
days or intermittent infusion (2 intravenous injection or
to 4 g) intermittent infusion should
be reconstituted
immediately before
administration.
Oral clindamycin has
excellent bioavailability;
intravenous therapy may
not be required.
clindamycin 7 days at 23°C
days continuous infusion
Stability data for
are lacking. Consider using
lincomycin instead.
Stability data for
are lacking.
350 mg to 1 g as a once-
daptomycin 24 hours 12 hours daily intravenous injection intravenous injection or
or intermittent infusion
be reconstituted
immediately before
administration.
be reconstituted
6 hours at 25°C immediately before
(20 mg/mL) 0.5 to 1 g as a once-daily administration.
ertapenem 5 days
intermittent infusion
20 hours at 25°C Subcutaneous infusion may
(10 mg/mL) be an alternative to
intravenous therapy in
patients without intravenous
access.
8 to 12 g by 24-hour Prepare in citrate buffer. For
flucloxacillin
continuous infusion or concentrations up to 50
more than 7
24 hours at 32°C intermittent intravenous mg/mL: dilute flucloxacillin
(buffered days
solution) injection via programmable in 0.3% citrate-buffered
pump saline at pH 7.0.
as above
due to relatively poor

stability at elevated
flucloxacillin 24 hours at 31°C temperatures, give 50% of
the daily dose over 12 Consider using a buffer to
6 days
(unbuffered less than 12 hours improve stability.
hours, then attach new
solution) at 37°C
refrigerated bag and give
the remaining 50% of the
dose over the next 12 hours
[NB11].
See Principles of
aminoglycoside use for
dosage, preparation and
gentamicin – – administration as for Ideally, doses given by
inpatient management intravenous injection or
be reconstituted
immediately before
administration.
Oral clindamycin has
excellent bioavailability;
intravenous lincomycin
therapy may not be
required.
lincomycin 24 hours at 37°C Severe cardiopulmonary
days continuous infusion reactions (particularly
hypotension) have occurred
with lincomycin infusion
rates more than 1 g/hour
and concentrations more
than 1 g/100 mL.
3 g daily
dosing schedule depends on

12 hours at 25°C shelf life of product, which Consider using an
meropenem 5 days varies between alternative antibiotic with
6 hours at 37°C manufacturers; consult better stability.
local protocols and
manufacturer’s advice
[NB11]
13.5 to 18 g by 24-hour Tazocin EF contains
continuous infusion or disodium edetate (EDTA)
piperacillin+
5 days 24 hours at 37°C intermittent intravenous and citrate to reduce the
tazobactam
injection via programmable formation of subvisible
pump particulate matter and to
meet Food and Drug
13.5 to 18 g by 24-hour Administration (FDA)
piperacillin+ continuous infusion or criteria on limits of
tazobactam more than 7 intermittent intravenous subvisible particulate
(Tazocin EF) days 24 hours at 37°C injection via programmable matter. If manufactured in
pump advance, Tazocin EF is
recommended.

intravenous injection or
6 days in
be reconstituted
glucose 5% 6 to 12 mg/kg by once- immediately before
teicoplanin 24 hours in 24 hours at 25°C daily intravenous injection administration.
or intermittent infusion
sodium
Monitor plasma
chloride 0.9%
concentration in patients
with severe infections (see
Monitoring teicoplanin).
100 mg daily
dosing schedule depends on
shelf life of product, which
tigecycline 48 hours 24 hours at 25°C be reconstituted
varies between
immediately before
manufacturers; consult
local protocols and administration.
manufacturer’s advice
initial dosage as for
be reconstituted
inpatient management
immediately before
more than 7 administered by 24-hour administration.
vancomycin 72 hours at 37°C
days
continuous infusion or
See Principles of
twice-daily intermittent
vancomycin use for
infusions
NB1: This table is provided as an overview and is not intended to replace local protocols. Drug administration practices in community-based
parenteral antimicrobial therapy programs vary across Australia, largely as a consequence of the way the program is delivered (eg once- or twice-
daily visits) and local experience. Local patient outcome data are sometimes used to inform protocols, but are usually unpublished.
NB2: Stability data for antimicrobial infusions are limited and difficult to translate to community settings. The information presented here is a
conservative interpretation of the available data to minimise the risk of patients receiving substandard care.
NB3: Stability is usually defined as more than 90% of the original concentration remaining at the end of the infusion, and is dependent on drug
concentration, temperature of the preparation, and, in some cases, the buffer and diluent used. For infusions, data given are generally applicable to
standard doses in 250 to 500 mL sodium chloride 0.9% (see stability studies listed in Key references below).
NB4: Temperature in stability studies varies between 2 to 8°C.
NB5: A maximum of 7 days microbiological stability is given for products produced by a nonlicensed manufacturing facility.
NB6: Preparations left out of the fridge in hot climates or placed close to the patient’s body during infusion often reach high temperatures (up to
35°C).
NB7: A maximum shelf life of 24 hours is applied for microbiological stability at elevated temperatures for products not prepared in a high-grade
clean room. When a period longer than 24 hours is given, this only applies if the product is prepared in a high-grade clean room.
NB8: Check the recommended dose for the indication being treated—see the clinical topics in these guidelines.
NB9: Clinical trials using continuous infusions for most indications are lacking. The recommended dose for 24-hour continuous infusion is the
sum of intermittent doses given over 24 hours.
NB10: Drugs that are administered by intravenous injection or intermittent infusion for community-based therapy are usually given at the same
dosage, and are prepared and administered, as for inpatient management.
NB11: Storing freezer packs next to infusion (and changing frequently when defrosted) may help to reduce temperatures and improve stability.
NB12: Based on a study where the diluent was water for injection.
NB13: Data to support the use of these cefazolin regimens for indications other than cellulitis (eg osteomyelitis, endocarditis) are lacking.
Drugs not recommended for community-based parenteral antimicrobial therapy due to

inadequate stability (Table 2.71) [NB1]
Antibiotic Stability on refrigeration at 2 to Stability at elevated temperature

8°C [NB2] [NB3] [NB4] [NB2] [NB5]
amoxicillin no published data less than 4 hours at 25°C
8 hours when added to a pre-
amoxicillin+clavulanate 5 hours at 25°C
refrigerated bag
ampicillin 1 to 3 days less than 12 hours at 30°C
8 to 12 hours at 26°C
less than 12 hours at over 26°C
benzylpenicillin (unbuffered
6 days 95 to 99% of the original
solution)
concentration lost after 24 hours at
37°C
24 hours at 25°C
cefalotin 7 days
no published data above 25°C
NB1: These antibiotics are not recommended because appropriate alternatives with better stability are available.
NB2: Stability is usually defined as greater than 90% of the original concentration remaining at the end of the infusion, and is dependent on drug
concentration, temperature of the preparation, and, in some cases, the buffer and diluent used. Data given are generally applicable to standard
doses in 250 to 500 mL sodium chloride 0.9% (see stability studies listed in Key references below).
NB3: Temperature in stability studies varies between 2 to 8°C.
NB4: A maximum of 7 days microbiological stability is given for products produced by a nonlicensed manufacturing facility.
NB5: Preparations left out of the fridge in hot climates or placed close to the patient’s body during infusion often reach high temperatures (up to
35°C).
Information for patients receiving community-based parenteral

Patients receiving community-based parenteral antimicrobial therapy, and their carers, should be educated and
provided with written information explaining their treatment.
The antimicrobial product, including the expiry date and storage instructions. If the product needs to be
refrigerated, it should be stored in the body of the fridge away from the door, and not in the freezer.
How to care for the infusion while it is running, for example:
store in the pouch or ‘bum bag’ provided
at night, store away from bed if possible and not under the blankets or on the body
avoid immersing the device in water.
How to care for the intravenous line and delivery device:
the usual appearance and performance of the intravenous line should be demonstrated; any
changes should be reported by the patient or carer to the service staff
how to recognise if the pump or delivery device malfunctions, and what to do
avoid immersing the administration site in water, and what to do if this happens. Protect with a
plastic bag or plastic cling wrap while washing.
How to recognise complications of infection (eg rash; diarrhoea; fever; pain, redness or swelling around
the intravenous access site) or progression of the infection, and who to contact if these occur.
Contact details for the community-based parenteral antimicrobial therapy team or local health service
for problems or questions (24 hours a day, 7 days a week).
Monitoring patients receiving community-based parenteral

Studies have shown in patients receiving community-based parenteral antimicrobial therapy:
up to 25% develop adverse reactions or intravenous access device complications

5 to 10% require readmission
around 5% request urgent telephone advice or unscheduled home visits, most commonly for infusion
device or vascular access problems.
Accordingly, a member of the managing team should be available for contact by the patient or carer 24 hours
a day, 7 days a week, and there should be a process for arranging rapid review of the patient. The patient
should have written contact information and education material on common problems and adverse events (see
Information for patients receiving community-based parenteral antimicrobial therapy).
Patients receiving community-based parenteral antimicrobial therapy must have regular medical review;
usually, this should be at least weekly. The purpose of medical review is to:
monitor response to treatment

monitor for antibiotic adverse effects and other complications, including device-related complications
review the results of investigations (including kidney and liver function monitoring)
consider if the duration of antimicrobial therapy should be revised, including whether an earlier switch
to oral therapy is appropriate
discuss the patient’s experience of treatment.
Specialist community-based parenteral antimicrobial therapy staff may visit the patient daily, or other clinical
staff may see the patient in the community periodically; the frequency will depend on the model of care
employed. In some services, suitable patients (or carers) are trained to manage their own treatment (including
line care and recognising complications or deterioration) so staff visits are less frequent.
Patients should have blood tests performed at least once a week (eg full blood count, urea and electrolytes,
liver biochemistry). More frequent testing may be required. Some antimicrobials, such as aminoglycosides
(gentamicin, amikacin) and glycopeptides (vancomycin, teicoplanin), require plasma concentration and other
relevant clinical monitoring for safety and efficacy (see Principles of aminoglycoside use, Principles of
vancomycin use and Monitoring teicoplanin). Patients discharged on aminoglycosides must be carefully
monitored for nephrotoxicity as well as vestibular and auditory toxicity (see Clinical monitoring for
aminoglycoside toxicity). Glycopeptide therapy requires regular measurement of kidney function.
Governance of patients being treated in the community setting may be compromised, so extra vigilance is
required when checking the results of blood tests, including those for plasma concentration monitoring.
Additionally, the patient’s diet, fluid intake, level of activity and nonairconditioned environment at home can
increase the risks of dehydration, drug toxicity, hypoglycaemia and other complications, and monitoring of
kidney function, plasma drug concentrations and other relevant parameters is particularly important.
Fever in a patient receiving community-based parenteral antimicrobial therapy should prompt early review of
the intravascular access device. Collect blood for culture from the device and peripherally. If the patient has
signs of sepsis or haemodynamic compromise, or if the area around the access site is inflamed, remove the
device immediately and send the tip for culture (see Bloodstream infections associated with an intravascular
device for further information).
Key references
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Patel S, Abrahamson E, Goldring S, Green H, Wickens H, Laundy M. Good practice recommendations for
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Hodgson KA, Huynh J, Ibrahim LF, Sacks B, Golshevsky D, Layley M, et al. The use, appropriateness and
outcomes of outpatient parenteral antimicrobial therapy. Arch Dis Child 2016;101(10):886–93.
Mujal A, Sola J, Hernandez M, Villarino MA, Baylina M, Tajan J, et al. Safety and effectiveness of outpatient
parenteral antimicrobial therapy in older people. J Antimicrob Chemother 2016;71(5):1402–7.
Shrestha NK, Shrestha J, Everett A, Carroll D, Gordon SM, Butler RS, et al. Vascular access complications during
outpatient parenteral antimicrobial therapy at home: a retrospective cohort study. J Antimicrob Chemother
2016;71(2):506–12.
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Chapman AL, Seaton RA, Cooper MA, Hedderwick S, Goodall V, Reed C, et al. Good practice recommendations
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Halilovic J, Christensen CL, Nguyen HH. Managing an outpatient parenteral antibiotic therapy team: challenges
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parenteral antimicrobial therapy in older people. J Antimicrob Chemother 2016;71(5):1402–7.
National Health & Medical Research Council (NHMRC). Australian Guidelines for the Prevention and Control of
Infection in Healthcare. Canberra: Commonwealth of Australia; 2010. http://www.nhmrc.gov.au
Pedersen MG, Jensen-Fangel S, Olesen HV, Tambe SD, Petersen E. Outpatient parenteral antimicrobial therapy
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Ravelingien T, Buyle F, Deryckere S, Sermijn E, Debrauwere M, Verplancke K, et al. Optimization of a model of

out-of-hospital antibiotic therapy (OPAT) in a Belgian university hospital resulting in a proposal for national
implementation. Acta Clin Belg 2016:1–6.
Rentala M, Andrews S, Tiberio A, Alagappan K, Tavdy T, Sheppard P, et al. Intravenous home infusion therapy
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Shrestha NK, Shrestha J, Everett A, Carroll D, Gordon SM, Butler RS, et al. Vascular access complications during
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Principles of aminoglycoside use
The role of aminoglycosides in treating infection
The aminoglycosides gentamicin, amikacin and tobramycin are highly effective drugs for parenteral treatment
of Gram-negative infections. They are often preferred to broad-spectrum penicillins or cephalosporins for
empirical therapy of serious infections because they are more rapidly bactericidal, and rates of
aminoglycoside resistance are generally low in both community- and healthcare-associated Gram-negative
pathogens. Aminoglycosides have different spectrums of activity; for example, organisms that are not
susceptible to gentamicin may be susceptible to amikacin.
The parenteral aminoglycoside kanamycin is increasingly used to treat resistant mycobacterial infections, but
is inferior to other aminoglycosides for the treatment of Gram-negative infections. Along with amikacin, it has
largely replaced streptomycin for treatment of mycobacterial infections because of higher rates of
susceptibility and better availability.
When given in combination with some cell-wall–active drugs (eg penicillins, glycopeptides), aminoglycosides
provide useful synergistic killing of some difficult-to-treat pathogens (eg enterococci, viridans streptococci,
Bartonella species). Indeed, combination therapy has a higher rate of clinical cure for serious enterococcal
infections (eg endocarditis) than therapy with a cell-wall–active drug alone. Similarly, for uncomplicated
endocarditis caused by viridans streptococci, the duration of therapy can sometimes be reduced with
combination therapy.
Aminoglycoside toxicity has led some clinicians to argue that other less toxic antibiotics (eg carbapenems,
broad-spectrum cephalosporins) should be used instead; these are generally more broad-spectrum. Given the
rapid emergence of resistance to other classes of antibiotics, and the increased incidence of Clostridium
difficile infection, concerns about toxicity must be balanced against the known advantages of
aminoglycosides. While aminoglycosides should be used cautiously in several patient groups (see Box 2.42),
there are few contraindications to aminoglycoside use.
In neonates, infants and children, short-course aminoglycoside therapy is usually well tolerated.
The benefit–harm profile of aminoglycoside therapy is dependent on both the infection for which it is used (eg
severity of infection, likelihood of the pathogen being resistant to other antibiotics) and patient factors (eg risk
factors for adverse effects).
When aminoglycoside therapy is recommended in these guidelines, it is the consensus view of the Antibiotic
Expert Groups that the potential benefits of aminoglycoside therapy outweigh potential harms.
Significant advantages and disadvantages of aminoglycoside use are listed in Box 2.43.
Aminoglycoside contraindications and precautions (Box 2.42)
Contraindications
Do not use aminoglycosides in patients with:
a history of aminoglycoside-induced vestibular or auditory toxicity

a history of a severe hypersensitivity reaction to an aminoglycoside, but these reactions are rare
myasthenia gravis.
Precautions
Aminoglycosides should not generally be used in patients with:
pre-existing significant auditory impairment

a pre-existing vestibular condition
a first-degree relative with aminoglycoside-induced auditory toxicity, since some people have a rare
inherited genetic predisposition.
A single dose of an aminoglycoside can be used [NB1] in patients:
with chronically impaired kidney function (adults with a creatinine clearance less than 40 mL/minute
and children with an estimated glomerular filtration rate less than 50 mL/minute/1.73 m2) [NB2]
with rapidly deteriorating kidney function unrelated to sepsis
who are frail and elderly (eg 80 years or older).
NB1: Multiple doses of an aminoglycoside should not be used in these patients unless recommended by an expert.
NB2: Aminoglycosides need not be avoided in patients with minimal residual kidney function receiving long-term dialysis.
Advantages and disadvantages of aminoglycosides (Box 2.43)
Advantages of aminoglycosides
Aminoglycosides are bactericidal and associated with rapid control of Gram-negative infections.
Most community- and healthcare-associated Gram-negative pathogens are susceptible to
aminoglycosides [NB1].
Aminoglycosides have a ‘postantibiotic effect’ that allows for effective once-daily therapy with
reduced rates of toxicity.
When combined with cell-wall–active drugs (eg beta lactams, glycopeptides), aminoglycosides are
synergistic for enterococcal and streptococcal infections.
Aminoglycosides rarely cause hypersensitivity reactions.
Aminoglycosides are rarely associated with Clostridium difficile infection.
Aminoglycosides are cheap.
Disadvantages of aminoglycosides
Aminoglycosides cause nephrotoxicity, usually associated with prolonged treatment courses (longer
than 5 to 7 days) and pre-existing kidney impairment. Nephrotoxicity is generally reversible.
Aminoglycosides cause vestibular and, less commonly, auditory toxicity, mostly associated with
prolonged treatment courses. Vestibular and auditory toxicity are generally irreversible.
NB1: Some Enterobacteriaceae strains exhibit resistance to aminoglycosides; these strains are also resistant to other drug classes.
Approach to aminoglycoside use

Aminoglycosides are primarily used for short-term empirical therapy of serious Gram-negative infections,
pending the outcome of investigations. In a limited number of circumstances, they also have a role in directed
therapy. These include:
treatment of pathogens confirmed, or suspected to be, resistant to antibiotics more appropriate for
longer term use
initial combination therapy for Pseudomonas aeruginosa infections, until susceptibility results are
available
combination therapy for brucellosis, nontuberculous mycobacterial infections, and tuberculosis
combination therapy for synergistic therapy of streptococcal, enterococcal and Bartonella endocarditis.
When used for empirical therapy, aminoglycoside dosing should not continue beyond 48 hours (ie a maximum
of three empirical doses at 0, 24 and 48 hours). Given the ‘postantibiotic effect’ of aminoglycosides, whereby
bacterial killing continues for many hours after plasma concentration is undetectable, this effectively provides
72 hours of therapy.
When used for empirical therapy, aminoglycoside dosing should not continue beyond 48 hours.
The principles of aminoglycoside dosing and monitoring are summarised in Once-daily or less frequent
aminoglycoside dosing for empirical and directed therapy, Multiple-daily (synergistic) aminoglycoside
dosing, Monitoring aminoglycoside plasma concentrations and Clinical monitoring for aminoglycoside
toxicity. A checklist for prescribing aminoglycosides is given in Box 2.44.
Prescribers must be able to monitor kidney function and, if therapy will continue for more than 48 hours,
measure the aminoglycoside plasma concentration. As with other potentially toxic drugs, appropriate hospital
policies should be in place to guide use of aminoglycosides.
The use of aminoglycosides for surgical prophylaxis is not addressed in this topic—see Principles of
gentamicin use for surgical antibiotic prophylaxis.
Aminoglycosides have traditionally been administered by intravenous infusion; however, there is significant
evidence for safe gentamicin and tobramycin administration by slow intravenous injection over 3 to 5 minutes
in both adults and children. There are limited data for amikacin administration by slow intravenous injection.
Further advice on administration of aminoglycosides can be found in the Australian Injectable Drugs
Handbook [Note 1].
Checklist for prescribing aminoglycosides (Box 2.44)
Is there a clear indication for aminoglycoside therapy?
See the indications for aminoglycoside therapy in these guidelines or local protocols. Aminoglycosides are
primarily indicated for short-term empirical therapy, but may also be used for directed therapy.
Does the patient have contraindications or precautions that preclude aminoglycoside use?
There are few contraindications to aminoglycoside use. However, use aminoglycosides with caution in
patients at increased risk of toxicity (see Box 2.42).
Is the patient likely to have altered pharmacokinetics?
For patients with altered pharmacokinetics (see Box 2.45), modified dosages may be required and close
monitoring is necessary.
Is the patient’s kidney function known?
The patient’s kidney function influences aminoglycoside dosage (eg initial dose in adults, frequency of
dosing, whether repeated doses can be used). If the patient is acutely unwell, it is appropriate to administer
an initial empirical dose without ascertaining kidney function.
How is the appropriate dosage determined?
The choice of dosage should be made with consideration of the patient’s clinical status and comorbidities.
The appropriate aminoglycoside dosage is determined by the patient’s weight and kidney function. Adjusted
body weight is used for children who are obese and adults who are obese class I (BMI 30 to 34.9 kg/m2).
Expert advice is required for adults who are obese class II or III (BMI 35 kg/m2 or more).
Table 2.73 provides calculated initial gentamicin dosages for adults based on the information in Table 2.72,
including adults with altered pharmacokinetics due to critical illness or obesity. For dosages in adults with
altered pharmacokinetics due to other causes, seek expert advice.
For initial aminoglycoside dosages for children, including children with altered pharmacokinetics due to
critical illness or obesity, see Table 2.74. For dosages in children with altered pharmacokinetics due to other
causes, seek expert advice.
For initial aminoglycoside dosages for neonates, including preterm neonates, see Table 2.74.
When gentamicin is used for synergy with cell-wall–active drugs (eg beta lactams, glycopeptides), multiple-
daily dosing is generally required.
Is aminoglycoside therapy empirical or directed?
Empirical aminoglycoside dosing should not continue beyond 48 hours. If continued antibiotic therapy is
required at 72 hours, switch to an alternative antibiotic.
If directed therapy is expected to be prolonged (eg for enterococcal endocarditis), confirm aminoglycoside
susceptibility.
Is plasma concentration monitoring required?
Plasma concentration monitoring is generally not required for therapy that will be stopped within 48 hours.
However, consider monitoring from the first dose if kidney function is changing rapidly or substantially, or
in patients with altered pharmacokinetics (eg obese patients).
Plasma concentration monitoring is mandatory from the first dose if therapy is expected to continue for
more than 48 hours.
Undertake clinical monitoring for toxicity in all patients.
See Clinical monitoring for aminoglycoside toxicity.

Note 1: Available for purchase from The Society of Hospital Pharmacists of Australia website.
Once-daily or less frequent aminoglycoside dosing for empirical and

directed therapy
The aminoglycoside dosage depends on the patient’s renal clearance and the drug’s volume of distribution,
which are related to lean body weight [Note 2]. Therefore, the appropriate dosage is determined by the
patient’s weight and kidney function (for adults, creatinine clearance [CrCl] estimated using the Cockcroft–
Gault formula; for children older than 1 year, glomerular filtration rate [GFR] estimated using the modified
Schwartz formula). Patients with altered pharmacokinetics may require modified dosages; see
Aminoglycoside use in special patient groups.
The choice of dosage should be made with consideration of the patient’s clinical status and comorbidities.
Table 2.72 shows the recommended weight-based aminoglycoside doses for adults, stratified by kidney
function and whether the patient is critically ill. Table 2.73 provides initial gentamicin doses, calculated based
on the information in Table 2.72, to assist with appropriate dose selection.
Table 2.74 shows the recommended weight-based aminoglycoside doses for neonates and children.
The dosages in these tables are not suitable for resistant Mycobacterium avium complex infection,
brucellosis or nocardiosis.
Although the aminoglycoside dosage depends on the patient’s renal clearance, if the patient is acutely unwell
it is appropriate to administer an initial empirical dose without ascertaining kidney function. A single dose of
aminoglycoside is generally safe, even in patients with impaired kidney function, and can be life-saving;
however, subsequent dosing requires careful consideration. See Patients with renal impairment for more
information.
If plasma concentration monitoring is indicated, see here for monitoring advice.
Initial aminoglycoside dosage for treating infection in adults (Table 2.72)
Creatinine clearance Dose [NB3] [NB4] [NB5] [NB6] Dosing Maximum

(CrCl) [NB1] [NB2] gentamicin or amikacin [NB10] frequency number of
tobramycin [NB7] [NB11] empirical doses
[NB8] [NB9]
noncritically critically noncritically critically
ill adults ill adults ill adults ill adults
more than 60 16 to 20 3 doses (at 0, 24
4 to 5 mg/kg 7 mg/kg 28 mg/kg 24-hourly
mL/minute mg/kg and 48 hours)
16 to 20 2 doses (at 0 and
40 to 60 mL/minute 4 to 5 mg/kg 5 mg/kg 20 mg/kg 36-hourly
mg/kg 36 hours)
single dose, then seek expert
advice for subsequent dosing or
less than 40 mL/minute 4 mg/kg 4 mg/kg 16 mg/kg 16 mg/kg
selection of alternative drug
[NB12]
NB1: Use the Cockcroft–Gault formula to estimate creatinine clearance—see Estimating glomerular filtration rate in adults or use the online
calculator. If serum creatinine is less than 60 micromol/L, use a value of 60 micromol/L in the calculation.
NB2: The renal function thresholds for reducing the aminoglycoside dosage are based on the consensus view of the Antibiotic Expert Groups,
because clinical evidence is lacking.
NB3: If the patient is obese (body mass index [BMI] 30 kg/m2 or more), use adjusted body weight (see Box 2.46) to calculate the dose. However,
the adjusted body weight–based dose for obese patients who have a BMI just above 30 kg/m2 may be lower than the actual body weight–based
dose for overweight patients with a BMI just below 30 kg/m2; an obese patient should not receive a dose smaller than an overweight patient of the
same height. For obese patients with a BMI of 35 kg/m2 or more, seek expert advice.
NB4: If actual body weight (for patients who are not obese) or adjusted body weight (for patients who are obese) is greater than 100 kg, use a
weight of 100 kg to calculate the dose.
NB5: In patients with altered pharmacokinetics (see Box 2.45), the dosages in this table may not achieve the target area under the concentration–
time curve. Consider monitoring the aminoglycoside plasma concentration from the first dose to optimise dosing. More frequent measurement of
the plasma concentration is needed if the patient’s renal function or volume of distribution is not stable.
NB6: Do not use the dosages in this table for synergistic therapy (see Bartonella infections, streptococcal endocarditis or enterococcal
endocarditis), resistant Mycobacterium avium complex infection, brucellosis or nocardiosis.
NB7: Table 2.73 provides calculated initial gentamicin doses based on the information in this table; the choice of dosage should be made with
consideration of the patient’s clinical status and comorbidities, the potential toxic effects of the drug, and the likely consequences of underdosing.
NB8: Most clinical studies of once-daily aminoglycoside (gentamicin, tobramycin, netilmicin) therapy have suggested that a dose of 4 to 5 mg/kg
is effective and associated with limited toxicity. The doses recommended in this table are based on these data and the consensus view of the
Antibiotic Expert Groups.
NB9: Round dose down to the nearest multiple of 40 mg.
NB10: Round dose down to the nearest multiple of 125 mg.
NB11: The amikacin doses in this table are derived by multiplying the gentamicin dose by four. Some respected references recommend amikacin
doses that are approximately three times the gentamicin dose. When selecting an appropriate dose, consider local protocols and the available
literature.
NB12: The recommendation to give a single dose to patients with creatinine clearance less than 40 mL/minute is based on the consensus view of
the Antibiotic Expert Groups, because clinical evidence is lacking.
Calculated initial gentamicin doses for adults (Table 2.73) [NB1] [NB2]
Printable table
Height Actual body weight Suggested dose for noncritically ill Suggested dose for critically ill
adults, and critically ill adults with adults without known or likely pre-
(body mass index known or likely pre-existing kidney existing kidney impairment [NB6]
[BMI] category) impairment [NB4] [NB5] [NB7]
[NB3]
less than 42 kg
see Table 2.72 to calculate the dose see Table 2.72 to calculate the dose
(underweight)
42 to less than 56 kg
200 to 240 mg [NB8] 280 to 360 mg
(healthy weight)
150 cm 280 mg 360 to 440 mg
(overweight)
280 mg 360 to 440 mg
(obese class I)
79 kg or more
seek expert advice seek expert advice
(obese class II or III)
less than 47 kg
(underweight)
200 to 280 mg [NB9] 320 to 440 mg
(healthy weight)
160 cm 320 mg 440 to 520 mg
(overweight)
320 mg 440 to 520 mg
(obese class I)
90 kg or more
less than 53 kg
(underweight)
240 to 320 mg [NB10] 360 to 480 mg
(healthy weight)
170 cm 360 mg 480 to 600 mg
(overweight)
87 kg to less than
101 kg 360 mg 480 to 600 mg
(obese class I)
101 kg or more
less than 60 kg
(underweight)
280 to 360 mg [NB11] 400 to 560 mg
(healthy weight)
81 to less than 97 kg 560 to 680 mg; seek expert advice
400 mg before prescribing a dose more than
180 cm (overweight) 600 mg
97 to less than 113 560 to 680 mg; seek expert advice
kg
400 mg before prescribing a dose more than
600 mg
(obese class I)
113 kg or more
less than 67 kg
(underweight)
320 to 360 mg [NB12] 440 to 600 mg
(healthy weight)
90 to less than 108
600 to 680 mg; seek expert advice
kg 400 to 440 mg before prescribing a dose more than
190 cm
(overweight) 600 mg
108 to less than 126
600 to 680 mg; seek expert advice
kg 400 to 440 mg before prescribing a dose more than
(obese class I) 600 mg
126 kg or more
NB1: The doses in this table are calculated using the information in Table 2.72, and are provided to assist with appropriate dose selection.
However, the choice of dosage should be made with consideration of the patient’s clinical status and comorbidities, the potential toxic effects of
the drug, and the likely consequences of underdosing. In patients with altered pharmacokinetics, the dosing in this table may not achieve the target
area under the concentration–time curve.
NB2: Once an initial dose has been selected, see Table 2.72 for the appropriate dosing frequency and maximum number of empirical doses.
NB3: For underweight, healthy weight or overweight patients, actual body weight was used to calculate the dose. For obese class I patients,
adjusted body weight was used to calculate the dose; however, if this dose was smaller than the dose for an overweight patient of the same height,
then the dose for the overweight patient was used instead. If actual or adjusted body weight was greater than 100 kg, a weight of 100 kg was used.
NB4: The doses in this column are based on a dose of 4 to 5 mg/kg, rounded down to the nearest 40 mg.
NB5: Use the doses in this column for critically ill adults with creatinine clearance known or likely to be less than 60 mL/minute.
NB6: The doses in this column are based on a dose of 7 mg/kg, rounded down to the nearest 40 mg. Choose a dose within this range according to
the individual patient weight—the lower dose corresponds to the lower limit of the weight range and the higher dose corresponds to the upper limit
of the weight range.
NB7: Consider monitoring the gentamicin plasma concentration from the first dose to optimise dosing.
NB8: Choose a dose within this range according to the individual patient weight—a 200 mg dose is appropriate for patients who weigh close to 42
kg and a 240 mg dose is appropriate for patients who weigh close to 56 kg.
NB9: Choose a dose within this range according to the individual patient weight—a 200 mg dose is appropriate for patients who weigh close to 47
kg and a 280 mg dose is appropriate for patients who weigh close to 64 kg.
NB10: Choose a dose within this range according to the individual patient weight—a 240 mg dose is appropriate for patients who weigh close to
53 kg and a 320 mg dose is appropriate for patients who weigh close to 72 kg.
Initial aminoglycoside dosage for treating infection in neonates and children (Table 2.74)
Age Dose [NB1] [NB2] [NB3] Dosing Maximum number

gentamicin or amikacin [NB4] frequency of empirical doses
tobramycin [NB5]
neonates younger than 30
weeks postmenstrual age 5 mg/kg 2 doses (at 0 and 48
20 mg/kg 48-hourly
[NB6] [NB7] hours)
neonates 30 to 34 weeks
2 doses (at 0 and 36
postmenstrual age 5 mg/kg 20 mg/kg 36-hourly
hours)
[NB6] [NB7]
neonates 35 weeks
3 doses (at 0, 24 and
postmenstrual age or older 5 mg/kg 20 mg/kg 24-hourly
48 hours)
[NB6] [NB7]
children 1 month to 7.5 mg/kg up to 320 30 mg/kg up to 1.25 3 doses (at 0, 24 and
24-hourly
younger than 10 years mg [NB8] [NB9] g [NB8] [NB9] 48 hours)
6 mg/kg up to 560 24 mg/kg up to 2.25
mg g
children with septic children with septic

children 10 years and 3 doses (at 0, 24 and
shock or requiring shock or requiring 24-hourly
older 48 hours)
intensive care intensive care
support: 7 mg/kg support: 28 mg/kg
[NB8] [NB8]
NB1: There are few data on aminoglycoside dosing in children. The dosages recommended in this table are based on the available data and the
consensus view of the Antibiotic Expert Groups.
NB2: Do not use the dosages in this table for children with cystic fibrosis or receiving chemotherapy, or for synergistic therapy (see Bartonella
infections, streptococcal endocarditis or enterococcal endocarditis), resistant Mycobacterium avium complex infection, brucellosis or nocardiosis.
NB3: In patients with altered pharmacokinetics (see Box 2.45), the dosages in this table may not achieve the target area under the concentration–
time curve. Consider monitoring the aminoglycoside plasma concentration from the first dose to optimise dosing. More frequent measurement of
the plasma concentration is needed if the patient’s renal function or volume of distribution is not stable.
NB4: The amikacin doses in this table are derived by multiplying the gentamicin dose by four. Some respected paediatric references recommend
amikacin doses that are approximately three times the gentamicin dose. When selecting an appropriate dose, consider local protocols and the
available literature.
NB5: For children with impaired kidney function (estimated glomerular filtration rate less than 50 mL/minute/1.73 m2), give a single dose, then
seek expert advice for subsequent dosing or selection of an alternative antibiotic. Use the modified Schwartz formula to estimate glomerular
filtration rate in children older than 1 year.
NB6: Postmenstrual age is the time elapsed between the first day of the last menstrual period and birth (gestational age) plus the time elapsed after
birth (postnatal age).
NB7: Preterm infants (gestational age less than 37 weeks), especially if small for gestational age, may have altered pharmacokinetics. The
recommendations in this table provide a guide to initial dosing—expert advice may be needed.
NB8: For obese children, use adjusted body weight to calculate the dose—see Children who are obese.
NB9: The dose cap does not apply to children with septic shock or requiring intensive care support.
Note 2: Aminoglycosides are hydrophilic drugs that are preferentially distributed into lean tissue, so lean body weight is the most accurate
weight descriptor for calculating aminoglycoside doses. However, the calculation of lean body weight is relatively complicated, so for
practicality, in these guidelines actual body weight is used for dose calculations in people who are underweight, healthy weight or overweight,
and adjusted body weight (see Box 2.46) is used for aminoglycoside dose calculations in people who are obese. Expert advice is required for
obese adults with a body mass index (BMI) of 35 kg/m2 or more. If actual or adjusted body weight is greater than 100 kg, a weight of 100 kg
should be used to calculate the dose.
Multiple-daily (synergistic) aminoglycoside dosing

Seek expert advice for the management of patients treated with multiple-daily (synergistic) aminoglycoside
dosing.
Most studies suggest that a detectable aminoglycoside plasma concentration throughout the dosing period is
necessary for effective synergistic activity. Multiple-daily dosing is generally required to achieve this, unless
there is substantial kidney impairment [Note 3].
If plasma concentration monitoring is indicated, see here for monitoring advice.
Note 3: Once-daily dosing of gentamicin is not yet widely accepted for use as synergistic therapy. See Gentamicin for the treatment of infective
endocarditis for further details.
Monitoring aminoglycoside plasma concentrations

Indications for plasma concentration monitoring
Aminoglycoside plasma concentration monitoring is generally not required for therapy that will be stopped
within 48 hours. However, consider monitoring from the first dose if the patient’s kidney function is changing
rapidly or substantially (eg critically ill patients with sepsis, patients with suspected acute kidney failure), and
in patients with altered pharmacokinetics (see Box 2.45).
Aminoglycoside plasma concentration monitoring is mandatory from the first dose if therapy is expected to
continue for more than 48 hours, and in neonates with renal impairment.
Plasma concentration monitoring is generally not required for empirical therapy. It is mandatory from the first dose if
therapy is expected to continue for more than 48 hours.
Plasma concentration monitoring ensures adequacy of dosing and avoids excessive drug exposure, which can
be associated with nephrotoxicity, and occasionally vestibular and auditory toxicity.
Plasma concentration monitoring for once-daily or less frequent dosing
Adults and children
Measure the plasma concentration every 48 hours, or more frequently if kidney function is changing rapidly
or substantially.
For once-daily or less frequent dosing of aminoglycosides, clinical efficacy is correlated with the area under
the concentration–time curve (AUC); toxicity is minimised if there is an undetectable trough plasma
concentration. The appropriate target AUC depends on the minimum inhibitory concentration (MIC) of the
pathogen, because the ratio of the AUC to MIC appears to best predict aminoglycoside efficacy. For
mycobacterial infections, the AUC target associated with clinical efficacy is less clear, and peak and trough
plasma concentrations are sometimes monitored instead—seek expert advice.
For Gram-negative organisms, a target 24-hour AUC/MIC of 80 to 100 mg.hr/L has been advocated, but
consensus is lacking. For pathogens with a gentamicin or tobramycin MIC of 1 mg/L or less, this correlates to
a target AUC of 80 to 100 mg.hr/L. If prolonged therapy is anticipated, consider requesting the MIC of the
pathogen to guide dosing. If the MIC of the pathogen is more than 1 mg/L, the AUC must be adjusted
accordingly—seek expert advice.
Dose optimisation software provides the most sophisticated method for AUC monitoring because it accounts
for significant individual variation in aminoglycoside pharmacokinetics. Some software also considers
uncertainty in sampling and the assay method. This complexity is not accounted for when the AUC is
calculated manually (using pharmacokinetic equations, such as the trapezoidal rule) [Note 4] or using a
spreadsheet [Note 5]. Regardless of the method used for AUC calculation, clinical judgement is required
when determining the appropriate dosage adjustment for a patient.
Most computerised methods require two plasma concentration measurements (usually 30 minutes after
completion of the infusion, and 6 to 8 hours after the dose), but software that uses population pharmacokinetic
models and Bayesian predictive models can function with only one measurement.
Trough plasma concentrations provide evidence of accumulation but correlate poorly with overall exposure,
so cannot be used to monitor once-daily or less frequent dosing in adults or children. If monitoring is required
and AUC methods are not available, seek expert advice.
Note 4: Manual AUC calculation is described in: Begg EJ, Barclay ML, Duffull SB. A suggested approach to once-daily aminoglycoside dosing.
Br J Clin Pharmacol 1995;39(6):605-9. [URL]
Note 5: A spreadsheet for AUC calculation and dosage adjustment for a target AUC of 80 mg.hr/L is included in: Wong C, Kumar SS, Graham
GG, Begg EJ, Chin PK, Brett J, et al. Comparing dose prediction software used to manage gentamicin dosing. Intern Med J 2013;43(5):519-25.
[URL]
Neonates
Seek expert advice on plasma concentration monitoring in neonates. AUC monitoring in neonates is less
established than in adults and children. AUC calculation requires repeated blood sampling, which is
problematic because of the small blood volume of some neonates. Some paediatricians prefer to adjust the
dosing interval based on a single aminoglycoside plasma concentration.
Plasma concentration monitoring for multiple-daily (synergistic) dosing
AUC monitoring is not used for patients treated with multiple-daily dosing regimens; instead, the trough
(predose) plasma aminoglycoside concentration is measured. A detectable trough concentration is required for
efficacy; however, to minimise toxicity the trough concentration should not exceed 0.5 to 1 mg/L. In patients
with impaired kidney function, 12-hourly dosing may be necessary to maintain the trough concentration in
this range.
In patients without renal impairment or with stable renal impairment, measure the trough concentration at
least twice weekly. In patients with rapidly or substantially changing kidney function, monitor more
frequently (in some cases daily). If kidney function deteriorates substantially, consider stopping gentamicin—
seek expert advice.
Clinical monitoring for aminoglycoside toxicity

Nephrotoxicity
Undertake clinical monitoring for nephrotoxicity in patients treated with aminoglycoside therapy. Multiple-
daily dosing regimens have a higher risk of nephrotoxicity.
Undertake clinical monitoring for nephrotoxicity in all patients.
Aminoglycoside-induced nephrotoxicity is usually associated with prolonged treatment courses (longer than 5
to 7 days) and pre-existing kidney impairment. It is generally reversible. Check the patient’s kidney function
before starting an aminoglycoside; however, if the patient is acutely unwell, it is appropriate to administer an
initial empirical dose without ascertaining kidney function. If therapy is ongoing, assess kidney function two
to three times each week, or more frequently if kidney function is unstable.
Decreasing aminoglycoside dosage requirements can be an early indicator of deteriorating kidney function.
Vestibular and auditory toxicity
Undertake clinical monitoring for vestibular and auditory toxicity in patients treated with aminoglycoside
therapy.
Undertake clinical monitoring for vestibular and auditory toxicity in all patients.
Aminoglycoside-induced vestibular and auditory toxicity are not predicted by plasma concentrations. Toxicity
may become apparent early in the course of treatment, or weeks after therapy has stopped, and can persist
after stopping aminoglycoside therapy. Sudden idiosyncratic deafness (which has a genetic basis) occurs
rarely.
Inform patients of the potential for vestibular and auditory toxicity if possible, and ask them to report balance
or hearing problems, even after therapy has stopped. Regularly ask patients about:
gait ataxia and imbalance

oscillopsia (the subjective sensation of bouncing vision) or blurred vision during head movement
hearing loss.
Contrary to popular belief, spontaneous vertigo is not a feature of vestibular toxicity.
To check for vestibular toxicity, measure visual acuity (using a Snellen or other visual acuity chart) at rest and
during passive sinusoidal head rotation at 2 Hz. A drop of more than two lines of acuity suggests vestibular
hypofunction [Note 6].
Consider formal vestibular function testing and high-frequency audiometric testing if available, for patients
treated with an aminoglycoside for more than 5 days. In patients treated with gentamicin for endocarditis,
record baseline audiometry when therapy is started and periodically if therapy extends beyond 14 days.
If vestibular or auditory toxicity is detected, stop the aminoglycoside and seek expert advice.
Note 6: For practical advice about performing vestibular function tests, see Petersen JA, Straumann D, Weber KP. Clinical diagnosis of bilateral
vestibular loss: three simple bedside tests. Ther Adv Neurol Disord 2013;6(1):41-5. [URL]
Aminoglycoside use in special patient groups

Patients with altered pharmacokinetics
Box 2.45 lists patient groups with altered pharmacokinetics.
Patients with altered pharmacokinetics (Box 2.45)
The following patient groups may have altered pharmacokinetics (eg clearance, drug distribution), so may
require modified aminoglycoside dosages. Close monitoring is necessary. Expert advice is recommended.
Critically ill patients with sepsis or septic shock—see here for critically ill adults.
Patients treated with renal replacement therapy.
Patients with severe burns.
Patients with cystic fibrosis.
Pregnant women.
Patients with ascites.
Obese patients—see here for obese adults and here for obese children.
Preterm infants, especially if small for gestational age—see Table 2.74 for initial aminoglycoside
dosage and here for monitoring plasma concentrations in neonates.
Patients treated with chemotherapy that causes kidney dysfunction (eg cisplatin).
Critically ill adults with sepsis or septic shock

Critically ill adults with sepsis or septic shock (usually those requiring intensive care support) often have an
increased volume of drug distribution and enhanced renal drug clearance. Pharmacokinetic/pharmacodynamic
modelling studies predict that an initial gentamicin dose of 7 mg/kg daily is required to achieve the target area
under the concentration–time curve (AUC) in these patients. Higher doses also ensure that pathogens with a
relatively high minimum inhibitory concentration (MIC) to gentamicin (eg Pseudomonas aeruginosa) would
be adequately treated. However, most published studies of clinical efficacy (which included some critically ill
patients) used daily gentamicin doses of 4 to 5 mg/kg, and there are currently no large studies showing a
clinical advantage of using 7 mg/kg.
Clinical experience suggests an initial gentamicin dose of 7 mg/kg is unlikely to cause toxicity in
appropriately selected patients. In patients with known or likely pre-existing kidney impairment (such as
patients with advanced age [eg older than 80 years]), a lower gentamicin dose should be used (see Table 2.72).
However, prompt antibiotic initiation in critically ill patients improves outcomes, so do not delay gentamicin
administration to ascertain kidney function. Consider monitoring from the first dose, particularly if the
patient’s kidney function is not known.
Adults who are obese
Choosing an appropriate aminoglycoside dose in adults who are obese class I (body mass index [BMI] 30 to
34.9 kg/m2) or obese class II or III (BMI 35 kg/m2 or more) can be difficult because it is hard to predict the
volume of distribution. Data support calculating the dose using adjusted body weight (see Box 2.46), because
this reflects the mass of the patient’s metabolically active tissue. However, the adjusted body weight–based
dose for obese patients who have a BMI just above 30 kg/m2 may be lower than the actual body weight–based
dose for overweight patients with a BMI just below 30 kg/m2; an obese patient should not receive a dose
smaller than an overweight patient of the same height. If a patient’s adjusted body weight is greater than 100
kg, use a weight of 100 kg to calculate the dose.
Careful monitoring of the plasma aminoglycoside concentration is needed to ensure adequate concentrations
and avoid toxicity. For patients with a BMI of 30 to 34.9 kg/m2, consider monitoring from the first dose and
seeking expert advice to optimise dosing. For patients with a BMI of 35 kg/m2 or more, expert advice for
dosing and monitoring is essential.
Adjusted body weight formula (Box 2.46)
To estimate IBW for adults, see Table 2.79 or use the calculator. A child’s ideal body weight can be
estimated using the corresponding weight for the height percentile on the growth chart (eg
www.cdc.gov/growthcharts) or, if the child’s height cannot be determined, the average weight-for-age (50th
centile) on the growth chart [NB1]
IBW = ideal body weight
NB1: Alternative methods of estimating ideal body weight are described by Phillips S, Edlbeck A, Kirby M, Goday P. Ideal body weight in
children. Nutr Clin Pract 2007;22(2):240-5. [URL]
Children who are obese

For children who are obese, use adjusted body weight (see Box 2.46) to calculate the aminoglycoside dose.
and avoid toxicity. Consider monitoring from the first dose and seeking expert advice to optimise dosing.
Pregnant women
It is widely accepted that gentamicin can be safely used to treat serious infections in pregnancy (eg sepsis or
septic shock, acute pyelonephritis), despite its category D classification by the Therapeutic Goods
Administration. There are fewer data on the use of amikacin and tobramycin in pregnancy.
Appropriate aminoglycoside dosing in pregnant women is poorly defined; aminoglycoside plasma

concentrations may be significantly altered by pregnancy-related increases in blood volume and kidney
function. Dosing regimens based on actual, ideal or adjusted body weight have been used in practice and
reported in the literature, but not directly compared. In the absence of comparative data, take the same dosing
approach in pregnant women as for other patients. See Table 2.72 for weight-based doses, and use adjusted
body weight (see Box 2.46) if the woman is obese.
and avoid toxicity. Consider monitoring from the first dose and seeking expert advice to optimise dosing.
Patients with renal impairment
For adults with creatinine clearance less than 40 mL/minute and children with estimated glomerular filtration
rate less than 50 mL/minute/1.73 m2, a single empirical aminoglycoside dose is generally safe and can be life-
saving, but subsequent dosing requires careful consideration. Although repeated once-daily aminoglycoside
dosing for patients with chronic kidney impairment is well accepted by many clinicians, the consensus view
of the Antibiotic Expert Groups is that repeat doses should not be used in these patients unless recommended
by an expert.
If more than a single aminoglycoside dose is administered, careful monitoring is required to optimise efficacy
and avoid toxicity.
When kidney impairment is caused by sepsis, repeat dosing may be appropriate because effective treatment
often improves kidney function. However, if kidney impairment persists or worsens, further aminoglycoside
doses may be inappropriate; an alternative antibiotic should be considered. Expert advice may be required.
Dialysis (eg intermittent haemodialysis, continuous renal replacement therapy [CRRT], sustained low-
efficiency dialysis [SLED]) can markedly alter aminoglycoside pharmacokinetics, so dosing and monitoring is
difficult. Expert advice is needed. AUC-based dose optimisation software must be used, and an alternative
antibiotic should be considered.
Key references
The role of aminoglycosides in treating infection
Johnston C, Hilmer SN, McLachlan AJ, Matthews ST, Carroll PR, Kirkpatrick CM. The impact of frailty on
pharmacokinetics in older people: using gentamicin population pharmacokinetic modeling to investigate changes
in renal drug clearance by glomerular filtration. Eur J Clin Pharmacol 2014;70(5):549–55.
Approach to aminoglycoside use
Loewenthal MR, Dobson PM. Tobramycin and gentamicin can safely be given by slow push. J Antimicrob
Chemother 2010;65(9):2049–50.
Once-daily or less frequent aminoglycoside dosing for empirical and directed therapy
Bijleveld YA, van den Heuvel ME, Hodiamont CJ, Mathôt RA, de Haan TR. Population pharmacokinetics and
dosing considerations for gentamicin in newborns with suspected or proven sepsis caused by Gram-negative
bacteria. Antimicrob Agents Chemother 2017;61(1): .
Boyd SE, Charani E, Lyons T, Frost G, Holmes AH. Information provision for antibacterial dosing in the obese
patient: a sizeable absence?. J Antimicrob Chemother 2016;71(12):3588–3592 .
de Montmollin E, Bouadma L, Gault N, Mourvillier B, Mariotte E, Chemam S, et al. Predictors of insufficient

amikacin peak concentration in critically ill patients receiving a 25 mg/kg total body weight regimen. Intensive
Care Med 2014;40(7):998–1005 .
El-Chaar GM, Supaswud-Franks T, Venugopalan L, Kohn N, Castro-Alcaraz S. Extended-interval gentamicin

administration in neonates: a simplified approach. J Perinatol 2016;36(8):660–665 .
Gálvez R, Luengo C, Cornejo R, Kosche J, Romero C, Tobar E, et al. Higher than recommended amikacin loading
doses achieve pharmacokinetic targets without associated toxicity. Int J Antimicrob Agents 2011;38(2):146–151
.
Hodiamont CJ, Juffermans NP, Bouman CS, de Jong MD, Mathôt RA, van Hest RM. Determinants of gentamicin
concentrations in critically ill patients: a population pharmacokinetic analysis. Int J Antimicrob Agents
2017;49(2):204–211 .
König K, Lim A, Miller A, Saker S, Guy KJ, Barfield CP. Gentamicin trough levels using a simplified extended-
interval dosing regimen in preterm and term newborns. Eur J Pediatr 2015;174(5):669–673 .
Medellín-Garibay SE, Rueda-Naharro A, Peña-Cabia S, García B, Romano-Moreno S, Barcia E. Population

pharmacokinetics of gentamicin and dosing optimization for infants. Antimicrob Agents Chemother
2015;59(1):482–489 .
Neonatal Medicines Formulary Consensus Group. Gentamicin. v2 [neonatal drug information sheet]. Sydney:
NSW Health; 2015. https://www.seslhd.health.nsw.gov.au/royal-hospital-for-women/neomed-formularies.
Plajer SM, Chin PK, Vella-Brincat JW, Buffery PJ, Begg EJ. Gentamicin and renal function: lessons from 15 years'
experience of a pharmacokinetic service for extended interval dosing of gentamicin. Ther Drug Monit
2015;37(1):98–103 .
Rao SC, Srinivasjois R, Hagan R, Ahmed M. One dose per day compared to multiple doses per day of gentamicin
for treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev 2011;(11):CD005091.
.
Roger C, Nucci B, Louart B, Friggeri A, Knani H, Evrard A, et al. Impact of 30 mg/kg amikacin and 8 mg/kg
gentamicin on serum concentrations in critically ill patients with severe sepsis. J Antimicrob Chemother
2016;71(1):208–212 .
Roger C, Nucci B, Molinari N, Bastide S, Saissi G, Pradel G, et al. Standard dosing of amikacin and gentamicin in
critically ill patients results in variable and subtherapeutic concentrations. Int J Antimicrob Agents 2015;46(1):21–
27 .
Ross AL, Tharp JL, Hobbs GR, McKnight R, Cumpston A. Evaluation of extended interval dosing aminoglycosides
in the morbidly obese population. Adv Pharmacol Sci 2013;2013:194389. .
Taccone FS, Laterre PF, Spapen H, Dugernier T, Delattre I, Layeux B, et al. Revisiting the loading dose of
amikacin for patients with severe sepsis and septic shock. Crit Care 2010;14(2):R53. .
Velissaris D, Karamouzos V, Marangos M, Pierrakos C, Karanikolas M. Pharmacokinetic changes and dosing

modification of aminoglycosides in critically ill obese patients: a literature review. J Clin Med Res 2014;6(4):227–
233 .
Zakova M, Pong S, Trope A, Atenafu EG, Papaioannou V, Bitnun SA, et al. Dose derivation of once-daily dosing
guidelines for gentamicin in critically ill pediatric patients. Ther Drug Monit 2014;36(3):288–294 .
Monitoring aminoglycoside plasma concentrations
Begg EJ, Barclay ML, Duffull SB. A suggested approach to once-daily aminoglycoside dosing. Br J Clin
Pharmacol 1995;39(6):605–609 .
Nezic L, Derungs A, Bruggisser M, Tschudin-Sutter S, Krähenbühl S, Haschke M. Therapeutic drug monitoring of

once daily aminoglycoside dosing: comparison of two methods and investigation of the optimal blood sampling
strategy. Eur J Clin Pharmacol 2014;70(7):829–837 .
Sundaram A, Alshaikh B, Dersch-Mills D, Dobry J, Akierman AR, Yusuf K. Extended-interval dosing of gentamicin
in premature neonates born at <32 weeks' gestation and >7 days of age. Clin Ther 2017;39(6):1233–1241
.
Wong C, Kumar SS, Graham GG, Begg EJ, Chin PK, Brett J, et al. Comparing dose prediction software used to
manage gentamicin dosing. Intern Med J 2013;43(5):519–525 .
Clinical monitoring for aminoglycoside toxicity
Ahmed RM, Hannigan IP, MacDougall HG, Chan RC, Halmagyi GM. Gentamicin ototoxicity: a 23-year selected
case series of 103 patients. Med J Aust 2012;196(11):701–704 .
Paquette F, Bernier-Jean A, Brunette V, Ammann H, Lavergne V, Pichette V, et al. Acute kidney injury and renal
recovery with the use of aminoglycosides: A large retrospective study. Nephron 2015;131(3):153–160 .
Petersen JA, Straumann D, Weber KP. Clinical diagnosis of bilateral vestibular loss: three simple bedside tests.
Ther Adv Neurol Disord 2013;6(1):41–45 .
Aminoglycoside use in special patient groups
Boyd SE, Charani E, Lyons T, Frost G, Holmes AH. Information provision for antibacterial dosing in the obese
patient: a sizeable absence?. J Antimicrob Chemother 2016;71(12):3588–3592 .
Chean R, Garland SM, Leung L. Gentamicin in pregnancy: seeing past the drug categorisation in pregnancy.
Intern Med J 2017;47(1):124–125 .
Glaser AP, Schaeffer AJ. Urinary tract infection and bacteriuria in pregnancy. Urol Clin North Am 2015;42(4):547–
560 .
Lulic-Botica M, Sheer T, Edwards D, Thomas RL, Natarajan G. Impact of small-for-gestational age (SGA) status
on gentamicin pharmacokinetics in neonates. J Clin Pharmacol 2014;54(1):39–45 .
Martingano D, Guan X, Renson A, Singh S, Kesavan Nasir M, Kim J, et al. Daily dosing of gentamicin using ideal
body weight for the treatment of intrapartum chorioamnionitis: a pilot study. J Matern Fetal Neonatal Med
2018;31(9):1194–1197 .
Neonatal Medicines Formulary Consensus Group. Gentamicin. v2 [neonatal drug information sheet]. Sydney:
NSW Health; 2015. https://www.seslhd.health.nsw.gov.au/royal-hospital-for-women/neomed-formularies.
Principles of vancomycin use
Introduction to using vancomycin
Vancomycin is a glycopeptide antibiotic primarily used for empirical or directed treatment (and, less
frequently, prophylaxis) of infection with methicillin-resistant Staphylococcus aureus (MRSA), methicillin-
resistant coagulase-negative staphylococcal species (eg Staphylococcus epidermidis) or Enterococcus
faecium. It is inferior to beta-lactam antibiotics for the treatment of methicillin-susceptible S. aureus
(MSSA). Vancomycin also has a role in the treatment and prophylaxis of infection in patients hypersensitive
to penicillins. Vancomycin requires judicious use to limit the emergence of vancomycin resistance.
The use of vancomycin in patients undergoing haemodialysis, continuous renal replacement therapy (CRRT)
or extracorporeal membrane oxygenation (ECMO) requires expert advice; these guidelines include limited
advice on using vancomycin in these patient groups.
Vancomycin infusion advice in adults

Infuse vancomycin at a rate not exceeding 10 mg/minute to reduce the risk of the infusion-related ‘red-man’
syndrome. ‘Red-man’ syndrome is a histamine-mediated, nonallergic response to rapid vancomycin
administration that is characterised by rash, muscle spasms of the chest and back, and sometimes hypotension.
If ‘red-man’ syndrome occurs, extend the infusion time. If a 10 mg/minute infusion rate is tolerated, shorter
infusion times may be possible, but should not be less than 60 minutes for a 1 g dose, 90 minutes for a 1.5 g
dose, or 120 minutes for a 2 g dose.
Vancomycin loading dose for critically ill adults

Although a loading dose of vancomycin achieves a therapeutic concentration more quickly (by 12 hours),
clear evidence that this improves clinical or microbiological outcomes is lacking.
The approach to using vancomycin loading doses varies in clinical practice. It is the consensus view of the
Antibiotic Expert Groups that a loading dose should be considered for critically ill adults because these
patients are at high risk of poor outcomes, and may have reduced vancomycin exposure.
If a vancomycin loading dose is considered necessary, use:
vancomycin 25 to 30 mg/kg (actual body weight) intravenously, as a loading dose.
A weight-based loading dose is recommended because volume of distribution and clearance of vancomycin
correlate with actual body weight. However, seek expert advice on loading doses for obese patients because
vancomycin pharmacokinetics are not well defined in this group.
The loading dose may also need to be modified for patients with impaired kidney function (but do not delay
the dose to ascertain kidney function); central nervous system or other deep-seated infection; or infection
caused by a pathogen with a vancomycin minimum inhibitory concentration (MIC) more than 1.5 mg/L—seek
expert advice.
Loading doses do not appear to be associated with an increased risk of nephrotoxicity in large studies of
critically ill patients; however, further prospective data are required, especially for patients at increased risk of
nephrotoxicity. See also Vancomycin nephrotoxicity.
Intermittent vancomycin maintenance dosing for nonobese adults

For intermittent vancomycin dosing in nonobese adults, an appropriate initial maintenance dosage is:
vancomycin 15 to 20 mg/kg (actual body weight) intravenously; see Table 2.75 for
dosing frequency.
The frequency of initial vancomycin dosing depends on the patient’s kidney function, which correlates with
vancomycin clearance. For patients treated with vancomycin for more than 48 hours, dosage adjustments are
based on plasma concentration monitoring.
Calculated initial vancomycin maintenance dosages for adults (Table 2.75)
Actual Suggested dosage [NB2]

body creatinine clearance creatinine clearance creatinine clearance creatinine clearance
weight more than 60 40 to 60 mL/minute 20 to less than 40 less than 20
[NB1] mL/minute [NB3] [NB3] [NB5] mL/minute [NB3] mL/minute [NB3]
[NB4] [NB6] [NB7]
15 to 20 mg/kg (actual 15 to 20 mg/kg (actual 15 to 20 mg/kg (actual 15 to 20 mg/kg (actual
less than 40
body weight) 12- body weight) daily, in body weight) 24- body weight) 48- to
kg
hourly 1 or 2 divided doses hourly 72-hourly
750 mg daily, in 1 or 2 750 mg 48- to 72-
40 to 49 kg 750 mg 12-hourly 750 mg 24-hourly
divided doses hourly
1 g daily, in 1 or 2
50 to 64 kg 1 g 12-hourly 1 g 24-hourly 1 g 48- to 72-hourly
divided doses
1.25 g daily, in 1 or 2
65 to 78 kg 1.25 g 12-hourly 1.25 g 24-hourly 1.25 g 48- to 72-hourly
divided doses
1.5 g daily, in 1 or 2
79 to 92 kg 1.5 g 12-hourly 1.5 g 24-hourly 1.5 g 48- to 72-hourly
divided doses
93 to 107 1.75 g daily, in 1 or 2
1.75 g 12-hourly 1.75 g 24-hourly 1.75 g 48- to 72-hourly
kg divided doses
108 kg or 2 g daily, in 1 or 2
2 g 12-hourly 2 g 24-hourly 2 g 48- to 72-hourly
more divided doses
NB1: For obese patients, see Intermittent vancomycin maintenance dosing for obese adults.
NB2: The dosages in this table are for initial dosing only, up to 48 hours. Subsequent dosage adjustments should be based on plasma concentration
monitoring.
NB3: Use the Cockcroft–Gault formula (see Estimating glomerular filtration rate in adults) or online calculator to approximate creatinine
clearance.
NB4: For adults with creatinine clearance more than 60 mL/minute, 12-hourly dosing is recommended initially.
NB5: For adults with creatinine clearance 40 to 60 mL/minute, various regimens have been described; giving the total daily dose in two 12-hourly
doses or a single 24-hourly dose is therapeutically equivalent as long as the plasma concentration is maintained above 10 mg/L throughout the
dosing interval.
NB6: For adults with creatinine clearance 20 to less than 40 mL/minute, 24-hourly dosing is recommended initially.
NB7: For adults with creatinine clearance less than 20 mL/minute and not treated with dialysis, 48- to 72-hourly dosing is recommended initially.
Check the plasma concentration 48 hours after the first dose; the clinical context determines whether the next dose is given before the plasma
concentration result is available, or withheld until the result is known.
Intermittent vancomycin maintenance dosing for obese adults

Dosing recommendations for obese adults (body mass index [BMI] 30 kg/m2 or more) are uncertain. The
volume of distribution of vancomycin is increased in obesity; clearance may also be increased. However,
changes in clearance are difficult to predict because of obesity-related comorbidities (eg renal impairment).
Dosing recommendations for obese adults are uncertain.
In obese patients, vancomycin doses based on actual body weight may result in high plasma concentrations,
and increased rates of nephrotoxicity have been observed, especially in patients with pre-existing kidney
impairment or concomitantly treated with a nephrotoxin. Despite this, it is the consensus view of the
Antibiotic Expert Groups that the approach to initial vancomycin dosing taken for nonobese patients (ie a 15
to 20 mg/kg actual body weight–based dose) can also be taken for obese patients with a body mass index of
30 to 34.9 kg/m2. See Table 2.75 and consider expert advice to optimise dosing. Careful plasma concentration
monitoring is essential to optimise dosing and minimise toxicity. Alternative regimens are described in a
recent systematic review [Note 1].
For obese patients with a body mass index 35 kg/m2 or more, expert advice is essential.
Note 1: Durand C, Bylo M, Howard B, Belliveau P. Vancomycin dosing in obese patients: special considerations and novel dosing strategies.
Ann Pharmacother 2018;52(6):580-90. [URL]
Vancomycin monitoring and dosage adjustment in adults
Overview of plasma vancomycin concentration monitoring in adults
Plasma concentration monitoring is recommended for patients treated with vancomycin for longer than 48
hours, to optimise dosing. Monitoring is also important to minimise the risk of toxicity, especially in obese
patients or patients with impaired kidney function.
In practice, there are two approaches to monitoring the plasma vancomycin concentration—calculating the
area under the concentration–time curve (AUC) and measuring the trough plasma concentration. The
appropriate target AUC depends on the minimum inhibitory concentration (MIC) of the pathogen, because the
AUC/MIC ratio best predicts vancomycin efficacy. However, there are several practical barriers to using the
AUC for monitoring (see Using AUC for vancomycin monitoring and dosage adjustment in adults). Unless a
health service has expertise with AUC monitoring, it is recommended that trough plasma concentrations are
used to guide dosing.
Monitoring and dosage adjustment using the AUC may be preferable for complicated staphylococcal
infections.
There are few data to support the use of AUC monitoring in several patient groups (eg obese patients, patients
with altered pharmacokinetics).
Timing of plasma concentration measurement for intermittent vancomycin dosing in

adults
The appropriate timing of sampling depends on whether the vancomycin AUC or trough concentration is
monitored.
If the AUC is used for monitoring, seek expert advice on the timing of sampling; Bayesian models allow
AUC to be estimated before steady state is reached.
If the trough (predose) plasma concentration is monitored, the timing of initial sampling depends on kidney
function. For adults with normal kidney function (creatinine clearance 60 mL/minute or more), measure the
plasma concentration before the fourth dose (including the loading dose, if given). It is not necessary to wait
for the result to give the next scheduled dose.
For adults with impaired kidney function (creatinine clearance less than 60 mL/minute), the appropriate
timing of sampling is not clear because the half-life of vancomycin is increased. It is reasonable to check the
trough concentration 48 hours after the first dose. For patients with creatinine clearance 20 to less than 60
mL/minute, it is not necessary to wait for the result to give the next scheduled dose. For patients with
creatinine clearance less than 20 mL/minute, the clinical context determines whether the next dose is given
before the result is available, or withheld until the result is known.
Irrespective of the approach used, monitor the vancomycin concentration at least weekly in stable patients.
More frequent monitoring is required during dose optimisation, and may be required in patients with impaired
or changing kidney function, in patients concomitantly treated with nephrotoxins (see Vancomycin
nephrotoxicity) and if the patient’s clinical condition changes.
Target trough concentration for intermittent vancomycin dosing in adults

Clinical data suggest that a target 24-hour vancomycin AUC of 400 mg.hr/L or more is required for optimal
efficacy (but see Using AUC for vancomycin monitoring and dosage adjustment in adults). It is difficult to
determine an equivalent target trough concentration because the trough concentration is not tightly correlated
with AUC. Indeed, studies have reported similar rates of AUC target attainment with trough concentrations of
10 to more than 20 mg/L. This suggests that in addition to being dependent on the trough concentration, the
AUC is also affected by other factors (especially kidney impairment). Importantly, low trough concentrations
(eg less than 10 mg/L) have been associated with clinical treatment failure and emergence of vancomycin
heteroresistance among Staphylococcus aureus isolates.
For intermittent vancomycin dosing, the generally accepted target trough concentration for complicated
infections is 15 to 20 mg/L. In uncomplicated infections, a lower trough concentration (eg 10 to 14 mg/L)
may be appropriate. Vancomycin penetration into the cerebrospinal fluid is variable. When treating central
nervous system infections, a trough concentration up to 25 mg/L may be required.
Clinical data show there is a risk of nephrotoxicity with vancomycin trough concentrations in this range.
However, the relationship between the trough concentration and nephrotoxicity is unclear, because patients
often have other risk factors for nephrotoxicity (eg concurrent vasopressors; see also Vancomycin
nephrotoxicity). Dose optimisation needs to balance the risk of nephrotoxicity with the limited data to inform
the optimal target trough concentration.
Adjusting the vancomycin dosage in adults based on the trough concentration
When interpreting the vancomycin plasma concentration, consider if the timing of the sample was appropriate
(ie taken predose), and whether it is a steady-state concentration (in patients with normal kidney function,
steady state is usually reached after four vancomycin doses; in patients with impaired kidney function, it takes
longer to reach steady state).
If the trough plasma vancomycin concentration is not within the target range and the timing of the sample was
appropriate and steady state has been reached, see Table 2.76 for suggested dosage adjustment to achieve a
target of 15 to 20 mg/L.
If the trough concentration is far outside the target range, the timing of sampling was not appropriate, or
steady state has not been reached, clinical judgment is needed to interpret the result and determine subsequent
management. It may be appropriate to take another sample and repeat the test before adjusting the dosage.
Dosage adjustments should be made in a linear manner (eg if the trough concentration is two-thirds of the
target concentration, increase the dose by one-third).
Adjusting the vancomycin dosage in adults based on trough concentration (Table 2.76)
Trough plasma concentration Suggested dosage adjustment [NB2] [NB3]

[NB1]
Increase dosage by adjusting the dose or dose interval.
less than 10 mg/L Consider switching to continuous infusion for patients requiring high or
frequent daily doses—seek expert advice.
For patients with uncomplicated infection who are clinically improving,
maintain current dosage.
10 to 14 mg/L For patients with complicated infection, increase dosage by adjusting the
dose or dose interval, and monitor for nephrotoxicity. Alternatively, assess
the AUC/MIC because many patients with a trough concentration of 10 to
14 mg/L have an adequate AUC.
15 to 20 mg/L Maintain current dosage and monitor for nephrotoxicity.
Reduce dosage by adjusting the dose or dose interval, or withhold dose.
Monitor for nephrotoxicity.
21 to 25 mg/L
For patients in whom a trough concentration up to 25 mg/L is advised (eg
central nervous system infection), maintain current dosage.
Withhold the dose until concentration is less than 20 mg/L and seek expert
more than 25 mg/L
advice.
AUC/MIC = ratio of area under the concentration–time curve to minimum inhibitory concentration
NB1: The recommendations in this table assume the timing of the trough sample was appropriate (ie predose) and steady state has been reached.
NB2: Suggested dosage adjustments assume a target trough concentration of 15 to 20 mg/L is appropriate. A lower target trough concentration may
be appropriate for uncomplicated infections. A higher trough concentration (up to 25 mg/L) may be appropriate for central nervous system
infections.
NB3: Dosage adjustments should be made in a linear manner (eg if the trough concentration is two-thirds of the target concentration, increase the
dose by one-third).
Using AUC for vancomycin monitoring and dosage adjustment in adults
Compared to trough concentration monitoring, monitoring and dosage adjustment based on the AUC/MIC
ratio appears to achieve similar rates of clinical success with a reduced incidence of nephrotoxicity, lower
daily doses and lower trough concentrations.
The target AUC/MIC for vancomycin efficacy is uncertain. Data for AUC/MIC targets relate almost
exclusively to infections caused by S. aureus, and it is not known whether these data can be extrapolated to
other pathogens. The appropriate target is affected by the site of infection (eg increased exposure may be
needed for deep-seated infections) and the laboratory method used (eg broth microdilution, gradient diffusion
method) to determine the MIC. While 400 mg.hr/L or more using broth microdilution is generally considered
to be the optimal AUC/MIC target for clinical success in methicillin-resistant S. aureus (MRSA) infections,
efficacy has been demonstrated with alternative targets (eg more than 320 mg.hr/L in MRSA bacteraemia
using Etest; more than 373 mg.hr/L in S. aureus bacteraemia using broth microdilution; more than 400
mg.hr/L or more than 600 mg.hr/L using broth microdilution in staphylococcal endocarditis; more than 389
mg.hr/L in enterococcal bacteraemia using Etest).
MIC determination is not routine in many laboratories, and the result is influenced by the method used. Most
laboratories use gradient diffusion rather than the broth microdilution method used in key studies. Broth
microdilution determines the MIC in doubling dilutions (eg 0.5 mg/L, 1 mg/L, 2 mg/L), whereas gradient
diffusion provides more granular data (eg 0.5 mg/L, 0.75 mg/L, 1 mg/L, 1.5 mg/L, 2 mg/L). Although both
systems are accurate, clinicians need to choose an AUC/MIC target appropriate for the method used to
determine the MIC.
Automated susceptibility systems that provide an estimate of the MIC (eg Vitek2) may be less accurate than
broth microdilution or gradient diffusion, so should be used with caution for AUC/MIC calculations—seek
expert advice.
Dose optimisation software is increasingly available. Clinical judgment is required when determining the
appropriate dosage adjustment for a patient, because the software uses predictive models. Bayesian predictive
models use the patient’s weight, height and serum creatinine to model the pharmacokinetic parameters that
influence the AUC. A single plasma concentration measurement is usually adequate, except in some patient
groups (eg obese patients, patients with altered pharmacokinetics) in whom multiple plasma concentration
measurements should be used.
Continuous vancomycin infusion in adults

Dosing for continuous vancomycin infusions in adults
Continuous infusion of vancomycin is a practical alternative to intermittent dosing in some patients—those
requiring higher or more frequent doses (eg obese patients, patients with central nervous system infection);
those with infections caused by pathogens with a high vancomycin MIC; or those admitted to a community-
based parenteral antimicrobial therapy service.
For patients initially treated with intermittent infusion, the starting dose for a 24-hour continuous infusion is
usually the sum of the intermittent doses over the previous 24-hour period. However, dose adjustment may be
needed, particularly if the trough plasma concentration with the intermittent regimen was far outside the target
range.
For patients not initially treated with intermittent infusion, the continuous infusion should be preceded by an
initial dose. If the patient is critically ill, the initial dose is the same as a loading dose. If the patient is not
critically ill, the initial dose is the same as an intermittent maintenance dose (see here for nonobese adults or
here for obese adults). The subsequent 24-hour continuous infusion dose is the sum of the intermittent doses
that would have been given over a 24-hour period (eg a 70 kg patient with creatinine clearance more than 60
mL/minute would receive a 1.25 g dose 12-hourly [ie two doses over a 24-hour period], so the 24-hour
continuous infusion dose is 2.5 g).
Continuous infusion of vancomycin requires particular care in critically ill patients undergoing continuous
renal replacement therapy (CRRT), because vancomycin pharmacokinetics can be difficult to predict, and are
influenced by CRRT intensity.
Preliminary studies of continuous infusion vancomycin during extracorporeal membrane oxygenation

(ECMO) suggest there is little need for dosage adjustment.
Monitoring and dosage adjustment for continuous vancomycin infusions in adults

There is significant interpatient variability in vancomycin exposure with continuous infusion. Measure a ‘spot’
plasma vancomycin concentration within 24 hours of starting the infusion. Monitor the vancomycin
concentration at least weekly in stable patients. More frequent monitoring is required during dose
optimisation, and may be required in patients with impaired or changing kidney function, in patients
concomitantly treated with nephrotoxins (see Vancomycin nephrotoxicity) and if the patient’s clinical
condition changes.
When continuous infusion is used, the target ‘spot’ plasma concentration to achieve good efficacy but avoid
toxicity is poorly defined. Many clinicians aim for a target of 20 mg/L, but for many infections a lower
concentration may be adequate (eg a concentration of 15 to 20 mg/L is likely to be adequate for infections
caused by pathogens with a low vancomycin MIC). If vancomycin penetration at the site of infection is
limited (eg central nervous system), a target plasma concentration of up to 25 mg/L may be required—seek
expert advice.
Ideally, the target ‘spot’ concentration is based on an individualised AUC/MIC—see Using AUC for
vancomycin monitoring and dosage adjustment in adults. If specific data are not available, a reasonable
AUC/MIC target for S. aureus infections is 373 mg.hr/L using broth microdilution (based on Australian data).
The ‘spot’ concentration is the AUC divided by 24.
When vancomycin is administered as a continuous infusion, some studies suggest nephrotoxicity does not
occur until a plasma concentration of 28 mg/L is reached. However, it is not known if there is a therapeutic
vancomycin concentration below which toxicity is avoided.
Dosage adjustments should be made in a linear manner (eg if the ‘spot’ concentration is two-thirds of the
target ‘spot’ concentration, increase the 24-hour infusion dose by one-third).
Prescribing vancomycin for neonates and children

Vancomycin infusion advice in neonates and children
Infuse vancomycin over at least 60 minutes and at a rate not exceeding 10 mg/minute to reduce the risk of
infusion-related reactions such as ‘red-man’ syndrome. ‘Red-man’ syndrome is a histamine-mediated,
nonallergic response to rapid vancomycin administration that is characterised by rash, muscle spasms of the
chest and back, and sometimes hypotension. If ‘red-man’ syndrome occurs, extend the infusion time.
Vancomycin loading dose for critically ill neonates and children

The role of vancomycin loading doses in neonates and children is currently unclear—seek expert advice.
Although a loading dose of vancomycin achieves a therapeutic concentration more quickly (by 12 hours),
clear evidence that this improves clinical or microbiological outcomes is lacking. Rapidly achieving a
therapeutic concentration may be especially desirable for patients with septic shock or requiring intensive care
support.
The safety of vancomycin loading doses has not been evaluated in paediatric populations. However, loading
doses do not appear to be associated with an increased risk of nephrotoxicity in large studies of critically ill
adults, and are likely to be well tolerated in neonates and children.
If a loading dose is appropriate for a neonate, use:
vancomycin 20 mg/kg (actual body weight) intravenously, as a loading dose. See Table
2.77 for timing of the next dose.
If a loading dose is appropriate for a child, use:
vancomycin 25 to 30 mg/kg (actual body weight) intravenously, as a loading dose. See

Table 2.77 for timing of the next dose.
Intermittent vancomycin maintenance dosing for neonates and children

For the initial intermittent vancomycin dosage for neonates and children, see Table 2.77. The frequency of
initial vancomycin dosing depends on the patient’s kidney function. The doses in Table 2.77 account for
variability in kidney function relating to a neonate’s renal maturity. For neonates with impaired kidney
function unrelated to age, and for children with an estimated glomerular filtration rate less than 50
mL/minute/1.73 m2, give a single 15 mg/kg dose and seek expert advice for subsequent dosing.
After 24 hours’ treatment (earlier in some neonates—see Table 2.77), doses are based on plasma concentration
monitoring.
Initial vancomycin maintenance dosages for neonates and children (Table 2.77)
Age Starting dose (use Dosing frequency Timing of trough

actual body weight) [NB2] plasma
[NB1] concentration
measurement
before the second
postnatal age 0 to 2 dose
neonates younger 15 mg/kg 18-hourly
days
than 30 weeks (at 18 hours)
postmenstrual age
[NB3] [NB4] before the third dose
postnatal age 3 days
15 mg/kg 12-hourly
or older
(at 24 hours)
postnatal age 0 to 14 before the third dose
15 mg/kg 12-hourly
days (at 24 hours)
neonates 30 to 36
weeks postmenstrual before the fourth
age [NB3] [NB4] postnatal age 15 dose
15 mg/kg 8-hourly
days or older
(at 24 hours)
postnatal age 0 to 7 before the third dose
15 mg/kg 12-hourly
days (at 24 hours)
neonates 37 to 44
weeks postmenstrual before the fourth
age [NB3] [NB4] postnatal age 8 days dose
15 mg/kg 8-hourly
or older
(at 24 hours)
before the fifth dose
neonates 45 weeks postmenstrual age or
15 mg/kg 6-hourly
older [NB3] [NB4]
(at 24 hours)
15 mg/kg up to 750 before the fifth dose
6-hourly
mg (at 24 hours)
children [NB5] OR
before the third dose
30 mg/kg up to 1.5 g 12-hourly
(at 24 hours)
NB1: Use actual body weight to calculate the initial vancomycin dose, even in obese children (children with a body mass index above the 95th
percentile but below the 99th percentile for their age and sex), because volume of distribution and clearance of vancomycin correlate with actual
body weight. For morbidly obese children (children with a body mass index above the 99th percentile for their age and sex), seek expert advice.
NB2: For neonates with impaired kidney function unrelated to age, and for children with an estimated glomerular filtration rate less than 50
mL/minute/1.73 m2, give a single 15 mg/kg dose and seek expert advice for subsequent dosing.
NB3: Postmenstrual age is the time between the first day of the last menstrual period and birth (gestational age) plus the time since birth (postnatal
age).
NB4: There are few data on vancomycin dosing in neonates. The dosages recommended in this table are based on the available data and the
consensus view of the Antibiotic Expert Groups.
NB5: Giving the total daily dose in four 6-hourly doses or two 12-hourly doses is therapeutically equivalent. Similarly, the total daily dose can be
administered in three 8-hourly doses.
Dosing recommendations for obese children (children with a body mass index [BMI] above the 95th
percentile for their age and sex) are uncertain. The volume of distribution of vancomycin is increased in
obesity; clearance may also be increased.
Dosage recommendations for obese children are uncertain.
In obese children, vancomycin doses based on actual body weight may result in high plasma concentrations,
and increased rates of nephrotoxicity have been observed, especially in children with pre-existing kidney
impairment or concomitantly treated with a nephrotoxin. Dosing based on body surface area has been
proposed as an alternative. Despite this, it is the consensus view of the Antibiotic Expert Groups that
vancomycin dosing based on the child’s actual body weight is appropriate for children with a BMI above the
95th percentile but below the 99th percentile for their age and sex. Careful plasma concentration monitoring is
essential to optimise dosing and minimise toxicity.
For children with a BMI above the 99th percentile for their age and sex, expert advice is essential.
Dosing for continuous vancomycin infusions in neonates and children
Continuous vancomycin infusion in neonates and children has been shown to increase the likelihood of
achieving therapeutic plasma concentrations, achieve therapeutic plasma concentrations more quickly and
require fewer blood samples for monitoring, without an increase in adverse effects. It should be considered in
certain circumstances, especially in children who are critically ill—seek expert advice [Note 2].
For neonates or children initially treated with intermittent infusion, the starting dose for a 24-hour continuous
infusion is usually the sum of the intermittent doses over the previous 24-hour period. However, dose
adjustment may be needed, particularly if the trough plasma concentration with the intermittent regimen was
far outside the target range [Note 3].
For neonates or children not initially treated with intermittent infusion, the continuous infusion should be
preceded by an initial dose. If the patient is critically ill, the initial dose is usually the same as a loading dose
—seek expert advice. If the patient is not critically ill, the initial dose is the same as an intermittent
maintenance dose. The subsequent 24-hour continuous infusion dose is the sum of the intermittent doses that
would have been given over a 24-hour period (eg a neonate 45 weeks postmenstrual age would receive a 15
mg/kg dose 6-hourly [ie four doses over a 24-hour period], so the 24-hour continuous infusion dose is 60
mg/kg).
Note 2: Continuous vancomycin infusion in young infants is described by Gwee A, Cranswick N, McMullan B, Perkins E, Bolisetty S, Gardiner
K, et al. Continuous versus intermittent vancomycin infusions in infants: A randomized controlled trial. Pediatrics 2019;[epub]. [URL]
Note 3: Some centres reduce the total daily dose when switching from intermittent to continuous vancomycin infusion, to limit higher-than-
target concentrations.
Overview of plasma vancomycin concentration monitoring in neonates and children

Plasma concentration monitoring is recommended for children treated with vancomycin for longer than 24
hours to optimise dosing; earlier monitoring is required in some neonates (see Table 2.77). Monitoring is also
important to minimise the risk of toxicity, especially in obese children, or neonates or children with impaired
kidney function.
In practice, there are two approaches to monitoring the plasma vancomycin concentration for intermittent
infusion—calculating the area under the concentration–time curve (AUC) and measuring the trough plasma
concentration. The appropriate target AUC depends on the minimum inhibitory concentration (MIC) of the
pathogen, because the AUC/MIC ratio best predicts vancomycin efficacy. Some experts recommend routine
use of AUC monitoring in neonates and children because trough concentrations correlate poorly with
AUC/MIC values; however, there are several practical barriers to using the AUC for monitoring (see Using
AUC for vancomycin monitoring and dosage adjustment in adults) and few data to support this approach in
children. Unless a health service has expertise with AUC monitoring, it is recommended that trough plasma
concentrations are used to guide dosing.
If a Bayesian predictive model is used for AUC-based dose optimisation, two samples (usually a peak and
trough) should be used because, in children, this appears to improve accuracy and precision compared with
single-sample estimates.
Timing of initial plasma concentration measurement in neonates and children

When intermittent infusion is used, the timing of sampling depends on whether the vancomycin AUC or
trough concentration is monitored. If continuous infusion is used, a ‘spot’ plasma vancomycin concentration
should be measured within 24 hours of starting the infusion.
If the AUC is used for monitoring, seek expert advice on the timing of sampling; Bayesian models allow
AUC to be estimated before steady state is reached.
If the trough (predose) plasma vancomycin concentration is monitored, see Table 2.77 for timing of initial
sampling. It is not necessary to wait for the result to give the next scheduled dose.
Irrespective of the approach used, once two plasma concentration measurements (taken 24 to 48 hours apart)
are in the target range, monitor the vancomycin concentration at least weekly in stable patients. More frequent
monitoring is required during dose optimisation, and may be required in patients with impaired or changing
kidney function, in patients concomitantly treated with nephrotoxins (see Vancomycin nephrotoxicity) and if
the patient’s clinical condition changes.
Target plasma vancomycin concentration and dosage adjustment in neonates and

children
General principles of monitoring continuous vancomycin infusions are outlined in Monitoring and dosage
adjustment for continuous vancomycin infusions in adults. In neonates, a plasma concentration target of 15 to
25 mg/L has been used. For the appropriate plasma concentration target for a neonate or child treated with
continuous vancomycin infusion, seek expert advice.
Clinical data suggest that a target 24-hour vancomycin AUC of 400 mg.hr/L or more is required for optimal
efficacy (but see Using AUC for vancomycin monitoring and dosage adjustment in adults). It is difficult to
determine an equivalent target trough concentration for intermittent dosing because the relationship between
the trough concentration and AUC is not linear. Furthermore, there are few data to support trough plasma
concentration targets in neonates and children.
When interpreting the vancomycin plasma concentration, consider if the timing of the sample was appropriate
(ie taken predose), and whether it is a steady-state concentration.
In neonates, and in children treated with a 6-hourly vancomycin regimen, the suggested target trough
concentration is 10 to 20 mg/L. Use the higher end of the target range (15 to 20 mg/L) for severe or
complicated infections. If the trough plasma vancomycin concentration is not within the target range and the
timing of the sample was appropriate and steady state has been reached, see Table 2.78 for suggested dosage
adjustment. For neonates, also see the advice in the Australasian Neonatal Medicines Formulary.
In children treated with a 12-hourly vancomycin regimen, a trough concentration of 7 to 10 mg/L appears to
provide adequate drug exposure.
Vancomycin penetration into the cerebrospinal fluid is variable; higher trough concentrations may be required
If the trough concentration is far outside the target range, the timing of sampling was not appropriate, or
steady state has not been reached, clinical judgment is needed to interpret the result and determine subsequent
management. It may be appropriate to take another sample and repeat the test before adjusting the dosage. For
patients with serious infections, seek expert advice if trough plasma concentration targets are not met.
When possible, dosage adjustments should be based on local protocols. In the absence of local
protocols, dosage adjustments should be made in a linear manner (eg if the trough concentration is two-thirds
of the target concentration, increase the dose by one-third); however, do not exceed a total daily dose of 70
mg/kg without expert advice.
Data on nephrotoxicity with therapeutic plasma concentrations in children are conflicting.
Adjusting the vancomycin dosage in neonates, and children treated with a 6-hourly regimen,
based on trough concentration (Table 2.78)
Trough plasma concentration Suggested dosage adjustment [NB2] [NB3]

[NB1]
Increase dosage by adjusting the dose or dose interval.
less than 10 mg/L
Consider switching to continuous infusion for patients requiring high or
frequent daily doses—seek expert advice.
For patients with uncomplicated infection who are clinically improving,
maintain current dosage.
10 to 14 mg/L For patients with severe or complicated infection, increase dosage by

adjusting the dose or dose interval, and monitor for nephrotoxicity.
Alternatively, assess the AUC/MIC because many patients with a trough
concentration of 10 to 14 mg/L have an adequate AUC.
15 to 20 mg/L Maintain current dosage and monitor for nephrotoxicity.
Reduce dosage by adjusting the dose or dose interval, or withhold dose.
Monitor for nephrotoxicity.
21 to 25 mg/L
If a trough concentration up to 25 mg/L is advised by an infectious diseases
physician or clinical microbiologist, maintain current dosage.
Withhold the dose until concentration is less than 20 mg/L and seek expert
more than 25 mg/L
advice.
AUC/MIC = ratio of area under the concentration–time curve to minimum inhibitory concentration
NB1: The recommendations in this table assume the timing of the trough sample was appropriate (ie predose) and steady state has been reached.
NB2: Suggested dosage adjustments assume a target trough concentration of 10 to 20 mg/L is appropriate. A higher trough concentration (up to 25
mg/L) may be used under expert advice.
NB3: When possible, dosage adjustments should be based on local protocols. In the absence of local protocols, dosage adjustments should be made
in a linear manner (eg if the trough concentration is two-thirds of the target concentration, increase the dose by one-third); however, do not exceed
a total daily dose of 70 mg/kg without expert advice. For patient groups with unstable kidney function or in whom kidney function measurements
are less reliable (eg patients with ongoing sepsis, oncology patients), seek expert advice on dosage adjustment.
Vancomycin nephrotoxicity
General principles
Vancomycin nephrotoxicity has been associated with higher daily vancomycin doses relative to kidney
function, higher trough vancomycin concentrations, prolonged therapy, concomitant nephrotoxins or
vasopressors, and actual body weight–based dosing in obese patients (especially in patients with pre-existing
kidney impairment or concomitantly treated with nephrotoxins).
If possible, avoid other nephrotoxic drugs (eg aminoglycosides, piperacillin+tazobactam, loop diuretics,
nonsteroidal anti-inflammatory drugs [NSAIDs], angiotensin converting enzyme inhibitors [ACEIs] or
angiotensin II receptor blockers [ARBs]) in patients treated with vancomycin. See also Nephrotoxicity when
vancomycin is co-administered with piperacillin+tazobactam for suggested approaches to minimise the risk of
acute kidney injury with vancomycin therapy.
If possible, avoid other nephrotoxic drugs in patients treated with vancomycin.
Nephrotoxicity when vancomycin is co-administered with piperacillin+tazobactam

An increased rate of nephrotoxicity when vancomycin is co-administered with piperacillin+tazobactam has
recently been observed. The combination has been linked to a 3- to 4-fold increase in the risk of
nephrotoxicity, and earlier onset, compared to vancomycin monotherapy or combination therapy with
vancomycin plus other beta lactams (including beta-lactamase inhibitor combinations). This effect has most
often been reported in patient groups in whom the combination is commonly used (eg haematology–oncology
patients, haematopoietic stem cell transplant recipients, patients with cystic fibrosis, burns patients, critically
ill patients). Despite a strong signal from retrospective and uncontrolled prospective studies, there is no high-
quality randomised controlled trial evidence of this interaction. The basis of the interaction is unknown.
Suggested approaches to limiting the risk of acute kidney injury with combination therapy with vancomycin
plus piperacillin+tazobactam include:
using alternative antibiotics

avoiding other nephrotoxic drugs
limiting the duration of treatment with vancomycin plus piperacillin+tazobactam
avoiding a vancomycin loading dose unless the patient is critically ill
maintaining adequate hydration
adjusting doses based on AUC (area under the concentration–time curve) monitoring rather than trough
concentration monitoring
closely monitoring kidney function.
Key references
Introduction to using vancomycin
Donadello K, Roberts JA, Cristallini S, Beumier M, Shekar K, Jacobs F, et al. Vancomycin population
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Udy AA, Covajes C, Taccone FS, Jacobs F, Vincent JL, Lipman J, et al. Can population pharmacokinetic
modelling guide vancomycin dosing during continuous renal replacement therapy in critically ill patients? Int J
Vancomycin loading dose for critically ill adults
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Reardon J, Lau TT, Ensom MH. Vancomycin loading doses: a systematic review. Ann Pharmacother
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Rosini JM, Davis JJ, Muenzer J, Levine BJ, Papas MA, Comer D, et al. High single-dose vancomycin loading is
not associated with increased nephrotoxicity in emergency department sepsis patients. Acad Emerg Med
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Rosini JM, Laughner J, Levine BJ, Papas MA, Reinhardt JF, Jasani NB. A randomized trial of loading vancomycin
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Wesolek JL, McNorton K, Delgado G Jr, Giuliano CA. Effect of vancomycin initial dosing on time to systemic
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Intermittent vancomycin maintenance dosing for obese adults
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Alobaid AS, Hites M, Lipman J, Taccone FS, Roberts JA. Effect of obesity on the pharmacokinetics of
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Choi YC, Saw S, Soliman D, Bingham AL, Pontiggia L, Hunter K, et al. Intravenous vancomycin associated with
the development of nephrotoxicity in patients with class III obesity. Ann Pharmacother 2017;51(11):937–44.
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Kosmisky DE, Griffiths CL, Templin MA, Norton J, Martin KE. Evaluation of a new vancomycin dosing protocol in
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Morrill HJ, Caffrey AR, Noh E, LaPlante KL. Vancomycin dosing considerations in a real-world cohort of obese and
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Richardson J, Scheetz M, O'Donnell EP. The association of elevated trough serum vancomycin concentrations
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Vancomycin monitoring and dosage adjustment in adults
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Martirosov DM, Bidell MR, Pai MP, Scheetz MH, Rosenkranz SL, Faragon C, et al. Relationship between day 1
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Moise PA, Forrest A, Bhavnani SM, Birmingham MC, Schentag JJ. Area under the inhibitory curve and a
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Ricard JD, Wolff M, Lacherade JC, Mourvillier B, Hidri N, Barnaud G, et al. Levels of vancomycin in cerebrospinal
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Rybak M, Lomaestro B, Rotschafer JC, Moellering R, Jr., Craig W, Billeter M, et al. Therapeutic monitoring of
vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the
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Seabury RW, Stoessel AM, Steele JM. Vancomycin trough concentration poorly characterizes AUC: is it time to
transition to auc-based vancomycin monitoring? Ann Pharmacother 2017;51(10):926–7.
Shokouhi S, Alavi Darazam I. Determination of vancomycin trough level in serum and cerebrospinal fluid of
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Stockmann C, Roberts JK, Yu T, Constance JE, Knibbe CA, Spigarelli MG, et al. Vancomycin pharmacokinetic
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and survival in patients with methicillin-resistant Staphylococcus aureus-associated septic shock. Int J Antimicrob
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Continuous vancomycin infusion in adults
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Ampe E, Delaere B, Hecq JD, Tulkens PM, Glupczynski Y. Implementation of a protocol for administration of
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Cristallini S, Hites M, Kabtouri H, Roberts JA, Beumier M, Cotton F, et al. New regimen for continuous infusion of
vancomycin in critically ill patients. Antimicrob Agents Chemother 2016;60(8):4750–4756 .
De Waele JJ, Danneels I, Depuydt P, Decruyenaere J, Bourgeois M, Hoste E. Factors associated with inadequate
early vancomycin levels in critically ill patients treated with continuous infusion. Int J Antimicrob Agents
2013;41(5):434–438 .
Donadello K, Roberts JA, Cristallini S, Beumier M, Shekar K, Jacobs F, Belhaj A, Vincent JL, de Backer D,
Taccone FS. Vancomycin population pharmacokinetics during extracorporeal membrane oxygenation therapy: a
matched cohort study. Crit Care 2014;18(6):632. .
Hanrahan TP, Harlow G, Hutchinson J, Dulhunty JM, Lipman J, Whitehouse T, et al. Vancomycin-associated
nephrotoxicity in the critically ill: a retrospective multivariate regression analysis*. Crit Care Med
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van Maarseveen EM, Gipmans S, Vasbinder E, Petjak M, van Zanten AR. Switching from intermittent to
continuous infusion of vancomycin in critically ill patients: Toward a more robust exposure. Ther Drug Monit
2016;38(3):398–401 .
Waineo MF, Kuhn TC, Brown DL. The pharmacokinetic/pharmacodynamic rationale for administering vancomycin
via continuous infusion. J Clin Pharm Ther 2015;40(3):259–265 .
Prescribing vancomycin for neonates and children
Alobaid AS, Hites M, Lipman J, Taccone FS, Roberts JA. Effect of obesity on the pharmacokinetics of
antimicrobials in critically ill patients: A structured review. Int J Antimicrob Agents 2016;47(4):259–68.
Choi YC, Saw S, Soliman D, Bingham AL, Pontiggia L, Hunter K, et al. Intravenous vancomycin associated with
the development of nephrotoxicity in patients with class III obesity. Ann Pharmacother 2017;51(11):937–44.
Cies JJ, Shankar V. Nephrotoxicity in patients with vancomycin trough concentrations of 15-20 mug/ml in a
pediatric intensive care unit. Pharmacotherapy 2013;33(4):392–400.
Gwee A, Cranswick N, Donath SM, Hunt R, Curtis N. Protocol for a randomised controlled trial of continuous
infusions of vancomycin to improve the attainment of target vancomycin levels in young infants: The VANC trial.
BMJ Open 2018;8(11):e022603. .
Gwee A, Cranswick N, McMullan B, Perkins E, Bolisetty S, Gardiner K, et al. Continuous versus intermittent
vancomycin infusions in infants: A randomized controlled trial. Pediatrics 2019;[epub]. .
Gwee A, Cranswick N, Metz D, Coghlan B, Daley AJ, Bryant PA, et al. Neonatal vancomycin continuous infusion:
still a confusion? Pediatr Infect Dis J 2014;33(6):600–5.
Hahn A, Frenck RW, Jr., Allen-Staat M, Zou Y, Vinks AA. Evaluation of target attainment of vancomycin area
under the curve in children with methicillin-resistant Staphylococcus aureus bacteremia. Ther Drug Monit
2015;37(5):619–25.
Hahn A, Frenck RW, Jr., Zou Y, Vinks AA. Validation of a pediatric population pharmacokinetic model for
vancomycin. Ther Drug Monit 2015;37(3):413–6.
Hwang D, Chiu NC, Chang L, Peng CC, Huang DT, Huang FY, et al. Vancomycin dosing and target attainment in
children. J Microbiol Immunol Infect 2017;50(4):494–9.
Janssen EJ, Välitalo PA, Allegaert K, de Cock RF, Simons SH, Sherwin CM, et al. Towards rational dosing
algorithms for vancomycin in neonates and infants based on population pharmacokinetic modeling. Antimicrob
Agents Chemother 2016;60(2):1013–1021 .
Kishk OA, Lardieri AB, Heil EL, Morgan JA. Vancomycin AUC/MIC and corresponding troughs in a pediatric
population. J Pediatr Pharmacol Ther 2017;22(1):41–47 .
Le J, Ngu B, Bradley JS, Murray W, Nguyen A, Nguyen L, et al. Vancomycin monitoring in children using
bayesian estimation. Ther Drug Monit 2014;36(4):510–8.
Le J, Ny P, Capparelli E, Lane J, Ngu B, Muus R, et al. Pharmacodynamic characteristics of nephrotoxicity

associated with vancomycin use in children. J Pediatric Infect Dis Soc 2015;4(4):e109–e116 .
Le J, Vaida F, Nguyen E, Adler-Shohet FC, Romanowski G, Kim J, et al. Population-based pharmacokinetic

modeling of vancomycin in children with renal insufficiency. J Pharmacol Clin Toxicol 2014;2(1):1017–26.
McKamy S, Hernandez E, Jahng M, Moriwaki T, Deveikis A, Le J. Incidence and risk factors influencing the
development of vancomycin nephrotoxicity in children. J Pediatr 2011;158(3):422–6.
Neonatal Medicines Formulary Consensus Group. Vancomycin. v1.4 [neonatal drug information sheet]. Sydney:
NSW NeoMed Formulary; 2017. https://www.slhd.nsw.gov.au/rpa/neonatal/NeoMedPaperCopy.html
Padari H, Oselin K, Tasa T, Metsvaht T, Loivukene K, Lutsar I. Coagulase negative staphylococcal sepsis in
neonates: do we need to adapt vancomycin dose or target? BMC Pediatr 2016;16(1):206.
Ploessl C, White C, Manasco K. Correlation of a vancomycin pharmacokinetic model and trough serum
concentrations in pediatric patients. Pediatr Infect Dis J 2015;34(10):e244–7.
Reardon J, Lau TT, Ensom MH. Vancomycin loading doses: a systematic review. Ann Pharmacother
2015;49(5):557–565 .
Ricard JD, Wolff M, Lacherade JC, Mourvillier B, Hidri N, Barnaud G, et al. Levels of vancomycin in cerebrospinal
fluid of adult patients receiving adjunctive corticosteroids to treat pneumococcal meningitis: a prospective
multicenter observational study. Clin Infect Dis 2007;44(2):250–5.
Rybak M, Lomaestro B, Rotschafer JC, Moellering R, Jr., Craig W, Billeter M, et al. Therapeutic monitoring of
vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the
Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst
Pharm 2009;66(1):82–98.
Shokouhi S, Alavi Darazam I. Determination of vancomycin trough level in serum and cerebrospinal fluid of
patients with acute community-acquired meningitis: a prospective study. J Infect 2014;69(5):424–9.
Tkachuk S, Collins K, Ensom MHH. The relationship between vancomycin trough concentrations and AUC/MIC
ratios in pediatric patients: A qualitative systematic review. Paediatr Drugs 2018;20(2):153–164 .
Zhao W, Lopez E, Biran V, Durrmeyer X, Fakhoury M, Jacqz-Aigrain E. Vancomycin continuous infusion in

neonates: dosing optimisation and therapeutic drug monitoring. Arch Dis Child 2013;98(6):449–453 .
Vancomycin nephrotoxicity
Clemmons AB, Bech CF, Pantin J, Ahmad I. Acute kidney injury in hematopoietic cell transplantation patients
receiving vancomycin and piperacillin/tazobactam versus vancomycin and cefepime. Biol Blood Marrow
Transplant 2018;24(4):820–826 .
Downes KJ, Cowden C, Laskin BL, Huang YS, Gong W, Bryan M, et al. Association of acute kidney injury with
concomitant vancomycin and piperacillin/tazobactam treatment among hospitalized children. JAMA Pediatr
2017;171(12):e173219. .
Giuliano CA, Patel CR, Kale-Pradhan PB. Is the combination of piperacillin-tazobactam and vancomycin
associated with development of acute kidney injury? A meta-analysis. Pharmacotherapy 2016;36(12):1217–1228
.
Hammond DA, Smith MN, Li C, Hayes SM, Lusardi K, Bookstaver PB. Systematic review and meta-analysis of
acute kidney injury associated with concomitant vancomycin and piperacillin/tazobactam. Clin Infect Dis
2017;64(5):666–674 .
Hanrahan TP, Harlow G, Hutchinson J, Dulhunty JM, Lipman J, Whitehouse T, et al. Vancomycin-associated
nephrotoxicity in the critically ill: a retrospective multivariate regression analysis*. Crit Care Med
2014;42(12):2527–2536 .
Hundeshagen G, Herndon DN, Capek KD, Branski LK, Voigt CD, Killion EA, et al. Co-administration of
vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in adult and pediatric burn
patients. Crit Care 2017;21(1):318. .
LeCleir LK, Pettit RS. Piperacillin-tazobactam versus cefepime incidence of acute kidney injury in combination
with vancomycin and tobramycin in pediatric cystic fibrosis patients. Pediatr Pulmonol 2017;52(8):1000–1005
.
Mullins BP, Kramer CJ, Bartel BJ, Catlin JS, Gilder RE. Comparison of the nephrotoxicity of vancomycin in
combination with cefepime, meropenem, or piperacillin/tazobactam: A prospective, multicenter study. Ann
Pharmacother 2018;52(7):639–644 .
Navalkele B, Pogue JM, Karino S, Nishan B, Salim M, Solanki S, et al. Risk of acute kidney injury in patients on
concomitant vancomycin and piperacillin-tazobactam compared to those on vancomycin and cefepime. Clin Infect
Dis 2017;64(2):116–123 .
Rutter WC, Burgess DS. Acute kidney injury in patients treated with IV beta-lactam/beta-lactamase inhibitor
combinations. Pharmacotherapy 2017;37(5):593–598 .
Rutter WC, Cox JN, Martin CA, Burgess DR, Burgess DS. Erratum for Rutter et al., Nephrotoxicity during
vancomycin therapy in combination with piperacillin-tazobactam or cefepime. Antimicrob Agents Chemother
2017;61(4): .
Rutter WC, Cox JN, Martin CA, Burgess DR, Burgess DS. Nephrotoxicity during vancomycin therapy in
combination with piperacillin-tazobactam or cefepime. Antimicrob Agents Chemother 2017;61(2): .
Watkins RR, Deresinski S. Increasing evidence of the nephrotoxicity of piperacillin/tazobactam and vancomycin
combination therapy-what is the clinician to do? Clin Infect Dis 2017;65(12):2137–43.
Monitoring antimicrobial blood concentrations
Principles of monitoring antimicrobial therapy
The aims of monitoring antimicrobial plasma concentrations are to maximise efficacy and minimise the risk of
toxicity. The clinical value of monitoring plasma concentrations is not well established for all antimicrobials,
but monitoring is clinically indicated for aminoglycosides and vancomycin, and certain patient groups taking
the drugs discussed in this topic. See Principles of aminoglycoside use for information about monitoring
aminoglycoside therapy, and Principles of vancomycin use for information about monitoring vancomycin
therapy.
The clinical value of monitoring antimicrobial concentrations in bodily fluids other than blood (eg
cerebrospinal fluid in ventriculitis) remains unproven, but the practice has been suggested as a means of
ensuring target concentrations are achieved at the site of infection.
In most cases, blood samples for antimicrobial concentration monitoring should be taken once steady state has
been reached (usually after at least 5 half-lives of the drug if a loading dose was not given). Recheck the
concentration as required (eg once steady state has been reached after a dose was changed, or an interacting
drug was started or stopped).
Few laboratories perform assays of antimicrobials other than aminoglycosides and vancomycin; for a list of
laboratories that perform other assays, see the Australian Society for Antimicrobials website.
Monitoring systemic antifungals

Fluconazole
Fluconazole has high bioavailability, and plasma concentrations after oral and intravenous administration are
generally predictable. Therefore, monitoring fluconazole plasma concentration is not routinely required, but
may be useful for some patients (eg those undergoing continuous renal replacement therapy or with an
infection caused by a pathogen with a high minimum inhibitory concentration [MIC]). It has been suggested
that an area under the concentration–time curve (over 24 hours) to MIC ratio (24-hour AUC/MIC) of at least
100 correlates with optimal fluconazole exposure.
For information on monitoring fluconazole plasma concentration in haematology patients, see the Australian
and New Zealand antifungal guidelines [Note 1].
Note 1: Chau MM, Kong DC, van Hal SJ, Urbancic K, Trubiano JA, Cassumbhoy M, et al. Consensus guidelines for optimising antifungal drug
delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014. Intern Med J
2014;44(12b):1364-88. [URL]
Itraconazole
The absorption of itraconazole is unpredictable and bioavailability of available formulations varies.
Monitor itraconazole plasma concentration when treating or preventing invasive fungal infections in
immunocompromised patients. Itraconazole has a long elimination half-life, so the concentration is best
measured at least 5 days after starting therapy; steady state may not be reached until after 14 days of therapy.
A trough concentration of at least 0.5 to 1.0 mg/L is appropriate for treatment regimens. For prophylaxis
regimens, a trough concentration of more than 0.5 mg/L has been associated with improved outcomes.
For information on monitoring itraconazole plasma concentration in haematology patients, see the Australian
2014;44(12b):1364-88. [URL]
Posaconazole
Newer parenteral and slow-release tablet formulations of posaconazole offer enhanced bioavailability
compared to the posaconazole oral suspension. Approximately 85% of patients taking newer formulations for
prophylaxis have adequate posaconazole concentrations; only 60% of patients taking the oral suspension have
adequate concentrations.
Consider monitoring posaconazole concentration in patients at risk of suboptimal drug concentration (eg
critically ill patients or haematology–oncology patients with invasive fungal infection, diarrhoea, mucositis,
high body weight, or taking interacting drugs such as proton pump inhibitors or phenytoin). Posaconazole has
a long half-life, so the concentration is best measured at least 5 to 7 days after starting therapy. A trough
concentration of at least 1.0 mg/L is appropriate for treatment regimens. A trough concentration of at least 0.7
mg/L is reasonable for prophylaxis.
For information on monitoring posaconazole plasma concentration in haematology patients, see the Australian
2014;44(12b):1364-88. [URL]
Voriconazole
Beneficial outcomes associated with monitoring voriconazole plasma concentration have been demonstrated
in a randomised controlled trial [Note 4] as well as retrospective and prospective studies.
Monitor voriconazole plasma concentration if voriconazole prophylaxis or treatment is likely to be used for
longer than a few days. The metabolism of voriconazole is saturable and varies considerably between patients.
Significant hepatotoxicity and neurotoxicity have been observed when a high voriconazole trough
concentration (more than 5 or 6 mg/L) is sustained. A trough concentration between 1 and 5 mg/L is
recommended for clinical efficacy.
For patients not given a loading dose, steady-state concentration is usually reached by 5 to 7 days. For patients
who received a loading dose, measure the trough concentration earlier (around day 5).
For information on monitoring voriconazole plasma concentration in haematology patients, see the Australian
Note 4: Park WB, Kim NH, Kim KH, Lee SH, Nam WS, Yoon SH, et al. The effect of therapeutic drug monitoring on safety and efficacy of
voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis 2012;55(8):1080-7. [URL]
2014;44(12b):1364-88. [URL]
Flucytosine
Monitor flucytosine plasma concentration in patients with kidney impairment, suspected toxicity (eg
neutropenia or abnormal liver biochemistry) and in patients receiving concomitant amphotericin B. See
Practical information on using flucytosine for information on clinical monitoring for flucytosine.
Measure flucytosine plasma concentration 3 to 5 days after starting therapy. The flucytosine trough plasma
concentration should be higher than 25 mg/L for clinical efficacy. Toxicity has been associated with a peak
plasma concentration higher than 100 mg/L (2 hours after an oral dose or 30 minutes after an intravenous
dose).
For information on monitoring flucytosine plasma concentration in haematology patients, see the Australian
2014;44(12b):1364-88. [URL]
Monitoring beta lactams

Indications for monitoring beta lactams
Beta lactams have a wide therapeutic window and routine monitoring is not required. However, monitoring
may be beneficial in patients at high risk of treatment failure due to suboptimal concentrations or at increased
risk of toxicity. Consider monitoring beta-lactam concentrations in patients:
with significantly altered pharmacokinetics (eg critically ill patients in intensive care, patients with
severe kidney impairment, febrile neutropenia, burns, pancreatitis, major trauma)
receiving long-term intravenous therapy (longer than 2 weeks)
taking long-term oral therapy, if poor absorption is suspected.
Between 15 and 50% of critically ill patients are reported to have suboptimal beta-lactam plasma
concentrations, particularly if they have augmented renal clearance (creatinine clearance more than 130
mL/minute), which can double the patient’s renal drug clearance.
Patients with acute kidney injury or receiving continuous renal replacement therapy (CRRT) may also benefit
from monitoring if the actual glomerular filtration rate (GFR) is unknown, or if the effect of the prescribed
continuous renal replacement therapy settings on drug clearance is poorly characterised. Neurotoxicity (eg
seizures, encephalopathy) has increasingly been associated with high beta-lactam concentrations (eg
cefepime, flucloxacillin), particularly in critically ill patients with kidney impairment. To reduce the risk of
toxicity, most beta lactams require dosage modification in patients with kidney impairment—see
Antimicrobial dosages for adults with impaired renal function.
Target beta-lactam concentrations

The target trough concentration for beta lactams is usually an unbound plasma concentration higher than the
minimum inhibitory concentration of the pathogen. A higher target concentration is required for continuous
infusions—seek expert advice.
Laboratories may report beta-lactam concentrations as total or unbound. Measuring the total concentration is
generally sufficient because, for most beta lactams, this correlates with the unbound concentration. However,
for drugs with over 80% protein binding (eg ceftriaxone), it is preferable to measure the unbound
concentration.
Although dicloxacillin and flucloxacillin are approximately 95% protein bound, measurement of unbound
trough concentrations is not required if investigating oral absorption of these drugs in patients who are not
critically ill. If oral absorption is normal, the target peak total plasma concentration of dicloxacillin and
flucloxacillin 1 hour after a 1 g oral dose is approximately 20 to 40 mg/L.
Monitoring guanine analogue antivirals

Data correlating antiviral plasma concentrations with clinical outcomes are limited; most data available are for
aciclovir and ganciclovir. Consequently, monitoring antiviral concentrations is uncommon. However, some
patients (eg critically ill patients, transplant recipients) are at risk of very low or high antiviral concentrations
and consequent treatment or prophylaxis failure, or concentration-related drug toxicity (eg bone marrow
suppression with ganciclovir and valganciclovir, neurotoxicity with aciclovir and valaciclovir).
If monitoring is required for patients taking aciclovir or valaciclovir (a prodrug of aciclovir), monitor aciclovir
plasma concentration. Suggested target concentrations are a trough concentration between 0.5 and 0.7 mg/L
and a peak concentration between 5 and 10 mg/L. These targets are based on concentrations observed in
healthy subjects taking aciclovir.
If monitoring is required for patients taking ganciclovir or valganciclovir (a prodrug of ganciclovir), monitor
ganciclovir plasma concentration. A minimum area under the concentration–time curve over 24 hours (24-
hour AUC) of 45 to 50 mg.hr/L is suggested for optimal viral suppression. A ganciclovir 24-hour AUC of
more than 50 mg.hr/L has been weakly associated with bone marrow suppression. AUC can be difficult to
determine if monitoring software is not available, a trough ganciclovir plasma concentration greater than 0.3
mg/L may be used as a surrogate target.
Monitoring linezolid
Monitoring linezolid plasma concentrations is uncommon in Australia, but may be useful for some patients
(eg transplant recipients, critically ill patients or those with severely impaired kidney function). Generally,
linezolid concentration is measured 3 days after starting therapy; a trough concentration range of 2 to 6 mg/L
is suggested. Linezolid toxicity (eg lactic acidosis, bone marrow suppression, neuropathy) has been associated
with trough concentrations above 6 mg/L. See Practical information on using linezolid for information on
clinical monitoring for linezolid.
Monitoring quinolones
Monitoring quinolone (eg ciprofloxacin, moxifloxacin) plasma concentrations has been performed in critically
ill patients and patients with mycobacterial infections. Current evidence is experimental, but indicates that the
achievement of drug concentration targets is associated with improved patient outcomes.
For ciprofloxacin, an area under the concentration–time curve (over 24 hours) to minimum inhibitory
concentration ratio (24-hour AUC/MIC) of 125 is suggested for Gram-negative pathogens. For Gram-positive
pathogens, a 24-hour AUC/MIC of 30 to 40 is suggested.
Monitoring teicoplanin
Optimum efficacy with teicoplanin is achieved when the total (bound and unbound) teicoplanin trough
concentration exceeds 15 mg/L. A higher plasma concentration is required in patients with serious, deep-
seated infections; monitor the trough concentration and increase the teicoplanin dose if the concentration falls
below 20 mg/L. Toxicity does not usually occur at a trough concentration less than 50 mg/L.
Teicoplanin is highly protein bound. The unbound teicoplanin concentration should be measured in patients
with hypoalbuminaemia or who are critically ill. The suggested unbound teicoplanin trough concentration is
between 1.5 and 3 mg/L.
Teicoplanin has a longer half-life than vancomycin, so it requires less frequent monitoring.
Key references
Monitoring systemic antifungals
Ashbee HR, Barnes RA, Johnson EM, Richardson MD, Gorton R, Hope WW. Therapeutic drug monitoring (TDM)
of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother
2014;69(5):1162–76.
Chau MM, Kong DC, van Hal SJ, Urbancic K, Trubiano JA, Cassumbhoy M, et al. Consensus guidelines for
optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with
haematological malignancy, 2014. Intern Med J 2014;44(12b):1364–88.
Dolton MJ, Ray JE, Chen SC, Ng K, Pont L, McLachlan AJ. Multicenter study of posaconazole therapeutic drug
monitoring: exposure-response relationship and factors affecting concentration. Antimicrob Agents Chemother
2012;56(11):5503–10.
Durani U, Tosh PK, Barreto JN, Estes LL, Jannetto PJ, Tande AJ. Retrospective comparison of posaconazole
levels in patients taking the delayed-release tablet versus the oral suspension. Antimicrob Agents Chemother
2015;59(8):4914–8.
European Committee on Antimicrobial Susceptibility Testing-Subcommittee on Antifungal Susceptibility Testing

(EUCAST-AFST). EUCAST technical note on fluconazole. Clin Microbiol Infect 2008;14(2):193–5.
Jager NG, van Hest RM, Lipman J, Taccone FS, Roberts JA. Therapeutic drug monitoring of anti-infective agents
in critically ill patients. Expert Rev Clin Pharmacol 2016;9(7):961–79.
Jung DS, Tverdek FP, Kontoyiannis DP. Switching from posaconazole suspension to tablets increases serum
drug levels in leukemia patients without clinically relevant hepatotoxicity. Antimicrob Agents Chemother
2014;58(11):6993–5.
Luong ML, Al-Dabbagh M, Groll AH, Racil Z, Nannya Y, Mitsani D, et al. Utility of voriconazole therapeutic drug
monitoring: a meta-analysis. J Antimicrob Chemother 2016;71(7):1786–99.
Miceli MH, Perissinotti AJ, Kauffman CA, Couriel DR. Serum posaconazole levels among haematological cancer
patients taking extended release tablets is affected by body weight and diarrhoea: single centre retrospective
analysis. Mycoses 2015;58(7):432–6.
Park WB, Kim NH, Kim KH, Lee SH, Nam WS, Yoon SH, et al. The effect of therapeutic drug monitoring on safety
and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis
2012;55(8):1080–7.
Pham AN, Bubalo JS, Lewis JS, 2nd. Comparison of posaconazole serum concentrations from haematological
cancer patients on posaconazole tablet and oral suspension for treatment and prevention of invasive fungal
infections. Mycoses 2016;59(4):226–33.
Monitoring beta lactams
Huwyler T, Lenggenhager L, Abbas M, Ing Lorenzini K, Hughes S, Huttner B, et al. Cefepime plasma
concentrations and clinical toxicity: a retrospective cohort study. Clin Microbiol Infect 2017;23(7):454–9.
McDonald C, Cotta MO, Little PJ, McWhinney B, Ungerer JP, Lipman J, et al. Is high-dose beta-lactam therapy
associated with excessive drug toxicity in critically ill patients? Minerva Anestesiol 2016;82(9):957–65.
Neuville M, El-Helali N, Magalhaes E, Radjou A, Smonig R, Soubirou JF, et al. Systematic overdosing of oxa- and
cloxacillin in severe infections treated in ICU: risk factors and side effects. Ann Intensive Care 2017;7(1):34.
Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, et al. Individualised antibiotic dosing for
patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 2014;14(6):498–509.
Scaglione F, Esposito S, Leone S, Lucini V, Pannacci M, Ma L, et al. Feedback dose alteration significantly affects
probability of pathogen eradication in nosocomial pneumonia. Eur Respir J 2009;34(2):394–400.
Udy AA, Varghese JM, Altukroni M, Briscoe S, McWhinney BC, Ungerer JP, et al. Subtherapeutic initial beta-
lactam concentrations in select critically ill patients: association between augmented renal clearance and low
trough drug concentrations. Chest 2012;142(1):30–9.
Wong G, Briscoe S, Adnan S, McWhinney B, Ungerer J, Lipman J, et al. Protein binding of beta-lactam antibiotics
in critically ill patients: can we successfully predict unbound concentrations? Antimicrob Agents Chemother
2013;57(12):6165–70.
Monitoring guanine analogue antivirals
Perrottet N, Decosterd LA, Meylan P, Pascual M, Biollaz J, Buclin T. Valganciclovir in adult solid organ transplant
recipients: pharmacokinetic and pharmacodynamic characteristics and clinical interpretation of plasma
concentration measurements. Clin Pharmacokinet 2009;48(6):399–418.
Wiltshire H, Paya CV, Pescovitz MD, Humar A, Dominguez E, Washburn K, et al. Pharmacodynamics of oral
ganciclovir and valganciclovir in solid organ transplant recipients. Transplantation 2005;79(11):1477–83.
Monitoring linezolid
Cattaneo D, Orlando G, Cozzi V, Cordier L, Baldelli S, Merli S, et al. Linezolid plasma concentrations and
occurrence of drug-related haematological toxicity in patients with gram-positive infections. Int J Antimicrob
Agents 2013;41(6):586–9.
Hiraki Y, Tsuji Y, Hiraike M, Misumi N, Matsumoto K, Morita K, et al. Correlation between serum linezolid
concentration and the development of thrombocytopenia. Scand J Infect Dis 2012;44(1):60–4.
Matsumoto K, Takeshita A, Ikawa K, Shigemi A, Yaji K, Shimodozono Y, et al. Higher linezolid exposure and
higher frequency of thrombocytopenia in patients with renal dysfunction. Int J Antimicrob Agents 2010;36(2):179–
81.
Nukui Y, Hatakeyama S, Okamoto K, Yamamoto T, Hisaka A, Suzuki H, et al. High plasma linezolid concentration
and impaired renal function affect development of linezolid-induced thrombocytopenia. J Antimicrob Chemother
2013;68(9):2128–33.
Pea F, Furlanut M, Cojutti P, Cristini F, Zamparini E, Franceschi L, et al. Therapeutic drug monitoring of linezolid:
a retrospective monocentric analysis. Antimicrob Agents Chemother 2010;54(11):4605–10.
Pea F, Viale P, Cojutti P, Del Pin B, Zamparini E, Furlanut M. Therapeutic drug monitoring may improve safety
outcomes of long-term treatment with linezolid in adult patients. J Antimicrob Chemother 2012;67(8):2034–42.
Monitoring quinolones
Pranger AD, Kosterink JG, van Altena R, Aarnoutse RE, van der Werf TS, Uges DR, et al. Limited-sampling
strategies for therapeutic drug monitoring of moxifloxacin in patients with tuberculosis. Ther Drug Monit
2011;33(3):350–4.
Monitoring teicoplanin
Brink AJ, Richards GA, Lautenbach EE, Rapeport N, Schillack V, van Niekerk L, et al. Albumin concentration
significantly impacts on free teicoplanin plasma concentrations in non-critically ill patients with chronic bone
sepsis. Int J Antimicrob Agents 2015;45(6):647–51.
Byrne CJ, Roberts JA, McWhinney B, Fennell JP, O'Byrne P, Deasy E, et al. Variability in trough total and
unbound teicoplanin concentrations and achievement of therapeutic drug monitoring targets in adult patients with
hematological malignancy. Antimicrob Agents Chemother 2017;61(6).
Roberts JA, Stove V, De Waele JJ, Sipinkoski B, McWhinney B, Ungerer JP, et al. Variability in protein binding of
teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: lessons from the DALI
Study. Int J Antimicrob Agents 2014;43(5):423–30.
Renal impairment and antimicrobial dosing
General principles of antimicrobial dosing in renal impairment
In people with renal impairment, antimicrobials or their metabolites that are excreted entirely, or in part, by
the kidneys can accumulate with standard dosing, and dosage reduction may be required. For example,
aminoglycosides and glycopeptides are excreted almost entirely by the kidneys, and rapidly reach toxic
concentrations in patients with impaired kidney function if standard dosing regimens are used. For many
commonly used beta-lactam antibiotics, a significant proportion of the dose is excreted by the kidneys; dosage
adjustment may be needed in patients with impaired kidney function to avoid potentially toxic concentrations.
It is crucial that dosage adjustments are informed by the patient’s clinical status and comorbidities, the
potential toxic effects of the relevant drug, and the likely consequences of underdosing. Furthermore, patients
with renal impairment can be more susceptible to drug adverse effects; specific monitoring may be required. If
possible, avoid the use of nephrotoxic drugs in patients with moderate to severe renal impairment. For further
information, consult appropriate drug information texts.
The advice in this topic and the dosage modification recommendations in Table 2.80 apply to adults (people
older than 18 years) with renal impairment. For dosage modification in children, seek expert advice. A
suitable equation to estimate glomerular filtration rate (GFR) in children older than 1 year is the modified
Schwartz formula.
Estimating glomerular filtration rate in adults

Dosage adjustment for patients with renal impairment is guided by an assessment of glomerular filtration rate
(GFR), which is usually proportional to renal drug clearance. Because of practical difficulties in measuring
GFR, estimates are often used: estimated creatinine clearance (CrCl) using the Cockcroft–Gault formula (see
Box 2.47); or estimated GFR (eGFR) using the Modification of Diet in Renal Disease Study (MDRD) or the
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. However, each of these
creatinine-based methods has inherent limitations when used as the basis for dosage adjustment.
Drug manufacturers’ recommendations for drug dosing in renal impairment are often based on historical
Cockcroft–Gault estimates of CrCl. The Cockcroft–Gault formula has not been revalidated with the
standardised creatinine assays now used throughout Australia, which produce creatinine values that are not
directly comparable to historical values. Consequently, CrCl calculated by the Cockcroft–Gault formula using
creatinine values from newer assays are not directly comparable to historical estimates.
The CKD-EPI equation for eGFR has been standardised for use with the new assay, and generally provides a
more accurate GFR estimate than CrCl (except if GFR is greater than 90 mL/minute). The CKD-EPI equation
has not been clinically validated for dosage adjustment, but is an accepted estimate of renal drug clearance
and is exclusively used to report eGFR by laboratories in Australia. Estimated GFR (eGFR) is normalised to a
body surface area of 1.73 m2; for patients at extremes of body size, adjust the eGFR by multiplying the eGFR
by the patient’s body surface area (in m2) and dividing by 1.73 m2 [Note 1].
For patients who are not critically ill, it is usually reasonable to estimate GFR by calculating CrCl (using the Cockcroft–
Gault formula) or using the eGFR (calculated using the CKD-EPI equation).
For patients who are not critically ill, it is usually reasonable to estimate GFR by either calculating CrCl
(using the Cockcroft–Gault formula) or using the eGFR (calculated using the CKD-EPI equation). Neither
CrCl nor eGFR accurately predicts renal clearance in patients who:
have unstable kidney function (eg patients in intensive care, patients with acute kidney injury or febrile
neutropenia); a measured (urinary) creatinine clearance is most accurate in this situation
have very high or low muscle mass (eg body builders or, conversely, cachectic patients, paraplegics,
amputees)
are undergoing dialysis
are taking a drug that elevates serum creatinine without affecting true kidney function (eg
trimethoprim).
Neither CrCl nor eGFR accurately predicts renal clearance in patients with unstable kidney function or abnormal muscle
mass, or who are undergoing dialysis or taking a drug that elevates serum creatinine.
Careful estimation of GFR and subsequent dosage modification is particularly pertinent for drugs with a
narrow therapeutic index (eg aminoglycosides); therapeutic drug monitoring, if available, should be used to
individualise dosing.
Cockcroft–Gault formula (Box 2.47)
The Cockcroft–Gault formula (below) or the online calculator can be used to estimate creatinine clearance.
Lean body weight is the preferred weight descriptor for use in the Cockcroft–Gault formula, because
creatinine is a muscle breakdown product; however, the calculation of lean body weight is relatively
complicated.
For patients who are not overweight (ie those who do not weigh more than 20% above their ideal body
weight [see Ideal body weight calculator or Table 2.79]), actual body weight can be used.
For patients who are overweight (ie those who weigh more than 20% above their ideal body weight), for
practicality, ideal body weight (see Ideal body weight calculator or Table 2.79) can be used and provides a
similar CrCl estimate to lean body weight.
Ideal body weight (Table 2.79)
Height Ideal body weight (kg) [NB1]

cm inches women men
155 61 48 53
160 63 53 57
165 65 57 62
170 67 62 66
175 69 66 71
180 71 71 75
185 73 75 80
190 75 80 84
195 77 84 89
200 79 89 93
205 81 93 98
210 83 98 102
215 85 102 107
220 87 107 111
NB1: Ideal weight for men = 50 kg + 0.9 kg per cm over 152 cm (2.3 kg per inch over 5 feet)
Ideal weight for women = 45.5 kg + 0.9 kg per cm over 152 cm (2.3 kg per inch over 5 feet)
Antimicrobial dosage modification in renal impairment

For patients with impaired kidney function, dosages can be altered by reducing the dose or by extending the
interval between doses. For some antimicrobials, therapeutic drug monitoring is needed to individualise
dosing and minimise potential toxicities. Monitoring can also be used to ensure therapeutic concentrations are
achieved—see Monitoring antimicrobial blood concentrations.
Estimates of glomerular filtration rate (GFR) are inherently limited as a basis for dosage adjustment.
Therefore, it is crucial that any dosage modification is considered in the context of the patient’s clinical status
and comorbidities, the potential toxic effects of the relevant drug, and the likely consequences of underdosing.
Drug choice and dosage modifications must be informed by the patient’s clinical status and comorbidities, the potential
toxic effects of the relevant drug, and the likely consequences of underdosing.
When choosing the appropriate dosage regimen for patients with renal impairment, consider the impact of
other drugs (eg phosphate binders) on antimicrobial bioavailability or concentration.
Read the following in conjunction with Table 2.80:
Table 2.80 is intended to support the practical implementation of the drug recommendations in these
guidelines, so only includes advice on dosage modification of antimicrobials recommended in eTG
complete. For advice on dosage modification of other drugs in patients with renal impairment, consult
the product information or an appropriate drug information text.
The recommendations only apply to antimicrobials administered systemically to adults; they do not
apply to regimens given via intraperitoneal administration. For antimicrobial dosing in children with
renal impairment, seek expert advice.
Many of the recommendations for dosage adjustment were derived using creatinine clearance (CrCl)
estimates; their use with estimated GFR (eGFR) is an extrapolation of the original data. See here for a
discussion of CrCl and eGFR.
A loading dose may be needed when rapid achievement of a therapeutic concentration is necessary, or
when the half-life of a drug is long in a patient with renal impairment. When information is available
about the use of a loading dose for a specific drug, it has been included in Table 2.80; however, the
absence of this information does not necessarily mean that a loading dose is not required.
Dialysis and continuous renal replacement therapy
Table 2.80 provides dosage guidance for adults undergoing continuous renal replacement therapy (CRRT),
peritoneal dialysis (PD), and intermittent haemodialysis (IHD).
The most common continuous renal replacement therapy modalities currently used in intensive care units are
continuous venovenous haemofiltration (CVVH), continuous venovenous haemodialysis (CVVHD), and
continuous venovenous haemodiafiltration (CVVHDF). Many of the dosing recommendations for continuous
renal replacement therapy are based on limited clinical data, or extrapolated from clinical experience and
knowledge of the pharmacokinetic and pharmacodynamic properties of the drug. Continuous renal
replacement therapy settings can vary markedly between hospitals, which may result in vastly different drug
clearances. Consequently, the dosing recommendations in Table 2.80 are a guide only; consult a clinical
pharmacist or other health professional with experience with the local continuous renal replacement therapy
settings for dosing advice where possible [Note 2]. Monitor patients undergoing continuous renal replacement
therapy for drug efficacy and potential adverse effects, and, if possible, monitor the plasma concentration of
the drug (see Monitoring antimicrobial blood concentrations).
Emerging prolonged intermittent renal replacement therapy techniques, including sustained low-efficiency
dialysis (SLED) and extended daily diafiltration (EDD-f), are beyond the scope of these guidelines; consult
published reviews for guidance on antimicrobial dosing [Note 3].
Peritoneal dialysis may be provided as continuous ambulatory peritoneal dialysis (CAPD) or automated
peritoneal dialysis (APD). Although most peritoneal dialysis dosing information is derived from continuous
ambulatory peritoneal dialysis rather than automated peritoneal dialysis, there are insufficient data to
recommend different antimicrobial dosages for each peritoneal dialysis form.
Drug clearance achieved by intermittent haemodialysis is consistent across institutions, because similar
dialysis settings are used. Consequently, the dosage adjustments for intermittent haemodialysis recommended
in Table 2.80 do not need to be modified locally. As a general rule, for drugs that are readily removed by
intermittent haemodialysis, the dose should be withheld until after the dialysis session. To reduce the risk of
missed doses, some units prefer to maintain the normal dosing schedule (ie dose at the same time as on
nondialysis days) for drugs that are administered more than once daily. For patients undergoing automated
peritoneal dialysis, it is also reasonable to administer once-daily doses of antimicrobials that are significantly
dialysed (eg meropenem) after dialysis is completed.
Note 2: For a review of the principles of dose optimisation in critically ill patients undergoing continuous renal replacement therapy, as well as a
summary of available data, see Choi G, Gomersall CD, Tian Q, Joynt GM, Freebairn R, Lipman J. Principles of antibacterial dosing in
continuous renal replacement therapy. Crit Care Med 2009;37(7):2268-82. [URL]
Note 3: Bogard KN, Peterson NT, Plumb TJ, Erwin MW, Fuller PD, Olsen KM. Antibiotic dosing during sustained low-efficiency dialysis:
special considerations in adult critically ill patients. Crit Care Med 2011;39(3):560-70. [URL]
Jamal JA, Economou CJ, Lipman J, Roberts JA. Improving antibiotic dosing in special situations in the ICU: burns, renal replacement therapy
and extracorporeal membrane oxygenation. Curr Opin Crit Care 2012;18(5):460-71. [URL]
Antimicrobial dosages for adults with impaired renal function

Antimicrobial doses for adults with impaired renal function (Table 2.80)
This table gives dosing recommendations for adults with impaired renal function. For antimicrobial dosing in
children with renal impairment, seek expert advice.
GFR = glomerular filtration rate
[A]|[B]|[C]|[D]|[E]|[F]|[G]|[I]|[L]|[M]|[N]|[O]|[P]|[Q]|[R]|[S]|[T]|[
V]|[Z]
Antimicrobial dosages for adults with impaired renal function (Table 2.80): A [NB1]
abacavir amphotericin B lipid complex
abacavir+lamivudine (Kivexa) amphotericin B liposomal
abacavir+lamivudine+zidovudine (Trizivir) ampicillin
aciclovir intravenous anidulafungin
aciclovir oral artemether+lumefantrine
albendazole artesunate
amikacin atazanavir
amoxicillin atazanavir+cobicistat (Evotaz)
amoxicillin+clavulanate intravenous atovaquone
amoxicillin+clavulanate oral atovaquone+proguanil
amphotericin B desoxycholate azithromycin

abacavir
Dosage adjustment based on GFR [NB2] [NB3]
more than 50 mL/min normal
10 to 50 mL/min normal
less than 10 mL/min normal
Dosages for dialysis [NB2] [NB3]
intermittent haemodialysis normal
peritoneal dialysis normal
continuous renal replacement therapy normal
abacavir+lamivudine (Kivexa)
10 to 50 mL/min avoid fixed-dose combination; see individual drugs
less than 10 mL/min avoid fixed-dose combination; see individual drugs
intermittent haemodialysis avoid fixed-dose combination; see individual drugs
peritoneal dialysis avoid fixed-dose combination; see individual drugs
continuous renal replacement therapy avoid fixed-dose combination; see individual drugs
abacavir+lamivudine+zidovudine (Trizivir)
aciclovir intravenous
25 to 50 mL/min 100% 12-hourly
less than 10 mL/min 50% 24-hourly
intermittent haemodialysis as for GFR less than 10 mL/min; dose after dialysis
peritoneal dialysis as for GFR less than 10 mL/min
continuous renal replacement therapy 5 to 10 mg/kg 24-hourly
aciclovir oral
10 to 50 mL/min dosage depends on the indication and patient’s immune status;
less than 10 mL/min see product information
intermittent haemodialysis
dosage depends on the indication and patient’s immune status;
peritoneal dialysis
see product information
continuous renal replacement therapy
albendazole
intermittent haemodialysis normal; dose after dialysis if dosed 24-hourly
amikacin
more than 50 mL/min
10 to 50 mL/min see Principles of aminoglycoside use
less than 10 mL/min
peritoneal dialysis seek expert advice
amoxicillin
intermittent haemodialysis as for GFR less than 10 mL/min
continuous renal replacement therapy as for GFR 31 to 50 mL/min
amoxicillin+clavulanate intravenous
less than 30 mL/min 1+0.2 g 12-hourly
continuous renal replacement therapy as for GFR less than 30 mL/min
amoxicillin+clavulanate oral
less than 30 mL/min 500+125 mg 12-hourly
amphotericin B desoxycholate
10 to 50 mL/min avoid; consider using a lipid formulation. If essential, normal
less than 10 mL/min avoid; consider using a lipid formulation. If essential, normal
intermittent haemodialysis if essential, normal (avoid during acute kidney injury)
peritoneal dialysis if essential, normal (avoid during acute kidney injury)
continuous renal replacement therapy if essential, normal (avoid during acute kidney injury)
amphotericin B lipid complex
amphotericin B liposomal
ampicillin
anidulafungin
artemether+lumefantrine
less than 10 mL/min normal (monitor ECG and blood potassium concentration)
intermittent haemodialysis normal (monitor ECG and blood potassium concentration)
peritoneal dialysis normal (monitor ECG and blood potassium concentration)
continuous renal replacement therapy no data
artesunate
atazanavir
intermittent haemodialysis see product information
atazanavir+cobicistat (Evotaz)
atovaquone
atovaquone+proguanil
azithromycin
ECG = electrocardiogram; GFR = glomerular filtration rate
NB1: Dosing in patients with renal impairment is complex, this table is intended as a guide only, see General considerations and if relevant,
Dialysis and continuous renal replacement therapy for further guidance on using this table.
NB2: ‘Normal’ indicates that the standard dosage regimen for the specific indication in these guidelines should be used.
NB3: For multiple-daily doses, percentage dosage adjustments are calculated using the intermittent dose rather than the total daily dose (eg if
standard dosing for drug X is 500 mg 6-hourly then: 50% at normal dosing interval = 250 mg 6-hourly; 100% 12-hourly = 500 mg 12-hourly).
Antimicrobial dosages for adults with impaired renal function (Table 2.80): B [NB1]
benzathine benzylpenicillin
benzylpenicillin
bithionol
benzathine benzylpenicillin
benzylpenicillin
10 to 50 mL/min 75% at normal dosing interval
less than 10 mL/min 25 to 50% at normal dosing interval (maximum of 6 g per day)
bithionol
more than 50 mL/min no data
10 to 50 mL/min no data
less than 10 mL/min no data
intermittent haemodialysis no data
peritoneal dialysis no data
Antimicrobial dosages for adults with impaired renal function (Table 2.80): C [NB1]
caspofungin
cefuroxime
cefalexin
cidofovir
cefazolin
ciprofloxacin intravenous
cefepime
ciprofloxacin oral
cefotaxime
clarithromycin
cefoxitin
clindamycin
ceftazidime
cotrimoxazole
ceftriaxone
caspofungin
cefalexin
less than 10 mL/min 50 to 100% 8- to 12-hourly
cefazolin (2 g loading dose may be required)
20 to 40 mL/min 50% 8-hourly or 100% 12-hourly
less than 20 mL/min 25% 12-hourly or 50% 24-hourly
as for GFR less than 20 mL/min; dose after dialysis, or
100% on dialysis days only; dose after dialysis
continuous renal replacement therapy 100% 12-hourly
cefepime (1 to 2 g loading dose may be required)
10 to 50 mL/min 50 to 100% 12- to 24-hourly (see product information)
less than 10 mL/min 25 to 50% 24-hourly (see product information)
25 to 50% 24-hourly (see product information); dose after
dialysis
peritoneal dialysis 1 g loading dose then 500 mg 24-hourly
continuous renal replacement therapy 50 to 100% 12-hourly
cefotaxime (2 g loading dose may be required)
20 to 50 mL/min 100% 8- to 12-hourly
less than 20 mL/min 50% 8- to 12-hourly
cefoxitin (2 g loading dose may be required)
30 to 80 mL/min 50 to 100% 8- to 12-hourly
10 to 29 mL/min 50 to 100% 12- to 24-hourly
intermittent haemodialysis 50% 24- to 48-hourly; dose after dialysis
peritoneal dialysis 50% 24-hourly
ceftazidime (1 to 2 g loading dose may be required)
less than 16 mL/min 25 to 50% 24-hourly
intermittent haemodialysis 25 to 50% 24-hourly, or 50% 48-hourly; dose after dialysis
ceftriaxone
cefuroxime
cidofovir
10 to 55 mL/min avoid; seek expert advice
less than 10 mL/min avoid; seek expert advice
intermittent haemodialysis avoid; seek expert advice
peritoneal dialysis avoid; seek expert advice
continuous renal replacement therapy avoid; if essential, 2 mg/kg weekly; seek expert advice
ciprofloxacin intravenous (for dosage adjustment in patients with infections caused by Pseudomonas
aeruginosa, seek expert advice)
ciprofloxacin oral (for dosage adjustment in patients with infections caused by Pseudomonas aeruginosa,
seek expert advice)
31 to 50 mL/min 500 mg 12-hourly
10 to 30 mL/min 250 mg 12-hourly or 500 mg 24-hourly
less than 10 mL/min 500 mg 24-hourly
continuous renal replacement therapy 250 to 500 mg 12-hourly
clarithromycin
clindamycin
cotrimoxazole—see trimethoprim+sulfamethoxazole
Antimicrobial dosages for adults with impaired renal function (Table 2.80): D [NB1]
dapsone
daptomycin dolutegravir
darunavir dolutegravir+abacavir+lamivudine (Triumeq)
darunavir+cobicistat (Prezcobix) dolutegravir+rilpivirine (Juluca)
dicloxacillin oral doxycycline
didanosine
dapsone
daptomycin
continuous renal replacement therapy seek expert advice
darunavir
darunavir+cobicistat (Prezcobix)
peritoneal dialysis see product information
dicloxacillin oral
didanosine
more than 50 mL/min
10 to 50 mL/min dosing depends on patient’s weight; see product information
less than 10 mL/min
peritoneal dialysis dosing depends on patient’s weight; see product information
dolutegravir
dolutegravir+abacavir+lamivudine (Triumeq)
dolutegravir+rilpivirine (Juluca)
doxycycline
Antimicrobial dosages for adults with impaired renal function (Table 2.80): E [NB1]
efavirenz enfuvirtide
emtricitabine ertapenem
emtricitabine+rilpivirine+tenofovir erythromycin
alafenamide (Odefsey)
ethambutol (daily regimen)
emtricitabine+tenofovir alafenamide
(Descovy) etravirine
efavirenz
emtricitabine
50 mL/min or more normal
emtricitabine+rilpivirine+tenofovir alafenamide (Odefsey)
emtricitabine+tenofovir alafenamide (Descovy)
enfuvirtide
ertapenem
erythromycin
less than 10 mL/min 50 to 75% at normal dosing interval
ethambutol (daily regimen)
10 to 30 mL/min avoid; if essential, 7.5 to 10 mg/kg 24-hourly
less than 10 mL/min avoid; if essential, 15 mg/kg 48-hourly
intermittent haemodialysis avoid; if essential, 15 mg/kg on dialysis days only (after dialysis)
peritoneal dialysis avoid; if essential, as for GFR less than 10 mL/min
continuous renal replacement therapy avoid; if essential, as for GFR 10 to 30 mL/min
etravirine
Antimicrobial dosages for adults with impaired renal function (Table 2.80): F [NB1]
famciclovir
fosamprenavir
flucloxacillin intravenous
foscarnet
flucloxacillin oral
fosfomycin (single-dose oral therapy)
fluconazole
fusidate sodium
flucytosine
famciclovir
peritoneal dialysis
flucloxacillin intravenous
continuous renal replacement therapy 100% 6- to 8-hourly
flucloxacillin oral
fluconazole (give normal dosage for the first 48 hours as a loading dose)
30 to 50 mL/min 50 to 100% 24-hourly
10 to 29 mL/min 25 to 50% 24-hourly
continuous renal replacement therapy 150% 24-hourly
flucytosine (if possible, monitor blood concentration in patients with kidney impairment)
continuous renal replacement therapy 100% 12- to 24-hourly
fosamprenavir
foscarnet see product information and seek expert advice
fosfomycin (single-dose oral therapy)
fusidate sodium
Antimicrobial dosages for adults with impaired renal function (Table 2.80): G [NB1]
ganciclovir treatment
ganciclovir prophylaxis
gentamicin
griseofulvin
ganciclovir treatment
50 to 69 mL/min 2.5 mg/kg 12-hourly
less than 10 mL/min 1.25 mg/kg 3 times weekly
ganciclovir prophylaxis
less than 10 mL/min 0.625 mg/kg 3 times weekly
gentamicin
more than 50 mL/min
less than 10 mL/min
griseofulvin
Antimicrobial dosages for adults with impaired renal function (Table 2.80): I [NB1]
imipenem+cilastatin
indinavir
isoniazid
itraconazole
ivermectin
imipenem+cilastatin (dose expressed as imipenem component) (0.5 to 1 g loading dose may be required)
30 to 50 mL/min 500 mg 6- to 8-hourly
20 to 29 mL/min 500 mg 8- to 12-hourly
avoid; if essential, 250 to 500 mg 12-hourly (usually 500 mg 12-
less than 20 mL/min
hourly)
continuous renal replacement therapy 500 mg 8-hourly
indinavir
isoniazid
intermittent haemodialysis normal; dose after dialysis
itraconazole
ivermectin
Antimicrobial dosages for adults with impaired renal function (Table 2.80): L [NB1]
lamivudine
lincomycin
linezolid
lopinavir+ritonavir (Kaletra)
lamivudine
peritoneal dialysis as for GFR 5 to 14 mL/min; see product information
continuous renal replacement therapy HIV: 100 mg initially, then 50 mg 24-hourly
lincomycin
as for GFR less than 10 mL/min; dose after dialysis if dosed 24-
hourly
linezolid
less than 10 mL/min 100% 24-hourly [NB4]
intermittent haemodialysis as for GFR less than 10 mL/min; dose after dialysis [NB4]
peritoneal dialysis as for GFR less than 10 mL/min [NB4]
lopinavir+ritonavir (Kaletra)
NB4: Some centres do not adjust linezolid dosage for patients with GFR less than 10 mL/min, or undergoing intermittent haemodialysis or
peritoneal dialysis. The resultant concentrations of linezolid and its metabolites, if the dosage is not adjusted, have been associated with toxicity—
close clinical monitoring is required (see Practical information on using linezolid).
Antimicrobial dosages for adults with impaired renal function (Table 2.80): M [NB1]
maraviroc
metronidazole
mebendazole
minocycline
mefloquine
moxifloxacin
meropenem
maraviroc
more than 50 mL/min use with caution. If used concurrently with cytochrome P450
10 to 50 mL/min 3A4 (CYP3A4) inhibitors, renal clearance may account for up to
70% of the total clearance of maraviroc. Patients with a GFR less
less than 10 mL/min than 50 mL/min should only receive maraviroc and CYP3A4
inhibitors if the potential benefits outweigh the harms
mebendazole
mefloquine
meropenem
metronidazole
micafungin
minocycline
less than 30 mL/min use alternative; if essential, normal
intermittent haemodialysis use alternative; if essential, normal
peritoneal dialysis use alternative; if essential, normal
continuous renal replacement therapy use alternative; if essential, normal
moxifloxacin
Antimicrobial dosages for adults with impaired renal function (Table 2.80): N [NB1]
nevirapine
niclosamide
nitazoxanide
nitrofurantoin
norfloxacin
nevirapine
niclosamide
nitazoxanide
nitrofurantoin
10 to 40 mL/min avoid [NB5]
less than 10 mL/min avoid
intermittent haemodialysis avoid
peritoneal dialysis avoid
continuous renal replacement therapy avoid
norfloxacin
NB5: If GFR is 30 to 40 mL/min, nitrofurantoin may be used for 5 to 7 days to treat urinary tract infections caused by multidrug-resistant bacteria.
Antimicrobial dosages for adults with impaired renal function (Table 2.80): O [NB1]
oseltamivir (consider zanamivir)

Dosage adjustment based on GFR [NB2] [NB3] [NB4]
treatment: 75 mg 24-hourly
10 to 30 mL/min
prophylaxis: 75 mg 48-hourly OR 30 mg 24-hourly
no data; if essential:
treatment: 75 mg 48-hourly OR 30 mg 24-hourly

less than 10 mL/min
prophylaxis: 30 mg 48-hourly
Dosages for dialysis [NB2] [NB3] [NB4]
treatment: 75 mg at the onset of symptoms, then 30 mg after
each dialysis session
prophylaxis: 30 mg after dialysis, then 30 mg after alternate
dialysis sessions
treatment: 75 mg at the onset of symptoms, then repeat dose
peritoneal dialysis after 5 days
prophylaxis: 30 mg after dialysis, then 30 mg every 7 days

NB4: Pharmacokinetic data indicate that adequate steady-state plasma concentrations in patients with impaired kidney function are achieved with
lower dosages (as outlined in the oseltamivir product information). The higher dosages in this table are recommended on the basis of oseltamivir’s
wide therapeutic index, to ensure timely initiation of oseltamivir therapy in patients at increased risk of influenza-related complications.
Antimicrobial dosages for adults with impaired renal function (Table 2.80): P [NB1]
paromomycin primaquine
pentamidine intravenous pristinamycin
phenoxymethylpenicillin procaine benzylpenicillin
piperacillin+tazobactam proguanil
posaconazole intravenous pyrantel
posaconazole oral pyrazinamide
praziquantel pyrimethamine
paromomycin
pentamidine intravenous
10 to 60 mL/min avoid; if essential, normal
less than 10 mL/min avoid; if essential, 100% 24- to 36-hourly
continuous renal replacement therapy avoid; if essential, 100% 24-hourly
phenoxymethylpenicillin
piperacillin+tazobactam
posaconazole intravenous (see product information about accumulation of intravenous solvent)
10 to 50 mL/min not recommended
less than 10 mL/min not recommended
intermittent haemodialysis not recommended
peritoneal dialysis not recommended
continuous renal replacement therapy not recommended
posaconazole oral
praziquantel
primaquine
pristinamycin
procaine benzylpenicillin
proguanil
less than 10 mL/min 25% weekly
continuous renal replacement therapy 25% 48-hourly to weekly
pyrantel
pyrazinamide
intermittent haemodialysis 25 to 30 mg/kg on dialysis days only; dose after dialysis
pyrimethamine
Antimicrobial dosages for adults with impaired renal function (Table 2.80): Q [NB1]
quinine bisulfate or quinine sulfate (oral)
quinine dihydrochloride (intravenous)

quinine bisulfate or quinine sulfate (oral)
quinine dihydrochloride (intravenous) (give a loading dose of 20 mg/kg over 4 hours; start the
maintenance dose 4 hours after the loading dose is completed) (for severe malaria, do not reduce dose or
interval in the first 48 hours)
20 to 50 mL/min 5 to 10 mg/kg 8-hourly
10 to 19 mL/min 5 to 10 mg/kg 12-hourly
less than 10 mL/min 5 to 10 mg/kg 24-hourly
Antimicrobial dosages for adults with impaired renal function (Table 2.80): R [NB1]
raltegravir
rifabutin
rifampicin
rilpivirine
ritonavir
roxithromycin
raltegravir
rifabutin
rifampicin
rilpivirine
ritonavir
roxithromycin
Antimicrobial dosages for adults with impaired renal function (Table 2.80): S [NB1]
saquinavir
stavudine
sulfadiazine
saquinavir
stavudine
sulfadiazine (if GFR is less than 20 mL/min, monitor blood concentration if possible)
20 to 50 mL/min avoid; if essential, normal
10 to 19 mL/min avoid; if essential, 50% at normal dosing interval
less than 10 mL/min avoid; if essential, 25% at normal dosing interval
Antimicrobial dosages for adults with impaired renal function (Table 2.80): T [NB1]
teicoplanin tenofovir disoproxil maleate+emtricitabine (Tenofovir

Disoproxil Emtricitabine Mylan 300/200)
tenofovir alafenamide
tenofovir disoproxil phosphate
tenofovir alafenamide+emtricitabine+bictegravir
(Biktarvy) tenofovir disoproxil phosphate+emtricitabine (Tenofovir
EMT GH)
tenofovir
alafenamide+emtricitabine+elvitegravir+cobicistat terbinafine
(Genvoya)
tigecycline
tenofovir disoproxil fumarate
tinidazole
tenofovir disoproxil fumarate+emtricitabine
(Truvada) tipranavir
tenofovir disoproxil tobramycin

fumarate+emtricitabine+efavirenz (Atripla)
triclabendazole
tenofovir disoproxil
fumarate+emtricitabine+elvitegravir+cobicistat trimethoprim
(Stribild)
trimethoprim+sulfamethoxazole (standard treatment
tenofovir disoproxil dosing)
fumarate+emtricitabine+rilpivirine (Eviplera)
trimethoprim+sulfamethoxazole (treatment of
tenofovir disoproxil maleate Pneumocystis jirovecii pneumonia)
teicoplanin (use normal dose for the first 3 days then adjust dosing on day 4. If possible, monitor blood
concentration)
tenofovir alafenamide
less than 15 mL/min avoid
intermittent haemodialysis avoid
peritoneal dialysis avoid
continuous renal replacement therapy avoid
tenofovir alafenamide+emtricitabine+bictegravir (Biktarvy)
less than 30 mL/min avoid fixed-dose combination
intermittent haemodialysis avoid fixed-dose combination
peritoneal dialysis avoid fixed-dose combination
continuous renal replacement therapy avoid fixed-dose combination
tenofovir alafenamide+emtricitabine+elvitegravir+cobicistat (Genvoya)
tenofovir disoproxil fumarate
100% 48-hourly
30 to 49 mL/min

tenofovir disoproxil fumarate+emtricitabine (Truvada)
tenofovir disoproxil fumarate+emtricitabine+efavirenz (Atripla)
tenofovir disoproxil fumarate+emtricitabine+elvitegravir+cobicistat (Stribild)
more than 50 mL/min do not use if GFR less than 70 mL/min
10 to 50 mL/min avoid fixed-dose combination
tenofovir disoproxil fumarate+emtricitabine+rilpivirine (Eviplera)
tenofovir disoproxil maleate
tenofovir disoproxil maleate+emtricitabine (Tenofovir Disoproxil Emtricitabine Mylan 300/200)
tenofovir disoproxil phosphate
tenofovir disoproxil phosphate+emtricitabine (Tenofovir EMT GH)
terbinafine
tigecycline
tinidazole
tipranavir
tobramycin
more than 50 mL/min
less than 10 mL/min
triclabendazole
trimethoprim
15 to 30 mL/min normal; monitor full blood count
avoid; if essential, up to 150 mg 24-hourly; monitor full
less than 15 mL/min
blood count
trimethoprim+sulfamethoxazole (standard treatment dosing)
26 to 50 mL/min normal for 14 days, then 50% at normal dosing interval
15 to 25 mL/min normal for 3 days, then 100% 24-hourly
avoid; if essential, normal for 3 days, then 100% 24-
less than 15 mL/min
hourly
as for GFR less than 15 mL/min; dose after dialysis if
dosed 24-hourly
trimethoprim+sulfamethoxazole (treatment of Pneumocystis jirovecii pneumonia)
5+25 mg/kg at normal dosing interval for 2 days, then
15 to 25 mL/min
5+25 mg/kg 12-hourly
less than 15 mL/min 5+25 mg/kg 12- to 24-hourly
as for GFR less than 15 mL/min; dose after dialysis if
dosed 24-hourly
Antimicrobial dosages for adults with impaired renal function (Table 2.80): V [NB1]
valaciclovir vancomycin
valganciclovir treatment voriconazole intravenous
valganciclovir prophylaxis voriconazole oral

valaciclovir
peritoneal dialysis
valganciclovir treatment [NB6]
200 mg 3 times weekly, or
less than 10 mL/min
only if full blood count is closely monitored, 450 mg 2 to 3 times
weekly
200 mg 3 times weekly; dose after dialysis, or, only if full blood
intermittent haemodialysis count is closely monitored, 450 mg 3 times weekly; dose after
dialysis
continuous renal replacement therapy avoid; use intravenous ganciclovir
valganciclovir prophylaxis [NB6]
10 to 24 mL/min 450 mg twice weekly
less than 10 mL/min 100 mg 3 times weekly [NB7]
vancomycin
more than 50 mL/min
10 to 50 mL/min see Principles of vancomycin use
less than 10 mL/min
voriconazole intravenous (see product information about accumulation of intravenous solvent)
10 to 50 mL/min not recommended
less than 10 mL/min not recommended
intermittent haemodialysis not recommended
peritoneal dialysis not recommended
continuous renal replacement therapy not recommended
voriconazole oral
NB6: Evidence suggests that estimated glomerular filtration rate (eGFR) is an inaccurate measure of true kidney function in solid organ transplant
recipients and that valganciclovir dosage adjustment should not be based on eGFR. For these patients, measure 24-hour urinary creatinine
clearance or use the Cockcroft–Gault formula (see Box 2.47) to assess kidney function.
NB7: An alternative valganciclovir maintenance therapy regimen for kidney transplant recipients with delayed graft function is 450 mg twice
weekly. Local protocols may vary.
Antimicrobial dosages for adults with impaired renal function (Table 2.80): Z [NB1]
zanamivir
zidovudine
zanamivir
zidovudine
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Contact details for health departments and public
health units
Australian government health contacts
Australian Government Department of Health website. Telephone: 1800 020 103
Australian Immunisation Handbook website
Australian Immunisation Register website. Enquiries: 1800 653 809
State and territory government health departments and public

health units
Australian Capital Territory
ACT Health website
Communicable Disease Control Section: 02 6205 2155
New South Wales

NSW Health website
Public health units website or call 1300 066 055 to connect to a local public health unit
Northern Territory
Department of Health website
Centre for Disease Control website. Phone: 08 8922 8044 (After hours: Royal Darwin Hospital 08 8922
8888)
Queensland
Queensland Health website
Public health units website
Communicable diseases contacts: 07 3328 9724 / 9728
South Australia
SA Health website
Communicable Disease Control Branch website. Phone: 1300 232 272
Tasmania
Department of Health and Human Services website
Communicable Diseases Prevention website
Public health hotline: 1800 671 738
Victoria
Department of Health and Human Services website
Communicable Disease Epidemiology and Surveillance: 1300 651 160
Western Australia
Department of Health website
Population/public health units website. Perth Metropolitan Communicable Disease Control: 08 9222 8588 or
1300 623 292 (After hours: 08 9328 0553). Outside Perth Metropolitan area: Contact regional population
health unit.
Thyroid disorders: overview
Classification of thyroid disorders
Thyroid disorders are classified as:
primary—caused by a disorder within the thyroid gland, affecting the production or secretion of thyroid
hormones (triiodothyronine [T3] and thyroxine [T4])
subclinical—serum T3 and T4 concentrations are within the normal range, but serum thyroid
stimulating hormone (TSH) concentration is outside the normal range. Subclinical disease is
usually asymptomatic
overt—serum T3, T4 and TSH concentrations are outside the normal range. Overt disease is
usually symptomatic
secondary—caused by a disorder within the anterior pituitary gland, affecting the production or
secretion of TSH, which in turn affects the production of thyroid hormones
tertiary—caused by a disorder within the hypothalamus, affecting the production or secretion of thyroid
releasing hormone, which in turn affects the production of TSH and thyroid hormones.
In a primary disorder, the negative feedback response of serum T4 and T3 concentrations on release of TSH
(and thyroid releasing hormone) remains intact, so primary hypothyroidism results in an elevated serum TSH
concentration, and primary thyrotoxicosis results in a suppressed serum TSH concentration.
Secondary and tertiary thyroid disorders are referred to as central thyroid disorders. In a central thyroid
disorder, the negative feedback response is dysfunctional; in hypothyroidism secondary to hypopituitarism,
serum TSH concentration remains low or inappropriately normal despite low serum T3 and T4 concentrations.
Central hyperthyroidism is rare.
Initial testing for thyroid disorders

Thyroid disorders can affect almost all body systems, causing diverse and nonspecific presentations, so
diagnosis requires laboratory testing for confirmation.
The most useful initial test for a suspected thyroid disorder is serum thyroid stimulating hormone (TSH)
concentration.
If the serum TSH concentration is within the reference range, a primary thyroid disorder is unlikely, but a
central thyroid disorder cannot be excluded. Additional thyroid function tests are usually unnecessary, unless
a central disorder is suspected based on presentation (see Overview of hypopituitarism for signs and
symptoms).
If the serum TSH concentration is above or below the reference range, additional thyroid function tests (eg
serum free thyroxine [T4] concentration) are usually necessary to differentiate the diagnosis and to confirm
that the abnormal serum TSH concentration is persistent. Table 19.1 outlines the interpretation of serum T4
concentration in the context of the serum TSH concentration.
Other tests such as thyroid peroxidase antibody and TSH-receptor antibody are useful to further differentiate
the diagnosis. Their use is discussed in the topics Hypothyroidism and Thyrotoxicosis and hyperthyroidism.
Thyroid ultrasound is useful for patients with known or palpable thyroid nodules to assess and define the
abnormality. It has no role in the diagnosis of thyroid disorders in the absence of known or palpable thyroid
nodules.
Thyroid ultrasound has no role in the diagnosis of thyroid disorders in the absence of known or palpable thyroid nodules.
Interpretation of serum TSH and free T4 concentrations (Table 19.1)
Printable Table
High serum TSH concentration
Normal serum TSH concentration
Low serum TSH concentration

High serum TSH concentration
Serum free T4 concentration Possible interpretations
possible laboratory error
high serum free T4 secondary hyperthyroidism (TSH-secreting pituitary adenoma) [NB1]

concentration thyroid hormone resistance [NB1]
intermittent poor adherence to levothyroxine

normal serum free T4 subclinical primary hypothyroidism (also called mild thyroid failure)
concentration recent severe nonthyroidal illness
overt primary hypothyroidism
low serum free T4 concentration recent severe nonthyroidal illness
antithyroid overtreatment
Normal serum TSH concentration
possible laboratory error
high serum free T4 secondary hyperthyroidism (TSH-secreting pituitary adenoma) [NB1]

concentration thyroid hormone resistance [NB1]
sampling within 6 hours of levothyroxine dose

normal serum free T4
normal thyroid function
concentration
secondary hypothyroidism (pituitary cause) or tertiary
hypothyroidism (hypothalamic cause)
low serum free T4 concentration severe nonthyroidal illness

use of drugs that affect serum free T4 concentration (see Table 19.3)
antithyroid overtreatment
Low serum TSH concentration
high serum free T4 overt primary hyperthyroidism [NB2] [NB3]
concentration levothyroxine overtreatment
subclinical primary hyperthyroidism [NB3]
levothyroxine overtreatment
normal serum free T4 nonthyroidal illness

concentration
treated secondary hypothyroidism (pituitary cause) or tertiary
hypothyroidism (hypothalamic cause)
recently started antithyroid drug

secondary hypothyroidism (pituitary cause) or tertiary
low serum free T4 concentration hypothyroidism (hypothalamic cause)
severe nonthyroidal illness
T4 = thyroxine; TSH = thyroid stimulating hormone
NB1: Secondary hyperthyroidism and thyroid hormone resistance are rare. Contact the laboratory for confirmation of test results; laboratory error
can distort results in up to 5% of tests.
NB2: TSH is usually suppressed (serum concentration less than 0.05 milliunits/L, and at least less than 0.1 milliunits/L), rather than just low
(serum concentration between the lower limit of the normal range and 0.1 milliunits/L).
NB3: Primary hyperthyroidism includes Graves disease, toxic multinodular goitre and toxic adenoma.
Thyroid function testing before conception and during pregnancy

Routine screening for thyroid dysfunction in women who are pregnant or planning to become pregnant is not
recommended.
Do not routinely screen pregnant women for thyroid dysfunction.
Screening is only recommended in women at increased risk of a thyroid disorder, including women with:
a history of any thyroid disorder

a family history of any thyroid disorder
type 1 diabetes or another autoimmune disorder
prior or current positive thyroid antibodies (eg euthyroid Hashimoto thyroiditis)
a history of infertility, recurrent miscarriage or preterm delivery
a goitre on examination
prior therapeutic head or neck irradiation.
In women with risk factors for a thyroid disorder, test thyroid function at the first antenatal visit, and consider
repeating the test every 4 to 6 weeks during the first trimester to monitor the need for treatment. If the serum
TSH concentration is normal, testing again at around 30 weeks is sufficient. In addition, women with a history
of Graves disease require specific monitoring to detect neonatal hyperthyroidism.
To avoid misinterpretation of thyroid function test results during pregnancy, use population-based, trimester-
specific reference ranges. Refer to local reference ranges supplied by the laboratory; if these are not available,
reasonable trimester-specific reference ranges for serum thyroid stimulating hormone (TSH) concentration are
shown in Table 19.2.
During a healthy pregnancy, production of thyroid hormones (triiodothyronine [T3] and thyroxine [T4])
increases by up to 50%, stimulated by human chorionic gonadotrophin (hCG) in the first trimester. TSH is
transiently suppressed by the elevated T3 and T4 concentrations. Although total T4 increases in pregnancy,
pregnancy-related changes in binding protein concentrations can cause standard laboratory tests to show a
reduced serum free T4 during the third trimester.
Trimester-specific reference ranges for serum TSH concentration during pregnancy (Table
19.2)
Trimester Serum TSH concentration reference range

first trimester 0.1 to 4.0 milliunits/L
second trimester 0.2 to 4.0 milliunits/L
third trimester 0.3 to 4.0 milliunits/L
TSH = thyroid stimulating hormone
Thyroid hormone changes during critical nonthyroidal illness

During critical illness, serum triiodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH)
concentrations often fall outside (usually below) the normal reference ranges. In the absence of clinical
features of a thyroid disorder, abnormal serum T3, T4 and TSH concentrations are usually a transient part of
the complex endocrine response to critical illness, and rarely reflect persistent thyroid disease. Do not start
treatment for a thyroid disorder during critical illness based on thyroid function test results alone.
Serum thyroid hormone concentrations are often abnormal during critical illness; do not start treatment for a thyroid
disorder based on thyroid function tests alone.
During critical illness, a common finding is a low serum TSH concentration with a low serum T4
concentration, which otherwise suggests hypothyroidism secondary to hypopituitarism; however, a persistent
pituitary abnormality is rare. These changes are usually caused by transient central inhibition of TSH
secretion (either spontaneous or caused by drugs), altered deiodination, and accelerated clearance of thyroid
hormones related to critical illness.
High serum TSH concentration with normal or low serum T4 concentration, which usually indicates primary
hypothyroidism, can occur transiently during recovery from critical illness.
Many drugs can influence thyroid function; these effects can be amplified during critical illness. Patients who
are critically ill are also likely to be taking multiple drugs, so always consider the effect of drugs on thyroid
function. See Drugs that influence thyroid hormones.
In a patient who had abnormal serum thyroid hormone concentrations during a critical illness, assess for
persistent thyroid disease by repeating thyroid function tests around 6 weeks after recovery.
Drugs that influence thyroid hormones

Many drugs can influence thyroid function, thyroid function tests, thyroxine replacement therapy or
antithyroid drug therapy (see Table 19.3). These effects can be amplified during critical illness.
Iodine excess can exacerbate thyroid dysfunction (both hypothyroidism and thyrotoxicosis); see Adverse
effects of iodine excess for more information.
Drugs that influence thyroid hormones (Table 19.3)
Effect Drugs
iodine excess, lithium, amiodarone, interferon alfa,
interleukin-2, tyrosine kinase inhibitors (eg sunitinib,
hypothyroidism
sorafenib), immune checkpoint inhibitors (eg ipilimumab,
nivolumab, pembrolizumab, atezolizumab)
iodine excess, amiodarone, interferon alfa, interleukin-2,
thyrotoxicosis
alemtuzumab
cholestyramine, sucralfate, ferrous sulfate, aluminium
impaired levothyroxine absorption [NB1]
hydroxide, sevelamer, calcium carbonate, soy preparations
increased hepatic metabolism of levothyroxine
phenytoin, barbiturates, carbamazepine, rifampicin
[NB2]
resistance to antithyroid drugs iodine excess
altered diagnostic test results—can include biotin (vitamin B7) [NB3]
false-positive results suggesting Graves disease
altered diagnostic test results—lower serum
dopamine, glucocorticoids
TSH concentration
altered diagnostic test results—altered serum T4 numerous drugs, depending on analytical method (eg
phenytoin, carbamazepine, frusemide, heparin, aspirin,
concentration some NSAIDs)
NSAIDs = nonsteroidal anti-inflammatory drugs; T4 = free thyroxine; TSH = thyroid stimulating hormone
NB1: Separating the dosage times of these drugs from levothyroxine (eg dosing 4 hours apart) minimises this effect.
NB2: Patients may require an increased levothyroxine dose.
NB3: Low-dose biotin therapy is unlikely to affect thyroid test results. Stopping high-dose therapy 3 or 4 days before testing should overcome any
effect on results.
Adverse effects of iodine excess on the thyroid

Iodine excess can be harmful in patients with established thyroid disorders. Iodine exposure commonly results
from:
radiographic contrast agents

iodine-containing topical preparations or drugs (eg amiodarone)
complementary medicines (eg kelp tablets), which are often taken in the mistaken belief that iodine is
routinely helpful for established thyroid disorders.
Topical iodine preparations can cause transient hypothyroidism in infants.
Iodine excess can precipitate drug-resistant hyperthyroidism in older patients with autonomous nodular
thyroid disease (multinodular goitre or toxic adenoma). Iodine excess can also impair thyroid hormone
formation in autoimmune hypothyroidism—correction of iodine excess has been reported to improve thyroid
function in these patients.
Key references
Initial testing for thyroid disorders
Endocrine Society. Choosing Wisely. 5 things clinicians and consumers should question. Philadelphia: ABIM
(American Board of Internal Medicine) Foundation; 2013 [updated 2018].
http://www.choosingwisely.org/societies/endocrine-society
Gurnell M, Halsall DJ, Chatterjee VK. What should be done when thyroid function tests do not make sense? Clin
Endocrinol (Oxf) 2011;74(6):673–8.
Topliss DJ, Eastman CJ. 5: Diagnosis and management of hyperthyroidism and hypothyroidism. Med J Aust
2004;180(4):186–93.
Walsh JP. Managing thyroid disease in general practice. Med J Aust 2016;205(4):179–84.
Wilson J, Morgan S, Magin PJ, van Driel ML. Fatigue--a rational approach to investigation. Aust Fam Physician
2014;43(7):457–61.
Thyroid function testing before conception and during pregnancy
Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 guidelines of the American
Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum.
Thyroid 2017;27(3):315–89.
Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, et al. Guidelines of the American
Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum.
Thyroid 2011;21(10):1081–125.
Published June 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Hypothyroidism
Introduction to hypothyroidism
Hypothyroidism refers to the clinical condition that results from insufficient production of thyroid hormones.
Primary hypothyroidism—hypothyroidism resulting from a disorder within the thyroid gland—is the most
common form of hypothyroidism. Other types of hypothyroidism include central hypothyroidism (caused by a
pituitary or hypothalamic disorder), drug-induced hypothyroidism and congenital hypothyroidism.
Typical symptoms of hypothyroidism include fatigue, weight gain, cold intolerance, constipation and dry skin.
Thyroid hormones affect almost all tissue and organ systems in the body, so atypical presentations are common
and diagnosis requires confirmation with laboratory testing. For information about testing thyroid function and
interpreting test results, see Initial testing for thyroid disorders. In the absence of known or palpable thyroid
nodules, thyroid ultrasound has no role in the diagnosis of hypothyroidism.
Hypothyroidism is associated with an increased incidence of cardiovascular risk factors, such as

hypercholesterolaemia, high blood pressure, and left ventricular systolic dysfunction. These abnormalities may
improve with treatment of hypothyroidism.
Severe hypothyroidism can alter the pharmacokinetics of some drugs, which can cause increased drug activity or
toxicity (eg sedatives, analgesics, anaesthetics, digoxin), or decreased drug activity (eg anticoagulants). If the
patient is taking other drugs, review the doses when treatment for hypothyroidism is started or adjusted.
Overview of primary hypothyroidism

Primary hypothyroidism refers to a disorder within the thyroid gland that reduces the production or secretion of
thyroid hormones (thyroxine [T4] and triiodothyronine [T3]). The negative feedback response of serum thyroid
hormone concentrations on thyroid stimulating hormone (TSH) results in an elevated serum TSH concentration.
Primary hypothyroidism can be either overt or subclinical:
Overt primary hypothyroidism is defined by an elevated serum TSH concentration and a low serum T4
concentration, and is usually symptomatic. It occurs in around 0.5% of the Australian population.
Subclinical primary hypothyroidism (also called mild thyroid failure) is defined by an elevated serum TSH
concentration, but a serum T4 concentration within the normal range. It is often asymptomatic. Subclinical
hypothyroidism occurs in around 5% of the Australian population.
Primary hypothyroidism is more common in:
women over 55 years

people with a history of Graves disease (remitted Graves disease can be followed by hypothyroidism)
people with an autoimmune disorder (eg type 1 diabetes, coeliac disease) or a condition that increases the
risk of an autoimmune disorder (eg Down syndrome, Turner syndrome)
people taking some drugs (see Table 19.3).
Most cases of spontaneous primary hypothyroidism are due to autoimmune thyroiditis (Hashimoto thyroiditis).
Thyroid peroxidase antibodies are almost always present in Hashimoto thyroiditis. They indicate an increased risk
of progression of disease—a patient with subclinical hypothyroidism who has a positive thyroid peroxidase
antibody is more likely to progress to overt disease than a patient a with negative thyroid peroxidase antibody.
Primary hypothyroidism is usually managed with thyroxine replacement therapy; see here for when to start therapy
in adults and see here for dosing and principles of use of thyroxine replacement therapy in adults.
For management of children with hypothyroidism, see here, and for pregnant women with hypothyroidism, see
here.
When to start treatment for primary hypothyroidism in adults

Primary hypothyroidism is treated with thyroxine replacement therapy (levothyroxine), with the aim of achieving
euthyroidism and symptom relief. The decision to treat depends primarily on:
whether the patient has overt or subclinical disease

whether the patient is symptomatic
the degree of thyroid stimulating hormone (TSH) elevation.
Overt symptomatic primary hypothyroidism is a clear indication to start treatment with levothyroxine. Testing
for serum thyroid peroxidase antibodies is not essential as it does not affect the decision to start treatment.
Overt asymptomatic primary hypothyroidism is rare—it sometimes occurs following recent critical
nonthyroidal illness. Before starting treatment, confirm that the illness is persistent by repeating the test after 4 to 8
weeks (or sooner if symptoms develop).
Subclinical symptomatic primary hypothyroidism (even if serum TSH concentration is only mildly elevated) is
a reasonable indication to trial therapy to relieve symptoms.
Subclinical asymptomatic primary hypothyroidism with a serum TSH concentration above 10 milliunits/L
indicates a high risk of progression to overt disease. Retest the serum TSH concentration after 4 to 8 weeks, and
start treatment if hypothyroidism is persistent.
Subclinical asymptomatic hypothyroidism with mildly elevated serum TSH concentration (in the range 4 to
10 milliunits/L) may not require treatment. Retest the serum TSH concentration after 4 to 8 weeks to confirm the
hypothyroidism is persistent, and also test for thyroid peroxidase antibody. Patients with a positive thyroid
peroxidase antibody are more likely to progress to overt hypothyroidism—repeat thyroid function tests after 3
months, then 6- to 12-monthly thereafter. Start treatment if the patient has a progressive rise in TSH or if
symptoms occur. Patients with a negative thyroid peroxidase antibody can be assessed less frequently (eg every 12
months).
Hypothyroidism (including subclinical hypothyroidism) increases the incidence of cardiovascular risk factors (eg
hypercholesterolaemia, elevated blood pressure), particularly in patients diagnosed at a young age (eg less than 60
years) and with higher serum TSH concentrations. In a young patient with hypothyroidism who does not meet
other criteria for treatment, but who has a significant cardiovascular risk factor, consider a 3- to 6-month trial of
levothyroxine. Stop treatment if a clear improvement does not occur (eg reduced low-density lipoprotein [LDL]
concentration), and continue monitoring serum TSH concentration.
Starting thyroxine replacement therapy for hypothyroidism in adults

The aim of thyroxine replacement therapy for hypothyroidism is to achieve euthyroidism and relieve hypothyroid
symptoms. The principles of starting replacement therapy for both primary and secondary hypothyroidism are the
same, but the dose adjustment strategy is different (see Dose adjustment).
For information about when to start treatment for primary hypothyroidism in adults, see here. For information
about hypothyroidism secondary to hypopituitarism, see Thyroid hormone replacement in hypopituitarism. For
hypothyroidism secondary to hypopituitarism, do not start thyroid replacement therapy before excluding or
correcting glucocorticoid deficiency, as this can precipitate adrenal crisis.
For thyroxine replacement therapy in children, see Hypothyroidism in children. Thyroxine therapy for thyroid
cancer involves different doses and treatment targets; see Thyroxine therapy for thyroid cancer.
Thyroxine replacement therapy in adults can be started with one of two strategies:
Initial full replacement—start therapy with a body weight–based dose that is expected to fully replace
thyroid hormone requirements immediately.
Initial partial replacement—start therapy with a low dose, and increase the dose slowly to achieve full
thyroxine replacement.
Initial full replacement is preferred in most patients with overt hypothyroidism; it relieves symptoms and achieves
euthyroidism more quickly, and is usually well tolerated. Initial full replacement is also used following total
thyroidectomy in patients who were euthyroid before surgery.
For initial full replacement, start treatment with:
levothyroxine 1.6 micrograms/kg (to the nearest 25 micrograms) orally, daily. Adjust the
dose every 4 to 8 weeks as required; see Dose adjustment.
For patients at extremes of body weight, use lean body weight rather than actual body weight to calculate the
levothyroxine dose [Note 1].
Initial partial replacement is recommended for patients with only mildly elevated serum thyroid stimulating
hormone (TSH) concentration or subclinical disease. It is also recommended for patients with cardiovascular
disease because a high starting dose can precipitate or exacerbate cardiac ischaemia. Partial replacement may also
be preferred for older patients, who typically need a lower maintenance dose than younger patients, and who are at
higher risk of cardiovascular disease.
For initial partial replacement, start treatment with:
levothyroxine 25 to 50 micrograms orally, daily. Adjust the dose every 4 to 8 weeks as

required; see Dose adjustment.
Start at the lower end of the dose range for a patient with cardiovascular disease.
Note 1: Click here for lean body weight calculator and formula.
Adjusting thyroxine replacement therapy for hypothyroidism in adults

Dose adjustment in primary hypothyroidism
After starting thyroxine replacement therapy for primary hypothyroidism (with either full or partial replacement),
measure serum TSH concentration and adjust the levothyroxine dose at 4- to 8-weekly intervals to achieve a serum
TSH concentration in an age-specific target range. Subtle dose adjustments can be achieved by prescribing
different strength tablets on different days of the week.
When the serum TSH concentration is in the target range, the serum free thyroxine (T4) concentration is usually in
the upper half of the normal range. A serum TSH concentration below the target range indicates overtreatment;
long-term overtreatment can cause atrial fibrillation and accelerated loss of bone mass. For patients who have an
inadequate response to levothyroxine (eg persistently elevated TSH, continued symptoms despite normalised
TSH), see Inadequate response to thyroxine replacement therapy.
For patients younger than 60 years, aim for a serum TSH concentration between 0.5 and 2.5 milliunits/L, which
approximates the median serum TSH concentration in the normal adult population.
In older patients, the serum TSH target range is less aggressive and the final levothyroxine dose is typically lower,
because:
thyroid hormone requirements decrease with age

the normal serum TSH concentration rises with age (most markedly in people aged over 80 years)
older patients are more susceptible to the consequences of overtreatment
the risk of provoking unrecognised cardiac ischaemia is higher in older patients.
For patients 60 years and older, a reasonable serum TSH target range is 1 to 5 milliunits/L.
For patients older than 80 years, consider an even higher serum TSH target range (eg 4 to 6 milliunits/L).
For frail elderly patients and patients with biochemically severe hypothyroidism at baseline, base initial dose
adjustments on clinical response rather than serum TSH concentration. Do not aim for normalisation of serum
TSH concentration within the first 3 months of treatment. If symptoms of cardiac ischaemia occur, do not increase
the dose further until the cardiac condition has been investigated and managed.
Full replacement may not be achievable for a patient with severe cardiovascular disease who cannot undergo
coronary artery revascularisation; a degree of persisting hypothyroidism is sometimes necessary in these patients.
Multiple brands of levothyroxine tablets are currently available in Australia. Minor dose adjustments may be
required if switching between brands that are not bioequivalent.
Dose adjustment in hypothyroidism secondary to hypopituitarism

For a patient with hypothyroidism secondary to hypopituitarism, base levothyroxine dose adjustments on
symptoms and serum T4 concentration—aim for a serum T4 concentration in the upper half of the reference range.
To measure the serum T4 concentration, the sample should be collected before the daily dose of levothyroxine;
sampling after the daily dose can spuriously elevate the T4 concentration.
Do not use serum TSH concentration as a basis for dose adjustment in hypopituitarism, as a low serum TSH
concentration is an expected finding in hypothyroidism secondary to hypopituitarism.
See also Thyroid hormone replacement in hypopituitarism.
Ongoing management of thyroxine replacement therapy for

hypothyroidism in adults
Once levothyroxine therapy is stabilised, measure serum TSH concentration (or in the case of hypopituitarism,
serum T4 concentration) at about 3 and 6 months, and annually thereafter. Most cases of hypothyroidism are
lifelong and require indefinite thyroxine replacement.
Transient deficiency can occur following subacute thyroiditis, radioiodine therapy, subtotal thyroidectomy,
pregnancy, or treatment with some drugs (see also Drugs that influence thyroid hormones). In these patients,
consider trialling a withdrawal of levothyroxine (for 4 to 6 weeks) after around a year of treatment to determine
whether long-term treatment is necessary. This could also be considered in a patient who is stable on a low dose of
levothyroxine (eg 25 to 50 micrograms). If the serum TSH and serum T4 concentrations are normal without
levothyroxine, therapy does not need to be restarted. If the serum TSH concentration increases (primary
hypothyroidism) or if the serum T4 concentration falls below the reference range without an elevated TSH (central
hypothyroidism), restart treatment at the previous dose.
Inadequate response to thyroxine replacement therapy for

Inadequate response to levothyroxine refers to persistence of high serum TSH or low serum T4 concentrations,
despite continuous uptitration of levothyroxine (eg higher than 300 micrograms daily).
Check that the patient is adhering to the dosage regimen. If adherence to a daily dose is not feasible, a single
weekly dose of levothyroxine, equal to the total weekly dose, can safely be used for maintenance therapy. If the
appropriate total weekly dose is unclear because the patient has not been taking their dose regularly, start with 11.2
micrograms/kg/week (ie 1.6 micrograms/kg/day) to the nearest 100 micrograms. Check thyroid function before
starting weekly dosing, and again after 4 to 8 weeks of stable dosing.
Also consider factors that impair levothyroxine absorption, such as concomitant drug therapy (see Table 19.3),
incorrect storage of levothyroxine [Note 2] and coeliac disease. The absorption of levothyroxine can also be
impaired by food—advise patients to take levothyroxine consistently in relation to food.
Persistently high serum TSH but normal or elevated serum T4 concentrations can be due to intermittent poor
adherence, but this should also prompt consideration of laboratory error (eg heterophile antibody interference).
Consider contacting the laboratory to confirm the result.
Although less common, inadequate response to treatment can also refer to a patient who reports continued
symptoms despite normalised thyroid function tests. The most commonly reported symptoms are fatigue,
neurocognitive symptoms and weight gain. Consider the presence of coexisting medical disorders (eg autoimmune
or psychological disorders).
If other contributing factors are excluded and the response to treatment is still inadequate, seek specialist advice.
Note 2: Incorrect storage of levothyroxine tablets can reduce the potency of thyroxine. For information about the correct storage of thyroxine, consult
the product information for the individual formulations.
Combination thyroxine and triiodothyronine replacement therapy for

Combination thyroxine (T4) and triiodothyronine (T3) replacement therapy has been suggested as an alternative to
levothyroxine monotherapy. Although improved quality of life and mood have been reported in some studies of
combination therapy, the majority of studies demonstrated no significant benefit over levothyroxine monotherapy.
Available T3 preparations (liothyronine, thyroid extracts prepared from animal tissues, and compounded
preparations) contain a much higher ratio of T3 to T4 than is normally produced by the body. They also have short
half-lives, leading to the potential for fluctuations outside the normal range of serum T3 concentration each day,
particularly if dosed once daily. Thyroid extracts and compounded formulations are not regulated by authorities for
potency or consistency.
Although the available evidence cannot rule out a benefit of combination treatment in a subgroup of patients,
levothyroxine monotherapy remains the treatment of choice. Combination therapy, including the interpretation of
thyroid function tests during treatment, should be managed by a specialist.
Interruption of oral thyroxine replacement therapy for hypothyroidism
in adults
If interruption of oral thyroxine replacement therapy is required (eg for elective surgery) in a patient who is
euthyroid on therapy, thyroxine can be safely withheld for up to 7 days.
Ideally, hypothyroidism should be adequately treated before proceeding with elective surgery. If delaying surgery
is not feasible, ensure the surgeon and anaesthetist are aware that the patient is hypothyroid.
Restart oral therapy as soon as the patient can take oral fluids. If oral therapy is still not possible after 7 days, start
parenteral levothyroxine or liothyronine. Use:
1 levothyroxine by slow intravenous injection, until oral therapy is tolerated [Note 3]
if usual oral dose is known: 75% of usual daily dose (to the nearest 25 micrograms), daily
if usual oral dose is not known: 1.2 micrograms/kg (to the nearest 25 micrograms), daily
OR
2 liothyronine 10 micrograms by slow intravenous injection, two or three times daily, until
oral therapy is tolerated [Note 4].
Note 3: Intravenous levothyroxine is not registered for use in Australia but is available via the Special Access Scheme.
Note 4: Intravenous liothyronine is not registered for use in Australia but is available via the Special Access Scheme.
Hypothyroidism in pregnancy
Overview of hypothyroidism in pregnancy
Untreated or inadequately treated maternal hypothyroidism during pregnancy is associated with an increased risk
of pregnancy complications (eg premature birth, low birth weight, miscarriage), as well as impaired fetal
neurocognitive development. The risk of neurocognitive impairment may be correlated with the degree of thyroid
stimulating hormone (TSH) elevation.
Routine testing of thyroid function in women who are pregnant or planning to become pregnant is only
recommended in women at increased risk of a thyroid disorder. For information about risk factors, as well as
thyroid hormone changes and reference ranges during pregnancy, see Thyroid function testing before conception
and during pregnancy.
The goal of treatment of hypothyroidism in pregnancy is to achieve and maintain maternal serum TSH
concentration within the trimester-specific reference range, using thyroxine replacement therapy. The principles of
thyroxine replacement therapy for pregnant women are the same as for nonpregnant adults, although more frequent
testing and dose adjustment may be required to maintain euthyroidism. Combination thyroxine (T4) and
triiodothyronine (T3) therapy should not be used during pregnancy.
With adequate treatment of maternal hypothyroidism, maternal and fetal outcomes are similar to those of the
healthy population.
Treatment of pre-existing hypothyroidism before conception and during pregnancy
If a woman taking levothyroxine for hypothyroidism is planning to become pregnant, optimise the levothyroxine
dose to achieve a preconception TSH concentration below 2.5 milliunits/L.
During a healthy pregnancy, thyroid hormone production increases by up to 50%. To avoid undertreatment,
particularly in the first trimester, women already taking levothyroxine before pregnancy usually require a 25 to
30% dose increase at 4 to 6 weeks gestation. Consider testing serum TSH concentration approximately every 4 to
6 weeks during the first trimester, and adjusting the levothyroxine dose accordingly. If the serum TSH
concentration is stable, testing again at around 30 weeks gestation is sufficient.
After delivery, reduce the dose of thyroxine to the maintenance dose used before pregnancy and measure the serum
TSH concentration approximately 6 weeks postpartum.
Women with hypothyroidism are at increased risk of Postpartum thyroid dysfunction.

New-onset or previously untreated hypothyroidism in pregnancy
Pregnancy can precipitate hypothyroidism in women with risk factors for thyroid disease, or exacerbate pre-
existing subclinical disease, because the body cannot meet the increased demand for thyroid hormone that occurs
during pregnancy.
New-onset hypothyroidism during pregnancy should be managed with specialist input.
If overt primary hypothyroidism is newly diagnosed in a pregnant woman, start thyroxine replacement
therapy immediately. The harms of untreated overt hypothyroidism in pregnancy are well established.
If subclinical hypothyroidism is newly diagnosed in a pregnant woman, or if the serum TSH concentration is at
the upper end of the normal range, test for thyroid peroxidase antibody. Thyroid peroxidase antibody–positivity
may increase the risk of pregnancy complications, including in women with a TSH concentration within the
normal range.
For subclinical hypothyroidism, start levothyroxine treatment if the serum TSH concentration is:
above the reference range and thyroid peroxidase antibody is positive

above 10 milliunits/L regardless of thyroid peroxidase antibody–positivity.
The evidence to support treatment at lower thresholds is less clear; however, the risk of harm with levothyroxine
therapy is low, so treatment can also be considered if the serum TSH concentration is:
at the upper end of the normal range and thyroid peroxidase antibody is positive
above the reference range but below 10 milliunits/L and thyroid peroxidase antibody is negative.
After delivery, monitor the serum TSH concentration—levothyroxine therapy can usually stopped.
Women with hypothyroidism during pregnancy are at increased risk of Postpartum thyroid dysfunction.
Euthyroid Hashimoto thyroiditis in pregnancy

Hashimoto thyroiditis is diagnosed in people with positive thyroid autoantibodies, usually thyroid peroxidase
antibodies. Hashimoto thyroiditis commonly exists without clinically significant hypothyroidism (euthyroid
Hashimoto thyroiditis), so treatment is often not required. However, these people are at increased risk of
developing subclinical or overt hypothyroidism, most notably during pregnancy when the thyroid is unable to meet
the increased requirement for thyroid hormone. Pregnant women with Hashimoto thyroiditis are also at increased
risk of spontaneous miscarriage and preterm delivery.
If a woman with euthyroid Hashimoto thyroiditis becomes pregnant, monitor her thyroid function to determine
whether she has progressed to hypothyroidism; see New-onset or previously untreated hypothyroidism in
pregnancy.
Women with Hashimoto thyroiditis are also at increased risk of postpartum thyroiditis (see Postpartum thyroid
dysfunction). Counsel women about the symptoms of postpartum thyroiditis and advise them to seek medical
advice if symptoms occur.
Iodine supplementation during pregnancy and lactation

Mild iodine deficiency in pregnant women is associated with maternal goitre, and possibly impaired
neurocognitive development in the child. The iodine requirement increases during pregnancy and lactation, so a
daily supplement containing 150 micrograms of iodine is recommended for all pregnant and breastfeeding women.
Hypothyroidism in children
Hypothyroidism in children is usually caused by autoimmune thyroiditis; it can also be late-diagnosed congenital
hypothyroidism. The symptoms and signs can be subtle and easily missed. Typical features include lethargy,
constipation, cold intolerance, mood changes, slowing of growth, reduced school performance and myxoedema
(puffy facial features). Pseudopuberty is an unusual presentation that is more common in girls than boys.
If an elevated serum thyroid stimulating hormone (TSH) concentration is found, repeat the test after 4 to 8 weeks
and consider testing for thyroid peroxidase antibody and thyroglobulin antibody. Refer the child to a specialist if
the TSH is persistently significantly elevated (eg higher than 10 milliunits/L), or if the child is symptomatic.
Referral could also be considered for a child with persistent but mild TSH elevation if thyroid peroxidase antibody
or thyroglobulin antibody is positive, as this increases the risk of progression.
The decision to start treatment should be made under specialist guidance. Thyroxine replacement in children is
usually started at a low dose and titrated up slowly (unlike in adults, in whom initial full-replacement can often be
used). A reasonable starting dose is:
levothyroxine 25 micrograms orally, daily. Adjust the dose every 4 to 8 weeks as required.
For a child with primary hypothyroidism, titrate the dose according to serum TSH and free thyroxine (T4)
response. The aim of treatment is to keep:
serum TSH concentration in the lower half of the normal range

serum T4 concentration in the upper half of the normal range.
For a child with hypothyroidism secondary to hypopituitarism, titrate the dose according to clinical response and
serum T4 concentration (not serum TSH concentration), targeting a serum T4 concentration in the upper half of the
normal range. A low serum TSH concentration is to be expected in hypopituitarism and is not a basis to reduce the
dose.
Subtle dose adjustments can be achieved by prescribing different strength tablets on different days of the week.
Temporary neonatal hypothyroidism is uncommon; it can be caused by transplacental passage of maternal

antibodies. The neonate may require early thyroxine replacement—seek advice from a paediatric endocrinologist.
Congenital hypothyroidism
Congenital hypothyroidism occurs in 1 in 2500 to 3500 neonates, and is usually identified through neonatal
screening programs. Most cases are caused by thyroid dysgenesis, including athyreosis (an absence of the thyroid
gland) and thyroid ectopia (thyroid tissue is outside the usual location). The next most common cause is thyroid
dyshormonogenesis (dysfunctional synthesis of thyroid hormone). A technetium thyroid scan, performed as an
urgent procedure before starting thyroxine replacement, helps to differentiate between the causes. Thyroid
ultrasound can also be useful.
Congenital hypothyroidism should be managed in consultation with a paediatric endocrinologist. Start replacement
therapy as soon as the diagnosis is made (within 24 to 48 hours), and ideally before 2 weeks of age, to prevent
intellectual disability.
The levothyroxine dose required in infants is relatively higher than in adults. A reasonable starting dose is:
levothyroxine 10 to 15 micrograms/kg orally, daily [Note 5].
The dose should be titrated according to serum thyroid stimulating hormone (TSH) and free thyroxine (T4)
response. The aim of treatment is to keep:
serum TSH concentration in the lower half of the normal range

serum T4 concentration in the upper half of the normal range.
Assess thyroid function weekly for the first month. If the serum TSH concentration is normalised, the frequency of
assessment can be gradually reduced. Assess intellectual and physical development, along with thyroid function
tests, every 2 to 3 months for the first 5 years of life, then every 3 to 6 months until the patient is fully grown. The
dose can usually be reduced progressively with age towards the dose used for acquired hypothyroidism (see
Thyroxine replacement in adults). Treatment is usually required lifelong but some cases can be transient.
Note 5: Crushed tablets are usually used for dosing in infants. For administration advice, see the Don’t Rush to Crush Handbook, published by the
Society of Hospital Pharmacists of Australia [URL].
Drug-induced hypothyroidism
Hypothyroidism induced by some drugs (eg lithium, amiodarone, interferon alfa) can be reversible if the drug is
stopped. For some other drugs (eg immune checkpoint inhibitors), hypothyroidism is less likely to be reversible.
See also Drugs that influence thyroid hormones.
The decision to continue or stop the causative drug depends on the harms of ongoing hypothyroidism versus the
benefit of the drug, the availability of alternative treatments, and the likelihood of reversing the hypothyroidism if
the drug is stopped.
If the drug is continued or the hypothyroidism is not reversible, long-term concurrent levothyroxine treatment may
be required. Treat drug-induced hypothyroidism with thyroxine replacement therapy.
If levothyroxine therapy is started, but the causative drug is subsequently stopped, assess the need for continued
levothyroxine by stopping therapy and measuring serum thyroid stimulating hormone (TSH) concentration 4 to 8
weeks later. Restart levothyroxine if the serum TSH concentration increases.
Central hypothyroidism
Central hypothyroidism refers to hypothyroidism caused by either a pituitary disorder (secondary hypothyroidism)
or a hypothalamic disorder (tertiary hypothyroidism).
If a patient has a low serum free thyroxine (T4) concentration and clinical features of hypothyroidism, but no
elevation in serum thyroid stimulating hormone (TSH) concentration (ie low or ‘inappropriately normal’ TSH),
assess the patient for hypopituitarism. See Chronic hypopituitarism and Thyroid hormone replacement in
hypopituitarism for more information.
A low serum T4 concentration with a low or normal serum TSH concentration can also indicate a hypothalamic
disorder.
Myxoedema coma
Myxoedema coma is a medical emergency caused by severe untreated hypothyroidism. It typically presents with
impaired consciousness, hypoventilation and hypothermia. Arrange immediate transport to hospital by ambulance,
with airway support, for care in a high-dependency ward. In addition to thyroid hormone replacement, manage
fluid and electrolyte balance, temperature, and glucocorticoid deficiency (see Adrenal crisis for glucocorticoid
doses).
Myxoedema coma is a rare condition with limited evidence to guide management. Intravenous therapy is favoured
over oral levothyroxine therapy because it has a more rapid onset, and because absorption of oral therapy may be
limited by intestinal pseudo-obstruction.
A typical regimen is:
levothyroxine 300 micrograms by slow intravenous injection over 30 minutes as a loading

dose, then 1.2 micrograms/kg (to the nearest 25 micrograms) intravenously, daily [Note 6].
If intravenous therapy is not available and oral administration is possible, use:
levothyroxine 500 micrograms orally, as a loading dose, then 1.6 micrograms/kg (to the
nearest 25 micrograms) orally, daily.
Conversion of thyroxine (T4) to triiodothyronine (T3) can be impaired in patients with myxoedema coma. If the
patient’s condition has not improved after 24 hours of levothyroxine therapy, consider adding liothyronine. Use:
liothyronine 20 micrograms by slow intravenous injection over 30 minutes, twice daily

[Note 7].
Once the patient is conscious, and if there is no evidence of intestinal pseudo-obstruction, start oral therapy and
continue intravenous therapy for the first 3 to 5 days of oral therapy. Use:
levothyroxine 1.6 micrograms/kg (to the nearest 25 micrograms) orally, daily.
Measure serum T4, T3 and thyroid stimulating hormone (TSH) concentrations after 3 to 5 days. Subsequent
management for the untreated hypothyroidism is usually required. See Thyroxine replacement therapy in adults or
Hypothyroidism in children for more information.
Note 6: Intravenous levothyroxine is not registered for use in Australia but is available via the Special Access Scheme.
Note 7: Intravenous liothyronine is not registered for use in Australia but is available via the Special Access Scheme.
Key references
Introduction to hypothyroidism
Biondi B, Cooper DS. Subclinical hyperthyroidism. N Engl J Med 2018;378(25):2411–9.

Endocrine Society. Choosing Wisely. 5 things clinicians and consumers should question. Philadelphia: ABIM
(American Board of Internal Medicine) Foundation; 2013 [updated 2018].
http://www.choosingwisely.org/societies/endocrine-society
Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al. Guidelines for the treatment of
hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid
2014;24(12):1670–751.
Overview of primary hypothyroidism
Biondi B, Cooper DS. Subclinical hyperthyroidism. N Engl J Med 2018;378(25):2411–9.
Peeters RP. Subclinical hypothyroidism. N Engl J Med 2017;376(26):2556–65.
When to start treatment for primary hypothyroidism in adults
Biondi B, Klein I. Hypothyroidism as a risk factor for cardiovascular disease. Endocrine 2004;24(1):1–13.
2014;24(12):1670–751.
Thyroxine replacement therapy for hypothyroidism in adults
Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ, Jr. Effects of thyroxine as compared with thyroxine plus
triiodothyronine in patients with hypothyroidism. N Engl J Med 1999;340(6):424–9.
Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, et al. Hormonal replacement in
hypopituitarism in adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2016;101(11):3888–
921.
2014;24(12):1670–751.
Nygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J. Effect of combination therapy with thyroxine (T4) and 3,5,3'-
triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study.
Eur J Endocrinol 2009;161(6):895–902.
Roos A, Linn-Rasker SP, van Domburg RT, Tijssen JP, Berghout A. The starting dose of levothyroxine in primary
hypothyroidism treatment: a prospective, randomized, double-blind trial. Arch Intern Med 2005;165(15):1714–20.
Hypothyroidism in pregnancy
Australian Bureau of Statistics (ABS). Australian Health Survery: Biomedical results for nutrients. Canberra: ABS;
2013 [updated 2014]. http://www.abs.gov.au/ausstats/abs@.nsf/Lookup/4364.0.55.006Chapter1202011-12
Casey BM, Thom EA, Peaceman AM, Varner MW, Sorokin Y, Hirtz DG, et al. Treatment of subclinical hypothyroidism
or hypothyroxinemia in pregnancy. N Engl J Med 2017;376(9):815–25.
Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during
pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341(8):549–55.
Klein RZ, Sargent JD, Larsen PR, Waisbren SE, Haddow JE, Mitchell ML. Relation of severity of maternal
hypothyroidism to cognitive development of offspring. J Med Screen 2001;8(1):18–20.
Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, et al. Antenatal thyroid screening and childhood
cognitive function. N Engl J Med 2012;366(6):493–501.
Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European Thyroid Association
guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 2014;3(2):76–
94.
Mitchell ML, Klein RZ. The sequelae of untreated maternal hypothyroidism. Eur J Endocrinol 2004;151 Suppl 3:U45–8.
Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant
women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab
2006;91(7):2587–91.
Nelson SM, Haig C, McConnachie A, Sattar N, Ring SM, Smith GD, et al. Maternal thyroid function and child
educational attainment: prospective cohort study. BMJ 2018;360:k452.
Thompson W, Russell G, Baragwanath G, Matthews J, Vaidya B, Thompson-Coon J. Maternal thyroid hormone

insufficiency during pregnancy and risk of neurodevelopmental disorders in offspring: a systematic review and meta-
analysis. Clin Endocrinol (Oxf) 2018;88(4):575–84.
van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn M, et al. Significance of
(sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic
review. Hum Reprod Update 2011;17(5):605–19.
Hypothyroidism in children
Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, et al. Antenatal thyroid screening and childhood
cognitive function. N Engl J Med 2012;366(6):493–501.
Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European Thyroid Association
guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 2014;3(2):76–
94.
Congenital hypothyroidism
Albert BB, Cutfield WS, Webster D, Carll J, Derraik JG, Jefferies C, et al. Etiology of increasing incidence of congenital
hypothyroidism in New Zealand from 1993-2010. J Clin Endocrinol Metab 2012;97(9):3155–60.
Connelly JF, Coakley JC, Gold H, Francis I, Mathur KS, Rickards AL, et al. Newborn screening for congenital
hypothyroidism, Victoria, Australia, 1977-1997. Part 1: The screening programme, demography, baseline perinatal data
and diagnostic classification. J Pediatr Endocrinol Metab 2001;14(9):1597–610.
Leger J, Olivieri A, Donaldson M, Torresani T, Krude H, van Vliet G, et al. European Society for Paediatric
Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. Horm
Res Paediatr 2014;81(2):80–103.
Myxoedema coma
2014;24(12):1670–751.
Thyrotoxicosis and hyperthyroidism
Overview of thyrotoxicosis and hyperthyroidism
Thyrotoxicosis refers to the clinical condition that results from excess thyroid hormones (thyroxine [T4] and
triiodothyronine [T3]) in body tissue, regardless of the cause. Most cases of thyrotoxicosis are due to hyperthyroid
disorders (disorders in which the thyroid produces excess thyroid hormones). The most common causes of
hyperthyroidism are Graves disease, multinodular goitre and an autonomously functioning thyroid nodule (toxic
adenoma). Hyperthyroidism secondary to a pituitary disorder (eg a thyroid stimulating hormone [TSH]-secreting
pituitary adenoma) is rare. Causes of thyrotoxicosis not associated with hyperthyroidism include excess exogenous
thyroid hormone intake, thyroiditis with leakage of preformed thyroid hormone, and amiodarone.
Common symptoms of thyrotoxicosis include weight loss, heat intolerance, tremor, muscle weakness and
palpitations. Thyroid hormones affect almost every tissue and organ system in the body, so atypical presentations
are common (particularly in older people).
Long-term untreated thyrotoxicosis is associated with cardiovascular disease (particularly atrial fibrillation) and
accelerated bone mass loss.
Table 19.4 gives an overview of the clinical and biochemical presentations, and usual treatment, for different
causes of thyrotoxicosis.
Overview of thyrotoxicosis (Table 19.4)
Graves disease
toxic multinodular goitre
toxic adenoma
painless postpartum thyroiditis
painful subacute thyroiditis
painless sporadic thyroiditis
amiodarone-induced thyrotoxicosis
exogenous thyroid hormone

Graves disease
five to ten times more common in females than males
onset usually between age 20 and 60 years
clinical presentation and course of disease diffuse, usually symmetrical goitre
Graves ophthalmopathy (see Graves-related eye disease)
often associated with other autoimmune diseases

laboratory results—TSH-receptor antibody elevated in
95% of cases (thyroid peroxidase antibody also often
positive, but is not a required investigation)
expected investigation findings
radionuclide thyroid scan—normal or elevated diffuse
uptake pattern [NB1]
TSH-receptor antibody increases thyroid hormone
pathophysiology
production and causes thyroid hyperplasia
see Overview of management of primary
hyperthyroidism for details
initial treatment with an antithyroid drug
treatment subsequent treatment determined by severity, patient

factors and patient preference (see Subsequent
management of primary hyperthyroidism)
beta blocker for hyperthyroid symptoms

toxic multinodular goitre
more common in females than males
clinical presentation and course of disease onset usually occurs above age 50 years
nodular goitre often present for years

laboratory results—TSH-receptor antibody absent;
thyroid peroxidase antibody absent or incidentally
positive in low titre
radionuclide thyroid scan—normal or elevated multifocal
pattern [NB1]
nodule autonomy
pathophysiology
hyperthyroidism can be precipitated by iodine exposure
(eg radiological contrast medium)
usually treated initially with an antithyroid drug
subsequent treatment determined by severity, patient

treatment
management of primary hyperthyroidism)—remission is
rare without definitive treatment (ie radioiodine or
thyroidectomy)

toxic adenoma

clinical presentation and course of disease
slowly growing solitary thyroid nodule, usually larger
than 3 cm
thyroid peroxidase antibody absent or incidentally
positive in low titre
radionuclide thyroid scan—focal uptake with suppression
of uptake into surrounding thyroid tissue [NB1]
mutation of TSH-receptor gene or of signal transduction
pathophysiology
gene (G protein gene)
usually treated initially with an antithyroid drug
subsequent treatment determined by severity, patient

treatment
management of primary hyperthyroidism)—remission is
rare without definitive treatment (ie radioiodine or
thyroidectomy)

painless postpartum thyroiditis
typically 1 to 6 months after delivery
diffuse, small goitre
clinical presentation and course of disease thyrotoxicosis for 1 to 2 months often followed by
hypothyroidism for 4 to 6 months; hypothyroidism can be
permanent (in around 20% of cases)
more common in women with type 1 diabetes
laboratory results—TSH-receptor antibody occasionally
shows transient minor elevation; thyroid peroxidase
expected investigation findings antibody high titre in most; normal erythrocyte
sedimentation rate
radionuclide thyroid scan—near absent uptake

autoimmune—destruction of thyroid follicles with release
pathophysiology
of stored thyroid hormone
treatment levothyroxine if the hypothyroid phase is prolonged or

symptomatic, or if breastfeeding or attempting to
conceive during the hypothyroid phase
painful subacute thyroiditis
five times more common in females than males
often follows an upper respiratory tract infection

clinical presentation and course of disease
tender goitre
hyperthyroidism for 1 to 2 months often followed by

permanent (in fewer than 10% of cases)
antibody low titre or absent; erythrocyte sedimentation
expected investigation findings rate almost always greater than 50 mm/hr; normal or
increased white blood cell count

probably a postviral syndrome; destruction of thyroid
pathophysiology
follicles with release of stored thyroid hormone
nonsteroidal anti-inflammatory drugs for thyroid pain;

treatment glucocorticoids may be required for more severe pain
levothyroxine if the hypothyroid phase is prolonged or

symptomatic
painless sporadic thyroiditis
cases peak between age 20 and 50 years
diffuse, small goitre

clinical presentation and course of disease thyrotoxicosis for 1 to 2 months often followed by
permanent (in around 20% of cases)
can present postpartum and should be differentiated from

postpartum Graves disease
antibody high titre in most; normal erythrocyte
sedimentation rate

autoimmune: destruction of thyroid follicles with release
pathophysiology
of stored thyroid hormone
treatment
levothyroxine if the hypothyroid phase is prolonged or
symptomatic
amiodarone-induced thyrotoxicosis
can present up to 12 to 18 months after ceasing
amiodarone
two clinical types exist:
clinical presentation and course of disease type 1—underlying thyroid disease present; more
common in iodine-deficient populations; diffuse or
nodular goitre
type 2—no underlying thyroid disease; normal
gland or small goitre
radionuclide thyroid scan—usually low uptake and not

discriminatory; uptake occasionally seen in type 1 disease
ultrasound—colour-flow Doppler vascularity normal or
increased in type 1 disease and diminished or absent in
type 2 disease
type 1—excess iodine
pathophysiology
type 2—destructive thyroiditis
type 1—antithyroid drugs
type 2—glucocorticoids
treatment can be difficult to distinguish between type 1 and type 2
disease, so empirical dual therapy sometimes required
thyroidectomy may be required

exogenous thyroid hormone
clinical presentation and course of disease usually no goitre (incidental if present)
thyroid peroxidase antibody low titre or absent; low
expected investigation findings thyroglobulin levels

pathophysiology excess ingestion of thyroid hormone
treatment stop or reduce thyroid hormone intake as appropriate
NB1: Uptake may be low in iodine-induced hyperthyroidism.
Differential diagnosis of thyrotoxicosis

Given the diversity of clinical presentations and aetiologies of thyrotoxicosis (see Table 19.4), diagnosis requires
confirmation with thyroid function tests. For information about initial testing of thyroid function and interpreting
test results, see Initial testing for thyroid disorders and Table 19.1 for interpreting results.
Thyrotoxicosis is usually indicated by a low or suppressed serum thyroid stimulating hormone (TSH)
concentration (with the uncommon exception of hyperthyroidism secondary to a pituitary disorder, in which the
TSH concentration is elevated or ‘inappropriately normal’). Overt disease is defined by a high serum free
thyroxine (T4) concentration, while subclinical disease presents with a serum T4 concentration in the normal range.
For a patient with subclinical or minimally overt thyrotoxicosis without symptoms, retest the serum TSH and T4
concentrations after 6 to 8 weeks to confirm that the disorder is persistent—transient disease can occur (eg
subacute thyroiditis). For a symptomatic patient with overt thyrotoxicosis, start beta-blocker therapy straight away
to relieve symptoms. For both groups of patients, further tests are required to differentiate the cause:
Test for TSH-receptor antibody—a significantly elevated TSH-receptor antibody concentration is diagnostic
of Graves disease.
If TSH-receptor antibody is absent, a radionuclide thyroid scan is useful to differentiate between other
causes of thyrotoxicosis (eg toxic multinodular goitre, toxic adenoma, subacute thyroiditis). See Table
19.4 for the expected results of a radionuclide scan in different types of thyrotoxicosis.
Ultrasound is only useful in patients taking amiodarone, or who have known or palpable thyroid nodules; it is not
useful or recommended in other patients.
If the aetiology remains unclear, seek specialist advice. If laboratory error is suspected, repeat the thyroid function
tests.
For management of hyperthyroidism (ie Graves disease, toxic multinodular goitre, toxic adenoma), see Overview
of management of primary hyperthyroidism. For management of other causes of thyrotoxicosis, see Subacute
thyroiditis, Amiodarone-induced thyrotoxicosis or Postpartum thyroiditis.
Overview of management of primary hyperthyroidism

Primary hyperthyroidism (ie Graves disease, toxic multinodular goitre, toxic adenoma) is usually managed initially
with an antithyroid drug with the aim of achieving euthyroidism; see Antithyroid drug therapy for primary
hyperthyroidism for more information. Some patients can achieve remission with an antithyroid drug alone (eg
patients with mild Graves disease), while other patients use an antithyroid drug in preparation for definitive
treatment (ie radioiodine or thyroidectomy). For more information about treatment following initial antithyroid
therapy, see Subsequent management of primary hyperthyroidism.
Antithyroid drugs gradually relieve the symptoms of thyrotoxicosis as the patient becomes euthyroid. In the
interim, beta-blocker therapy can be used for symptomatic patients to rapidly improve symptoms. See Beta
blockers for symptoms of thyrotoxicosis for more information.
Acute, severe symptoms (eg fever, tachycardia, vomiting, dehydration, delirium or coma, organ system
dysfunction) indicate thyroid storm; this is a medical emergency requiring immediate hospitalisation and
treatment.
For management of other causes of thyrotoxicosis, see subacute thyroiditis, amiodarone-induced thyrotoxicosis or
postpartum thyroiditis. See also Table 19.4 for a summary of causes of thyrotoxicosis, and their presentation and
management.
For information about the management of hyperthyroidism in pregnancy, see here.
Antithyroid drug therapy for primary hyperthyroidism

Initial dosage regimens
Antithyroid drug therapy is used to correct hyperthyroidism and relieve symptoms of thyrotoxicosis.
Carbimazole is the first-line drug for initial treatment of hyperthyroidism. Propylthiouracil has been associated
with severe liver injury; it is only indicated if carbimazole is not tolerated, for maintenance therapy before
conception and in the first trimester of pregnancy, and for thyroid storm.
Start antithyroid therapy with an initial dose that is likely to control the hyperthyroidism. The initial dose is based
on symptom severity, size of the gland, degree of biochemical thyrotoxicosis, and medical urgency.
In an adult with significant symptoms (eg atrial fibrillation, heart failure, marked weight loss, proximal myopathy),
or biochemically severe hyperthyroidism (eg serum free triiodothyronine [T3] or free thyroxine [T4] concentrations
more than 2.5 times the upper limit of normal), use:
1 carbimazole 30 to 45 mg orally, daily in 2 or 3 divided doses. Adjust the dose at 4- to 6-

weekly intervals as required (see Dose titration)
OR
2 propylthiouracil 300 to 450 mg orally, daily in 2 or 3 divided doses. Adjust the dose at 4-
to 6-weekly intervals as required (see Dose titration).
In an adult with mild symptoms, or biochemically mild to moderate hyperthyroidism without symptoms, use:
1 carbimazole 10 to 20 mg orally, daily in 2 or 3 divided doses. Adjust the dose at 4- to 6-

weekly intervals as required (see Dose titration)
OR
2 propylthiouracil 100 to 200 mg orally, daily in 2 or 3 divided doses. Adjust the dose at 4-
to 6-weekly intervals as required (see Dose titration).
Thyrotoxicosis in a child should be managed by a specialist—antithyroid starting doses vary widely and dose
titration can be difficult. Propylthiouracil is contraindicated in children as it can cause severe liver injury. A typical
regimen is:
carbimazole 0.2 to 0.3 mg/kg orally, 3 times daily, titrated down as control is achieved to a
maintenance dose of 2.5 to 5 mg up to 3 times daily.
Dose titration
To avoid overtreatment, consider titrating the dose down after 4 to 6 weeks (or earlier if treatment was started at a
particularly high dose) according to clinical and biochemical response. Serum TSH concentration can remain
suppressed for several months after correction of hyperthyroidism, so base initial dose adjustment on serum T3 and
T4 concentrations. If the thyroid hormone concentrations drop by half, the dose can be halved.
Continue to assess clinical and biochemical response every 4 to 6 weeks, adjusting the dose of the antithyroid drug
to achieve thyroid hormone concentrations in the normal range. Hyperthyroidism can persist despite normalisation
of serum T4 concentration due to persistent elevation of T3. Consider increasing the dose of the antithyroid drug in
these patients, particularly if they are still symptomatic.
Once the patient is euthyroid, carbimazole can be given once daily as maintenance therapy. Propylthiouracil has a
shorter plasma half-life and tissue action, so should continue in divided doses.
Do not stop the antithyroid drug abruptly when thyroid hormone concentrations have normalised; see Subsequent
management of primary hyperthyroidism for management after starting antithyroid drug therapy.
Antithyroid drug therapy is usually effective; inadequate response may indicate nonadherence. Patients exposed to
marked iodine excess (eg contrast media, topical iodine preparations, amiodarone, complementary medicines
[particularly those containing kelp]) may be resistant to antithyroid drugs and often require a higher dose.
Adverse effects of antithyroid drugs
Antithyroid drugs can rarely cause agranulocytosis; it is most likely to occur in the first months of therapy. Advise
patients to immediately stop the drug and to seek medical assessment if they experience acute malaise, fever or
infection (typically severe pharyngitis).
Do not use carbimazole or propylthiouracil in a patient with a history of agranulocytosis caused by either drug.
Consider other options to treat hyperthyroidism (eg thyroidectomy, radioiodine).
Propylthiouracil has been associated with rare cases of severe liver injury causing death or requiring liver
transplantation. It is contraindicated in children. Advise adults taking propylthiouracil to immediately stop the drug
and to seek medical assessment if they experience malaise, anorexia, nausea, abdominal pain, discoloured urine or
jaundice.
Vasculitis with positive antineutrophil cytoplasmic antibodies (ANCA) is a rare complication of propylthiouracil
treatment. Seek specialist advice if this occurs.
Subsequent management of primary hyperthyroidism

Once the patient is euthryoid on antithyroid therapy, the options for subsequent management depend on the cause
and severity of the disease, and patient preference. See Table 19.5 for management options—specialist guidance is
recommended for the selection of subsequent treatment.
Refer the patient to a specialist for selection of subsequent management.
For long-term follow-up of hyperthyroidism, see here.
Options for subsequent management of primary hyperthyroidism (Table 19.5) [NB1]
a course of antithyroid drug therapy, followed by drug withdrawal
long-term antithyroid drug therapy
radioiodine
thyroidectomy
a course of antithyroid drug therapy, followed by drug withdrawal
usual patient groups who use this
young patient with first episode of mild Graves disease and a small goitre
option
previous severe adverse reaction to antithyroid drug therapy
contraindications and precautions liver disease
titrate the maintenance dose to achieve euthyroidism (see Dose titration)
in adults, continue antithyroid therapy for 12 to 18 months—this improves the

chance of sustained remission compared with a shorter course
treatment information in children, antithyroid therapy is usually continued for at least 2 years
the chance of sustained remission is also improved if the patient’s TSH-

receptor antibody concentration is normalised before stopping treatment. If the
TSH-receptor antibody remains elevated, the antithyroid drug can be continued
until the antibody concentration returns to the normal range
long-term antithyroid drug therapy
usual patient groups who use this persistent or recurrent Graves disease that is easily controlled with low-dose
option antithyroid therapy
previous severe adverse reaction to antithyroid drug therapy
contraindications and precautions
liver disease
titrate the maintenance dose to achieve continued euthyroidism (see Dose
titration)
treatment information
ongoing dose titration and monitoring requires specialist guidance
radioiodine
severe Graves disease with large goitre (eg causing tracheal obstruction or
narrowing)
recurrent severe Graves disease
severe hyperthyroidism in an older patient

option subclinical or mild hyperthyroidism in an older patient (usually associated with
nodular thyroid disease) [NB2]
hyperthyroidism due to a toxic adenoma or multinodular goitre
young patient with mild Graves disease whose TSH-receptor antibody remains
elevated despite antithyroid drug therapy
active Graves-related eye disease
contraindications and precautions
current or imminently planned pregnancy
high-dose radioiodine can achieve shrinkage and relief of obstructive
symptoms
antithyroid drug therapy usually used to achieve euthyroidism before

radioiodine [NB2]
treatment information the antithyroid drug should be stopped for 3 to 7 days before radioiodine
treatment—it can be restarted approximately 1 week after the dose, and then
gradually decreased over 2 to 4 months as the radioiodine becomes effective
radioiodine likely to be followed eventually by hypothyroidism, usually

requiring thyroxine replacement therapy
thyroidectomy
severe Graves disease with large goitre (eg causing tracheal obstruction or
narrowing)
recurrent severe Graves disease

hyperthyroidism due to a toxic adenoma or multinodular goitre [NB3]
option
young patient with mild Graves disease whose TSH-receptor antibody remains
elevated despite antithyroid drug therapy
thyroid cancer
high surgical risk
contraindications and precautions previously operated or externally irradiated neck
lack of access to high-volume surgeon
antithyroid drug therapy is used to achieve euthyroidism before surgery

treatment information thyroidectomy followed by permanent hypothyroidism, usually requiring
thyroxine replacement therapy
NB1: This table outlines the typical treatments used for different patient groups; however, the choice should be individualised with specialist advice, and
consideration of patient preference.
NB2: Preparation with an antithyroid drug is not required in older patients with mild or subclinical hyperthyroidism. Hyperthyroidism in these patients is
usually due to toxic adenoma or multinodular goitre, and early treatment with radioiodine is safe and effective and has a lower risk of subsequent
hypothyroidism than in patients with Graves disease.
NB3: For toxic adenoma or unilateral multinodular goitre, lobectomy is preferred over thyroidectomy.
Long-term follow-up of primary hyperthyroidism

In a patient who achieved remission of Graves disease with antithyroid drug therapy, long-term euthyroidism
cannot be guaranteed. Relapse can occur despite completing the recommended 12- to 18-month course of therapy,
including in patients whose thyroid stimulating hormone (TSH)-receptor antibody concentration normalised before
treatment was stopped. Hypothyroidism can also occur following remission, including many decades later.
Following remission of hyperthyroidism, clinical and biochemical follow-up is recommended every 3 to 4 months
for the first year, then annually for 5 years. Counsel the patient to seek prompt assessment if any symptoms of
recurrent hyperthyroidism, or of hypothyroidism, develop.
Thyroidectomy is followed by permanent hypothyroidism, and radioiodine is likely to be followed eventually by

hypothyroidism. Subsequent lifelong thyroxine replacement is usually required. See Thyroxine replacement in
adults for management.
If long-term maintenance therapy with an antithyroid drug is used, review thyroid function every 3 months
initially. Once the patient is stable and euthyroid, the review interval can be extended to 6-monthly.
Women with prior or current Graves disease who become pregnant require specific monitoring during pregnancy.
Their infants have a low risk of developing neonatal hyperthyroidism. Thyroidectomy or radioiodine before
pregnancy does not eliminate this risk. See Neonatal hyperthyroidism.
Beta blockers for symptoms of thyrotoxicosis

Antithyroid drugs eventually relieve the symptoms of thyrotoxicosis as the patient becomes euthyroid. In the
interim, a beta blocker can be used to rapidly improve some symptoms of thyrotoxicosis (eg palpitations, tremor,
sweating). Beta blockers do not reduce the high metabolic state of thyrotoxicosis, so do not replace the need for an
antithyroid drug.
For a patient with symptoms of thyrotoxicosis who is already taking a beta blocker for concurrent heart failure,
only consider increasing the dose of the beta blocker if it is safe to do so, and do not add a second beta blocker. For
patients taking a beta blocker for another indication, the dose can usually be increased safely. See Beta blockers for
heart failure for more information.
Historically, propranolol has been used for thyrotoxicosis; however, most beta blockers provide adequate symptom
relief. The most useful guide for dose titration is heart rate. A suitable regimen for an adult is:
1 atenolol 25 mg orally, once daily, increasing as required according to heart rate up to 50

mg daily
OR
1 propranolol 10 mg orally, twice daily, increasing as required according to heart rate up to

40 mg twice daily.
A severely symptomatic patient may require more frequent or higher doses.
If beta-blocker therapy is contraindicated in an adult, use:
diltiazem 60 mg orally, 4 times daily.
For a child, a suitable beta-blocker regimen is:
propranolol 0.5 to 1 mg/kg orally, daily in 3 or 4 divided doses.

Beta-blocker or diltiazem therapy is only necessary until the patient becomes euthyroid.
Other treatments for thyrotoxicosis

Other treatments for thyrotoxicosis are occasionally used by specialists in specific circumstances.
Stable iodide acutely inhibits hormone release from the thyroid in Graves disease. It can be given as potassium
iodide in tablet form, a saturated solution of potassium iodide, or Lugol solution. Stable iodide is most commonly
used for 7 days preoperatively to reduce thyroid vascularity. It can also be used in thyroid storm. A suitable dose of
Lugol solution preoperatively is:
iodine 5% + potassium iodide 10% in water (Lugol solution) 0.3 to 0.9 mL orally, daily in
2 or 3 divided doses, for the 7 days before an operation [Note 1].
The beneficial effects of stable iodide can be transient in some patients—longer-term use should be limited to
patients managed by experienced specialists. Stable iodide is contraindicated in patients with nodular thyroid
disease because it can worsen hyperthyroidism. Iodine therapy precludes use of radioiodine for several months
because iodine uptake into the thyroid is blocked.
Iodine contamination precludes radioiodine therapy for several months.
Cholestyramine increases elimination of thyroxine (T4) by impairing its reabsorption after biliary excretion, and
can lower serum T4 concentration by about 30%.
Glucocorticoids, which acutely inhibit thyroid hormone release and conversion of T4 to triiodothyronine (T3), can
also be used in severe uncontrolled Graves disease and thyroid storm.
Lithium impairs thyroid hormone release. It can be useful as additional treatment to antithyroid drugs in refractory
hyperthyroidism; it can also be combined with radioiodine. Lithium causes goitre in 30 to 50% of treated patients.
Block–replace treatment involves maintenance at a moderate or high antithyroid drug dosage, with thyroid
hormone replacement to prevent drug-induced hypothyroidism. It does not increase the chance of remission in
Graves disease, and is associated with higher risk of adverse effects. Block–replace treatment is reserved for rare
patient groups (eg an older patient with a large goitre who is not fit for surgery, a patient who changes easily from
hyperthyroidism to hypothyroidism), and should only be used under specialist supervision. It is contraindicated in
pregnancy.
Note 1: Lugol solution may need to be prepared extemporaneously; for formulation of Lugol solution, see the Australian Pharmaceutical Formulary
and Handbook (APF), 24th edition, 2018. [URL]
Other considerations in thyrotoxicosis and hyperthyroidism

Thyrotoxicosis can increase drug clearance, leading to increased dose requirements of many drugs. If a patient is
taking other drugs, review the doses after starting treatment to control thyrotoxicosis; doses may need to be
reduced as the patient becomes euthyroid. Paradoxically, sensitivity to warfarin can be increased in thyrotoxicosis,
as catabolism of vitamin K–dependent clotting factors is accelerated—a lower than normal dose of warfarin may
be required. At the time of writing, the effect of hyperthyroidism on non–vitamin K antagonist oral anticoagulants
(NOACs) has not been studied, but based on pharmacodynamics, a similar increase in sensitivity could be
expected.
Thyrotoxicosis can cause atrial fibrillation. Do not use amiodarone to manage atrial fibrillation caused by
thyrotoxicosis because it contains iodine, which impairs the response to antithyroid drugs, and also precludes use
of radioiodine for several months because iodine uptake into the thyroid is blocked. See also Amiodarone-induced
thyrotoxicosis.
Iodine exposure (particularly from radiological contrast media) can exacerbate hyperthyroidism, especially in
nodular thyroid disease. Iodine-induced hyperthyroidism can be self-limiting, so don’t start treatment with an
antithyroid drug unless thyrotoxicosis is persistent.
Hyperthyroidism in pregnancy
Overview
Poorly controlled maternal hyperthyroidism increases the risk of pregnancy complications (eg miscarriage,
premature birth, low birth weight). The goal of management of hyperthyroidism in pregnancy is to maintain
maternal euthyroidism, with the maternal serum free thyroxine (T4) concentration in the upper half of the
trimester-specific reference range.
Serum thyroid stimulating hormone (TSH) suppression commonly occurs as a normal part of early pregnancy, and
is usually not a cause for concern; see Thyroid function testing before conception and during pregnancy for
trimester-specific reference ranges for serum TSH concentration.
Thyrotoxicosis and hyperthyroidism in pregnancy should be managed with specialist input.
Infants of mothers with prior or current Graves disease have a low risk of developing neonatal hyperthyroidism.
Thyroid ablation (thyroidectomy or radioiodine) before pregnancy does not eliminate this risk. Specific monitoring
is required throughout pregnancy in these women; see Neonatal hyperthyroidism.
Considerations before conception

If a woman with hyperthyroidism is planning to become pregnant, ensure a stable euthyroid state is achieved
before conception.
Antithyroid drugs increase the risk of congenital abnormalities. Many patients with Graves disease, particularly
young patients with a first episode of mild hyperthyroidism, can achieve remission after a period of treatment with
an antithyroid drug. Although remission is often temporary, relapse within the first few months of stopping
antithyroid drug therapy is uncommon in patients whose TSH-receptor antibody normalised during treatment.
Well-timed remission could avoid the need for an antithyroid drug in the first trimester of pregnancy.
If treatment is required during pregnancy, propylthiouracil is favoured over carbimazole during the first trimester,
as it is associated with less severe congenital abnormalities. Switch existing carbimazole therapy to
propylthiouracil before conception. To prevent overtreatment and possible neonatal hypothyroidism or goitre, and
to minimise the risk of fetal congenital abnormalities, use the lowest effective dose of antithyroid drug therapy.
A patient with recurrent, severe or refractory hyperthyroidism who is planning to become pregnant should be
referred to a specialist for advice before conception.
Treatment of pre-existing hyperthyroidism in pregnancy
Carbimazole therapy should have been switched to propylthiouracil before conception, as it is associated with less
severe congenital abnormalities. If the woman is in the first trimester and is still taking carbimazole, switch to
propylthiouracil.
The goal of treatment of hyperthyroidism in pregnancy is to maintain maternal euthyroidism, with the maternal
serum T4 concentration in the upper half of the trimester-specific reference range. Measure maternal serum TSH
and T4 concentrations every 4 to 6 weeks in a patient who is stable and euthyroid on treatment. More frequent
testing is appropriate if the dose is adjusted or the patient is unstable. To prevent overtreatment and possible
neonatal hypothyroidism or goitre, and to minimise the risk of fetal congenital abnormalities, use the lowest
effective dose of antithyroid drug therapy.
Many women with Graves disease experience remission or improvement of disease during pregnancy, allowing
antithyroid therapy to be progressively reduced and often stopped. However, the disease often relapses postpartum
(see Postpartum thyroid dysfunction for more information).
If antithyroid therapy is still required during the second trimester, switch therapy back to carbimazole; the risk of
fetal congenital abnormalities has passed by this time, and carbimazole has a lower risk of liver injury.
If hyperthyroidism is difficult to control (eg requiring large doses of carbimazole), surgery can be considered
during pregnancy. Seek specialist advice.
Hyperthyroidism detected during pregnancy
A low or suppressed serum TSH concentration in the first trimester is not usually a cause for concern. It is usually
caused by the increased human chorionic gonadotrophin (hCG) concentration that occurs in the first trimester—
hCG stimulates TSH receptors, increasing triiodothyronine (T3) and T4 production, which in turn suppresses TSH
via negative feedback.
During the first trimester, a low or suppressed TSH concentration is usually not a cause for concern.
Gestational hyperthyroidism (also known as gestational transient thyrotoxicosis) can occur if the TSH receptor is
hypersensitive to hCG, resulting in excessive production of T3 and T4. However, gestational hyperthyroidism is
self-limiting, as the hCG concentration declines after approximately week 12 of gestation, and usually does not
require treatment.
It is important to differentiate gestational hyperthyroidism from both Graves disease and pre-existing toxic
multinodular goitre, which usually do require treatment. Serum hCG elevation is not differential. Gestational
hyperthyroidism is often associated with hyperemesis gravidarum, but also occurs in the absence of vomiting; in
addition, thyroid function tests usually normalise with declining hCG concentrations. Graves disease is usually
associated with positive TSH-receptor antibody and commonly also positive thyroid peroxidase antibody or
thyroglobulin antibody. If available, preconception thyroid function tests can be helpful. If in doubt, particularly if
the hyperthyroidism is more than mild, seek expert advice.
Radionuclide thyroid scans are contraindicated in pregnancy.
Postpartum thyroid dysfunction

The most common cause of postpartum thyroid dysfunction is postpartum thyroiditis. Postpartum thyroiditis
typically causes transient hyperthyroidism (due to release of preformed thyroid hormone from damaged thyroid
follicles), followed by hypothyroidism. Both phases are usually mild and transient, and most women revert to
euthyroidism within a year postpartum. Elevated thyroid peroxidase antibody is associated with more severe
disease, which may require treatment—beta blockers for symptom control during the hyperthyroid phase, and
short-term thyroxine replacement during the hypothyroid phase. Antithyroid drugs are not effective during the
hyperthyroid phase.
Postpartum thyroiditis must be differentiated from new-onset or relapsing Graves disease, which usually requires
antithyroid treatment. Positive TSH-receptor antibody suggests Graves disease. The risk of relapse in women with
remitted Graves disease is higher in the postpartum period.
Women who have had postpartum thyroid dysfunction are at increased risk of developing hypothyroidism in the 10
years postpartum. Counsel women about the symptoms of hypothyroidism and advise them to seek medical advice
if symptoms occur.
Neonatal hyperthyroidism
Infants of mothers with prior or current Graves disease have a low risk (around 1 to 2%) of developing neonatal
hyperthyroidism, which is caused by transplacental passage of thyroid stimulating hormone (TSH)-receptor
antibodies. Neonatal hyperthyroidism can cause heart failure in the neonate; if not recognised and managed early,
the neonate is at increased risk of morbidity and mortality. Maternal thyroid ablation (radioiodine or
thyroidectomy) before pregnancy does not eliminate the risk of neonatal hyperthyroidism, because TSH-receptor
antibody can persist after ablation.
Neonatal hyperthyroidism almost always occurs in the context of elevated maternal concentrations of TSH-
receptor antibody. To identify neonates at the highest risk, monitor maternal TSH-receptor antibody in all pregnant
women with a history of Graves disease (including women who had ablative treatment), or who are currently
taking an antithyroid drug for Graves disease. Measure TSH-receptor antibody in the first trimester; if the
concentration is elevated, repeat the measurement at around 20 and 32 weeks gestation to give some indication of
neonatal risk. However, a negative result does not preclude development of neonatal hyperthyroidism—not all
assays can detect maternal antibodies that are biologically active in the fetus.
All neonates at risk of hyperthyroidism require measurement of thyroid function in the early days of life, and
expert paediatric assessment. Measure serum TSH, free triiodothyronine (T3) and free thyroxine (T4)
concentrations at delivery and again at day 2 to 7 of life. For neonates of mothers who were taking an antithyroid
drug during pregnancy, further testing is recommended at day 10 to 14 of life; transplacental passage of the drug
can delay the presentation of hyperthyroidism until the drug is cleared from neonatal circulation.
Neonatal hyperthyroidism resolves spontaneously, usually within a few weeks, but it can persist for 3 months or
more. Short-term treatment with a beta blocker and an antithyroid drug may be needed; frequent assessment is
required as the infant can become hypothyroid quickly if antithyroid treatment is continued after resolution.
Graves-related eye disease

The majority of patients with Graves disease have minimal eye involvement. The relationship between eye disease
and Graves disease is not completely understood, but relates to an immunological disorder. Eye disease can be
difficult to manage and can occasionally threaten vision, as well as being severely disfiguring.
If Graves-related eye disease is suspected, assess the patient’s visual acuity and fields, and their ability to close the
eyes to achieve corneal protection. If any of these is compromised, the patient’s vision may be acutely threatened
—refer them to the emergency department for urgent specialist management. Patients without an acute threat to
vision require nonurgent referral to an ophthalmologist for more detailed assessment.
Achieving euthyroidism (usually with antithyroid drugs) is an important initial aim of therapy as euthyroidism is
thought to decrease risk. However, eye disease can progress unpredictably, sometimes without a clear relationship
to the severity of hyperthyroidism.
The association between smoking and Graves-related eye disease is well established. Counsel all patients with
Graves disease not to smoke, because of the potential to exacerbate severe eye disease; see also Smoking
cessation.
For patients with conjunctival irritation and dryness, or reactive lacrimation, use:
1 hypromellose eye drops , 1 to 2 drops into the affected eye(s), 2 to 4 times daily
OR
1 polyvinyl alcohol eye drops, 1 to 2 drops into the affected eye(s), 2 to 4 times daily.
Severe Graves-related eye disease is a complex condition and treatment requires both ophthalmologist and
endocrinologist involvement. If vision is threatened, weekly intravenous methylprednisolone (first line) or high-
dose oral prednis(ol)one (second line) can be used.
Severe eye disease requires specialist management.
Selenium can also be used—a randomised controlled trial of selenium versus placebo in patients with active mild
Graves-related eye disease demonstrated that selenium can improve clinical manifestations and quality of life, and
reduce progression to severe disease [Note 2].
Note 2: Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M, Stahl M, et al. Selenium and the course of mild Graves’ orbitopathy. N Engl J
Med 2011;364(20):1920-31. [URL]
Thyroid storm
Thyroid storm is a severe excess of thyroid hormone, usually occurring as a result of untreated or inadequately
treated thyrotoxicosis, or a severe acute systemic illness. It is a life-threatening emergency—arrange immediate
transport to hospital by ambulance. Thyroid storm usually presents with marked symptoms including fever,
tachycardia, vomiting, dehydration, delirium, coma, and organ system dysfunction (especially hepatic). It can also
be complicated by stroke, including cerebral venous thrombosis.
In addition to identifying and treating any underlying causes of thyroid storm, treatment involves:
controlling tachycardia and rate-dependent heart failure

blocking hormone synthesis
decreasing conversion of thyroxine (T4) to triiodothyronine (T3)
blocking hormone release
restoring hydration
providing sedation if required.
Control tachycardia with a beta blocker. A suitable oral option is:
propranolol 40 to 80 mg orally, 4 times daily.
Intravenous therapy provides a more rapid onset of action; suitable options include:
1 esmolol 250 to 500 micrograms/kg intravenously, as a loading dose, followed by 50 to

100 micrograms/kg/minute by continuous intravenous infusion
OR
1 metoprolol 5 mg intravenously over 2 to 3 minutes, repeated if necessary at 5-minute

intervals up to a total of 15 mg.
Antithyroid drugs block the synthesis of thyroid hormones. Propylthiouracil is preferred to carbimazole for the
treatment of thyroid storm because in high doses it also blocks the conversion of T4 to T3. Use:
1 propylthiouracil 200 mg orally, 4- to 6-hourly
OR
2 carbimazole 20 mg orally, 6- to 8-hourly.
Further dose adjustment depends on clinical and hormonal responses to treatment. If oral therapy with
propylthiouracil is not possible, rectal administration is also effective.
In addition to the antithyroid drug, block the release of thyroid hormone with:
iodine 5% + potassium iodide 10% in water (Lugol solution) 0.5 mL orally, 3 times daily
[Note 3].
Also consider using dexamethasone to reduce the conversion of T4 to T3. Use:
dexamethasone 4 mg orally or intravenously, 12-hourly.
Severe or refractory thyrotoxicosis sometimes requires additional therapy (see Other treatments for thyrotoxicosis).
Note 3: Lugol solution may need to be prepared extemporaneously; for formulation of Lugol solution, see the Australian Pharmaceutical Formulary
and Handbook (APF), 24th edition, 2018. [URL]
Amiodarone-induced thyrotoxicosis
Amiodarone-induced thyrotoxicosis requires specialist management. It can occur in patients with and without pre-
existing thyroid disease. Amiodarone-induced thyrotoxicosis can be related to the high iodine content of
amiodarone (type 1 amiodarone-induced thyrotoxicosis), but amiodarone can also directly damage thyroid cells
(type 2 amiodarone-induced thyrotoxicosis). See also Table 19.4 for details about the different types of
amiodarone-induced thyrotoxicosis.
Amiodarone-induced thyrotoxicosis can develop during long-term amiodarone treatment, or some months after
stopping treatment (because amiodarone has a long half-life). It has diverse presentations, and a poor correlation
between biochemical and clinical severity. Extreme weight loss and myopathy can indicate life-threatening
thyrotoxicosis. The decision to stop or continue the amiodarone should be made in consultation with the
cardiologist. Stopping treatment may not reverse the thyrotoxicosis.
Distinguishing the subtype of amiodarone-induced thyrotoxicosis can be difficult. If the cause is clear, and the
patient is stable, treat according to the disease type. Treat type 1 disease with antithyroid therapy, and treat type 2
disease with high-dose glucocorticoid therapy, tapering the dose based on clinical and biochemical responses. If a
patient is severely unwell or has not responded to monotherapy, use empirical dual therapy with a high-dose
glucocorticoid and a high-dose antithyroid drug, and seek urgent specialist review.
For a patient not responding to treatment at 4 to 6 weeks, thyroidectomy may be required. Seek specialist advice.
Key references
Overview of thyrotoxicosis and hyperthyroidism
Burch HB, Cooper DS. Management of Graves disease: a review. JAMA 2015;314(23):2544–54.
Howard-Thompson A, Luckey A, George C, Choby BA, Self TH. Graves' disease and treatment effects on warfarin
anticoagulation. Case Rep Med 2014;2014:292468.
Polmear JM, Hare MJL, Catford SR, Topliss DJ, Dooley MJ. Use of anticoagulation in thyroid disease. Aust Fam
Physician 2016;45(3). https://www.racgp.org.au/afp/2016/march/use-of-anticoagulation-in-thyroid-disease/
Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, et al. 2016 American Thyroid Association
guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid
2016;26(10):1343–421.
Differential diagnosis of thyrotoxicosis
2016;26(10):1343–421.
Overview of management of primary hyperthyroidism
2016;26(10):1343–421.
Antithyroid drug therapy for primary hyperthyroidism
Committee on Pharmaceutical Affairs, Japanese Society for Pediatric Endocrinology, Pediatric Thyroid Disease
Committee Japan Thyroid Association, Minamitani K, Sato H, Ohye H, et al. Guidelines for the treatment of childhood-
onset Graves' disease in Japan, 2016. Clin Pediatr Endocrinol 2017;26(2):29–62.
2016;26(10):1343–421.
Subsequent management of primary hyperthyroidism
2016;26(10):1343–421.
Hyperthyroidism in pregnancy
Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 guidelines of the American Thyroid
Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid
2017;27(3):315–89.
Neonatal hyperthyroidism
Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 guidelines of the American Thyroid
Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid
2017;27(3):315–89.
Ogilvy-Stuart AL. Neonatal thyroid disorders. Arch Dis Child Fetal Neonatal Ed 2002;87(3):F165–71.
Graves-related eye disease
Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, et al. The 2016 European Thyroid
Association/European Group on Graves' Orbitopathy guidelines for the management of Graves' orbitopathy. Eur
Thyroid J 2016;5(1):9–26.
Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M, Stahl M, et al. Selenium and the course of mild Graves'
orbitopathy. N Engl J Med 2011;364(20):1920–31.
Thyroid storm
Akamizu T. Thyroid storm: a Japanese perspective. Thyroid 2018;28(1):32–40.
Subacute thyroiditis
Subacute thyroiditis
Subacute (de Quervain) thyroiditis is an inflammation of the thyroid that results in transient thyrotoxicosis (due to
release of preformed thyroid hormone from damaged thyroid follicles), followed by hypothyroidism, and usually a
subsequent return to euthyroidism. It should be suspected when pain in the thyroid area, often radiating to the ears
or jaw, is associated with fever, malaise and variable symptoms of thyrotoxicosis (early) or hypothyroidism (late).
Erythrocyte sedimentation rate is markedly elevated, and nuclear thyroid scan shows near absent uptake.
If pain and constitutional symptoms are mild, the only therapy required may be temporary beta blockade to relieve
symptoms during the thyrotoxic stage—see Beta blockers for symptoms of thyrotoxicosis.
For initial treatment of painful thyroiditis, use:
1 aspirin 300 to 600 mg orally, 4- to 6-hourly
OR
1 ibuprofen 200 to 400 mg orally, 3 times daily
OR
1 indomethacin 25 to 50 mg orally, 6- to 12-hourly.
In severe or persistent cases, prednis(ol)one is effective for relieving pain and reducing inflammation. Use:
prednis(ol)one 40 mg orally, once daily, reducing over 2 to 4 weeks.
Antithyroid drugs are not effective during the thyrotoxic stage and have no place in treatment. If the hypothyroid
stage is persistent or symptomatic, thyroxine replacement may be required.
Thyroxine therapy for thyroid cancer
The most common forms of thyroid cancer are differentiated thyroid cancers (papillary and follicular cancers)
that arise from thyroid follicular cells. Many differentiated thyroid cancers respond to thyroid stimulating
hormone (TSH) suppression, so a major therapeutic objective in the follow-up of these cancers is to limit
potential TSH-mediated growth of residual tumour. To suppress TSH, a higher dose of levothyroxine than the
usual replacement dose is used, and the serum TSH target concentration is at least less than 0.1 milliunits/L.
If TSH suppression is indicated, ensure that all clinicians involved in the patient’s care understand the goal of
treatment, to avoid the levothyroxine dose being incorrectly lowered from a suppressive dose to a
replacement dose.
Ensure all clinicians involved in the patient’s care are aware that the goal of treatment is TSH suppression.
Not all patients with differentiated thyroid cancers should be treated with TSH-suppressive thyroxine therapy.
The managing specialist will consider the likely benefits of treatment related to the thyroid cancer versus the
risk of harms of treatment. Patients at highest risk of complications or harm from TSH suppression include
those with atrial fibrillation and reduced bone density (both of which can be worsened by levothyroxine
treatment). Patients unlikely to benefit from TSH suppression include those with low-risk thyroid cancer (eg
patients with low initial risk of recurrent disease, patients restratified as low risk after a prolonged disease-
free period).
If TSH suppression is not indicated, levothyroxine therapy may still be used to reduce the serum TSH
concentration, but with a less aggressive target concentration of 0.5 to 2 milliunits/L. An intermediate serum
TSH target concentration of 0.1 to 0.5 milliunits/L is reasonable for patients with both high risk of
complications from TSH-suppressive therapy and high-risk thyroid cancer, or for patients transitioning away
from full TSH suppression.
The appropriate individualised serum TSH target concentration for both short- and long-term follow-up of
thyroid cancer should be determined with endocrinologist consultation. The dose should be reviewed if
symptoms suggestive of thyrotoxicosis develop, or if thyroid cancer risk status changes. If long-term TSH-
suppressive therapy is essential, assess bone density and start appropriate treatment to prevent osteoporosis if
required. Patients with persistent or progressive thyroid cancer require subspecialist management.
Some thyroid cancer subtypes are not responsive to TSH suppression (eg medullary and anaplastic cancers).
Key references
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid
Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the
American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid
2016;26(1):1–133.
Adrenal insufficiency
Overview of adrenal insufficiency
The adrenal glands produce hormones in the:
adrenal cortex
glucocorticoids (eg cortisol)
mineralocorticoids (eg aldosterone)
androgens (eg dehydroepiandrosterone [DHEA])
adrenal medulla
catecholamines (eg adrenaline).
Adrenal insufficiency refers to insufficient production of glucocorticoids and mineralocorticoids by the adrenal
cortex; androgen production may also be insufficient. Adrenal insufficiency typically only occurs if both adrenal
glands are affected.
Primary adrenal insufficiency (also known as Addison disease) is usually caused by autoimmune-related atrophy
of the adrenal cortex; other causes include infection, metastatic cancer and some drugs.
Secondary adrenal insufficiency occurs when a pituitary or hypothalamic disorder causes a deficiency of
adrenocorticotrophic hormone (ACTH); see Hypopituitarism.
In children, adrenal insufficiency is usually caused by either a genetic disorder (eg congenital adrenal hyperplasia,
adrenoleukodystrophy, other rarer mutations such as SF-1) or an autoimmune disorder (affecting only the adrenal
glands, or part of an autoimmune polyglandular syndrome).
The hallmarks of primary adrenal insufficiency are fatigue, anorexia and weight loss, postural hypotension, and
skin and mucosal hyperpigmentation. Hyperpigmentation may be absent if adrenal insufficiency develops rapidly.
Hyperkalaemia and hyponatraemia are common, but their absence does not exclude primary adrenal insufficiency.
A diagnosis of primary adrenal insufficiency is confirmed by the combination of:
a positive short Synacthen test (ie an absent or severely blunted plasma cortisol response to tetracosactrin 30
to 60 minutes after injection)
elevated ACTH
elevated plasma renin (measured by direct concentration or plasma renin activity).
In patients with adrenal insufficiency, acute stress such as illness or surgery can precipitate acute cortisol
deficiency and adrenal crisis. Adrenal crisis can present with features that mimic sepsis, including nausea,
vomiting, diarrhoea, hypoglycaemia and hypercalcaemia, and is a medical emergency; see Adrenal crisis.
Principles of managing adrenal insufficiency

Adrenal insufficiency should be managed under specialist guidance; the aim of treatment is to correct hormone
deficiency. Catecholamines do not need to be replaced in adrenal insufficiency, as they are also produced by the
sympathetic nervous system.
Primary adrenal insufficiency requires lifelong glucocorticoid and mineralocorticoid replacement. Androgen
replacement is not routinely required; see Androgen replacement for adrenal insufficiency for more information.
Adrenal insufficiency secondary to hypopituitarism only requires glucocorticoid replacement; mineralocorticoid

replacement is not required because the renin–angiotensin–aldosterone axis remains intact.
During a significant systemic illness or a surgical procedure, the dose of glucocorticoid therapy must be increased
to simulate the normal increase in cortisol secretion in response to stress. See Glucocorticoid replacement during
intercurrent illness and surgery for more information. It is crucial that the patient or their carer is able to manage
glucocorticoid dose adjustments during illness; see patient education.
Before and during treatment of adrenal insufficiency, consider concurrent drugs that could affect steroid
replacement dose requirements; see drugs that affect steroid dose requirements.
A patient with adrenal insufficiency and coexisting elevated blood pressure or heart failure may require a lower
mineralocorticoid dose than other patients. See Hypertension and heart failure associated with adrenal
insufficiency for information about management.
Children with adrenal insufficiency related to a genetic disorder should be monitored for associated neurological
and gonadal disorders. For adrenal insufficiency that is part of an autoimmune polyglandular syndrome, monitor
the child for other endocrinopathies.
Patient education for adrenal insufficiency

Patient and carer education is crucial for successful long-term management of adrenal insufficiency. See Box
19.1 for key aspects of self-care. In particular, patients and carers must be able to manage glucocorticoid dose
adjustments during periods of illness or stress—see Glucocorticoid replacement therapy during intercurrent illness
and surgery—and be able to administer intramuscular hydrocortisone in an emergency. A patient with well-
controlled adrenal insufficiency does not usually require frequent follow-up, so can forget crucial advice that was
given years before; periodic reminders about self-care are essential.
An alert bracelet or necklace is strongly recommended for all patients with adrenal insufficiency. Knowledge about
the patient’s condition and usual treatment is helpful in the case of acute illness or hospitalisation. Advise patients
to carry a wallet card with this information; a template wallet card is available on the Hormones Australia website.
An alert bracelet or necklace is strongly recommended for patients with adrenal insufficiency.
The Royal Children’s Hospital website provides information for patients and carers about dosing of
glucocorticoids during illness to prevent adrenal crisis, and recognising signs of impending adrenal crisis.
Patients with adrenal insufficiency who live in remote areas, or who are travelling overseas or remotely, should
carry:
injectable hydrocortisone [Note 1]

syringes
instructions for intramuscular administration.
Key aspects of self-care for a patient with adrenal insufficiency (Box 19.1)
A patient with adrenal insufficiency should:
increase glucocorticoid dose during intercurrent illness

recognise early features of adrenal crisis (eg nausea, vomiting, dehydration, hypotension)
carry injectable hydrocortisone when away from medical care
wear an alert bracelet or necklace
carry a wallet card with details about their condition and treatment.
Note 1: Airlines may require documentation from the patient’s clinician to allow injectable drugs in baggage.
Glucocorticoid replacement for adrenal insufficiency

Patients with adrenal insufficiency require lifelong glucocorticoid replacement. The goal of therapy is to replicate
the steroid exposure of adrenal cortisol synthesis and relieve symptoms of glucocorticoid deficiency, using the
lowest effective glucocorticoid dose.
Long-term glucocorticoid therapy can reduce bone mineral density (BMD) and increase fracture risk; measure the
patient’s baseline BMD and assess their fracture risk (see Risk factors for minimal-trauma fracture) at diagnosis.
See also Monitoring of adrenal insufficiency for information about monitoring of BMD during treatment.
Hydrocortisone is the most commonly used glucocorticoid for adrenal insufficiency in both adults and children.
Cortisone acetate is converted to hydrocortisone in the body and is a suitable alternative. Prednis(ol)one should not
be used in children because it can cause growth suppression. In adults, prednis(ol)one is not usually used for initial
therapy, but is sometimes used for maintenance therapy; its longer duration of effect allows once daily dosing,
which is helpful if adherence is a concern. Dexamethasone is rarely used for replacement therapy because the
available tablet strengths are not suitable for adrenal insufficiency dosing, and its long duration of effect increases
the risk of overtreatment.
Table 19.6 lists the relative potency and duration of effect of glucocorticoids.
Approximate relative potency and duration of effect of glucocorticoids (Table 19.6) [NB1]
Glucocorticoid Relative Equivalent dose for Estimated duration of effect

glucocorticoid glucocorticoid effect
potency
hydrocortisone 1 20 mg 8 to 12 hours
cortisone acetate 0.8 25 mg 8 to 12 hours
prednis(ol)one 4 5 mg 12 to 36 hours
dexamethasone 25 800 micrograms 36 to 72 hours
methylprednisolone 5 4 mg 12 to 36 hours
NB1: These potencies only apply to oral or intravenous administration of glucocorticoids.
Adrenal cortisol synthesis can usually be approximated with hydrocortisone or cortisone acetate given twice daily
in adults, while children usually require dosing three times daily. Some adults benefit from more frequent dosing
(eg those who experience excessive evening fatigue).
Corticosteroid exposure in the evening is associated with adverse metabolic effects. To reduce these effects, the
daily dose should be weighted towards the morning. In a patient taking a twice-daily regimen, approximately two-
thirds of the daily dose should be taken in the morning immediately after waking, and one-third of the daily dose
should be taken in the mid-afternoon. If three daily doses are required, they can be taken in the morning
immediately after waking, in the middle of the day, and in the late afternoon (before 5 pm).
A suitable starting dose for an adult with adrenal insufficiency is:
1 hydrocortisone 12 mg orally, in the morning immediately after waking, and 8 mg in the

mid-afternoon
OR
2 cortisone acetate 15 mg orally, in the morning immediately after waking, and 10 mg in the
mid-afternoon.
If switching to prednis(ol)one in an adult, start with a dose equivalent to the total daily dose of existing therapy
(see Table 19.6 for equivalent glucocorticoid doses). The single daily dose of prednis(ol)one should be taken in the
morning immediately after waking.
A suitable starting dose for a child with primary adrenal insufficiency is:
1 hydrocortisone 8 to 12 mg/m2 orally, daily in 3 divided doses, weighted towards the

morning if practical [Note 2]
OR
2 cortisone acetate 10 to 15 mg/m2 orally, daily in 3 divided doses, weighted towards the
morning if practical [Note 2].
In a child with adrenal insufficiency secondary to pituitary or hypothalamic disease, a lower glucocorticoid dose
can be used. A suitable starting dose is:
hydrocortisone 5 to 8 mg/m2 orally, daily in 3 divided doses, weighted towards the

morning if practical [Note 2].
The glucocorticoid dose should be adjusted in small increments, aiming for the lowest effective dose. Dose
adjustments should be made under specialist guidance, based on clinical response; no one biomarker can be used
to guide dosing. Dose requirements vary significantly among patients. Patients with adrenal insufficiency
secondary to hypopituitarism often have a lower dose requirement than patients with primary adrenal insufficiency.
See also Monitoring of adrenal insufficiency for signs of overtreatment or undertreatment.
Although no specific upper dose limit exists for glucocorticoid replacement, if the patient has persistent symptoms
or requires a higher dose than expected, consider other factors that may be contributing to symptoms.
During illness and surgery, the glucocorticoid dose needs to be increased to simulate the normal increase in
cortisol secretion that occurs in response to stress (see Glucocorticoid replacement during intercurrent illness and
surgery).
Note 2: Click here for body surface area calculator and formula.
Glucocorticoid replacement during intercurrent illness and surgery
Overview of glucocorticoid replacement during intercurrent illness and surgery
During a significant systemic illness or surgery, patients with adrenal insufficiency require an increased
glucocorticoid dose. This applies to patients with glucocorticoid deficiency resulting from a primary adrenal
disorder, hypopituitarism, adrenocortical suppression or congenital adrenal hyperplasia. The increased dose
simulates the normal increase in cortisol secretion that occurs in response to stress, and is crucial to prevent acute
cortisol deficiency and adrenal crisis.
Ensure patients are well educated about the importance of adjusting glucocorticoid doses in response to illness; see
Patient education. The Royal Children’s Hospital website provides information for patients and carers about
dosing of glucocorticoids during illness to prevent adrenal crisis.
The dose of glucocorticoid must be increased at the onset of a systemic illness or before a surgical procedure.
Intercurrent illness
At the onset of symptoms of illness (eg significant nausea or dizziness), the patient should increase their
glucocorticoid dose promptly, regardless of the time of day and without waiting to consult a doctor. The higher
dose should usually be continued for 2 to 3 days. If the illness has not resolved after 3 days, the patient should seek
medical advice rather than continuing the high dose.
The patient may have an individualised ‘sick day’ action plan provided by their endocrinologist. Otherwise, for an
adult whose usual maintenance therapy is hydrocortisone, a reasonable regimen is:
hydrocortisone 20 mg orally, 3 times daily, gradually reducing to maintenance dose over 2

to 3 days.
For an adult whose usual maintenance therapy is cortisone acetate, a reasonable regimen is:
cortisone acetate 25 mg orally, 3 times daily, gradually reducing to maintenance dose over
2 to 3 days.
For an adult whose usual maintenance therapy is prednis(ol)one, a reasonable regimen is:
prednis(ol)one 15 mg orally, once daily, gradually reducing to maintenance dose over 2 to

3 days.
For a child whose usual maintenance therapy is hydrocortisone, a reasonable regimen is:
hydrocortisone 10 mg/m2 orally, 6- to 8-hourly, gradually reducing to maintenance dose

over 2 to 3 days [Note 3].
For a child whose usual maintenance therapy is cortisone acetate, a reasonable regimen is:
cortisone acetate 12.5 mg/m2 orally, 6- to 8-hourly, gradually reducing to maintenance

dose over 2 to 3 days [Note 3].
If the patient has features of impending adrenal crisis (eg abdominal pain, dehydration, hypotension), medical
attention and parenteral hydrocortisone are recommended. Parenteral therapy may also be required if the patient is
vomiting. For an adult, use:
hydrocortisone 100 mg intramuscularly.
For a child, use:
hydrocortisone
child younger than 3 years: 25 mg intramuscularly
child 3 to 12 years: 50 mg intramuscularly.
If a parenteral glucocorticoid is not available, an equivalent dose of oral therapy should be taken even if the patient
is vomiting.
Major illnesses (eg haemodynamic instability) should be managed in hospital with hydrocortisone replacement as
for adrenal crisis.
Surgery
If a patient with adrenal insufficiency requires an elective procedure, ensure all relevant clinicians are aware of the
need for increased glucocorticoid therapy.
For a minor procedure that does not require general anaesthetic, sedation or fasting (eg a skin lesion removal),
consider using a double dose of the patient’s usual glucocorticoid on the morning of the procedure.
For a procedure that requires general anaesthetic, sedation or fasting, parenteral glucocorticoid therapy
should be started at induction of anaesthesia or at the start of the procedure. Continue parenteral therapy until oral
intake can be tolerated following the procedure.
For an adult, give:
hydrocortisone 100 mg intravenously, initially, then 50 mg intravenously, 6-hourly until

oral therapy is tolerated.
For a neonate or child within the normal weight range for their age [Note 4], use:
hydrocortisone
neonate or child up to 6 weeks: 25 mg intravenously, initially, then 5 to 10 mg
intravenously, 6-hourly, until oral therapy is tolerated
child 6 weeks up to 3 years: 25 mg intravenously, initially, then 10 mg intravenously, 6-
hourly, until oral therapy is tolerated
child 3 to 7 years: 50 mg intravenously, initially, then 12.5 mg intravenously, 6-hourly,
until oral therapy is tolerated
child 7 to 12 years: 50 mg intravenously, initially, then 25 mg intravenously, 6-hourly,
until oral therapy is tolerated.
For children outside the normal weight range for their age [Note 4], use:
hydrocortisone 50 to 75 mg/m2 intravenously, initially, then 12.5 to 18.75 mg/m2

intravenously, 6-hourly until oral therapy is tolerated [Note 5].
Higher doses may be needed in very sick children.
Once the patient is stable and tolerating oral intake, resume the usual oral glucocorticoid at the dose used for
intercurrent illness. If the patient is recovering well, reduce the dose to the usual maintenance dose over 2 to 3
days.
Note 4: See the Centers for Disease Control and Prevention website for weight-for-age percentile charts.
Mineralocorticoid replacement for adrenal insufficiency

The aims of mineralocorticoid therapy for adrenal insufficiency are to maintain:
normal blood pressure (to avoid syncope)

serum sodium and potassium concentrations in the normal range
plasma renin concentration at the upper end of the normal range.
A moderately elevated plasma renin concentration is common and is acceptable if symptoms are well controlled. A
low plasma renin concentration suggests overtreatment.
For mineralocorticoid replacement for adrenal insufficiency in an adult, use:
fludrocortisone 100 micrograms orally, daily. Adjust dose according to postural blood
pressure, and serum potassium and plasma renin concentrations. Usual dose 50 to 300
micrograms daily.
The dose requirement of fludrocortisone in children varies significantly—it should be started and titrated by a
specialist. The usual maintenance dose in a child is:
fludrocortisone 50 to 200 micrograms orally, daily.
Infants may need a higher fludrocortisone dose in the first few months of life.
Acute adjustment of the mineralocorticoid dose is not required for stress or intercurrent illness.
Androgen replacement for adrenal insufficiency

If a patient with adrenal insufficiency remains symptomatic despite optimised glucocorticoid and
mineralocorticoid replacement, a trial of androgen replacement therapy with dehydroepiandrosterone (DHEA) can
be considered. DHEA replacement has been reported to improve sexual function in women, and general wellbeing
in women and men. It may also increase lean body mass and bone density. However, these benefits have not been
shown consistently, and DHEA replacement is not routinely recommended. Seek specialist advice.
Monitoring of adrenal insufficiency

Once a patient with adrenal insufficiency is stable and well controlled on replacement therapy, an annual review is
sufficient.
At each review, measure serum sodium and potassium and plasma renin concentrations. A plasma renin
concentration in the upper-normal reference range indicates optimal mineralocorticoid replacement.
Ask the patient about their general wellbeing, and assess for features of:
glucocorticoid excess—weight gain, facial puffiness, peripheral oedema, insomnia, low bone mineral
density (BMD), elevated blood pressure, hyperglycaemia
glucocorticoid deficiency—weight loss, lack of appetite, progressive skin pigmentation, lethargy
mineralocorticoid excess—elevated blood pressure, peripheral oedema, hypokalaemia, low plasma renin
concentration
mineralocorticoid deficiency—postural hypotension, tachycardia, hyperkalaemia.
Adjust the dose or timing of replacement therapy if required.
Plasma adrenocorticotrophic hormone (ACTH) concentration does not reliably correlate with the sufficiency of
glucocorticoid replacement, so is not useful for assessing the glucocorticoid dose.
Assess BMD every 2 years. A significant decrease in BMD may indicate excess glucocorticoid replacement—
review the glucocorticoid dose, and consider the possibility of coeliac disease or thyroid disease. See also
Glucocorticoid-induced osteoporosis.
Patients with autoimmune adrenal insufficiency have increased prevalence of other autoimmune disorders (eg
coeliac disease, autoimmune thyroid disease, type 1 diabetes, pernicious anaemia). Counsel patients to be aware of
the signs and symptoms of these disorders. In addition to clinical monitoring, consider biochemical screening after
1 year, then every 5 years.
Adrenal crisis
Adrenal crisis (also known as acute adrenal insufficiency or Addisonian crisis) is a medical emergency caused by a
severe cortisol deficiency.
The primary manifestations are gastrointestinal symptoms and symptoms of acute circulatory failure (eg
hypotension, confusion). Laboratory findings can include:
hypoglycaemia
hyponatraemia
hyperkalaemia
hypercalcaemia
increased urea and creatinine concentrations.
Adrenal crisis usually occurs in patients with primary adrenal insufficiency, precipitated by acute stress (such as
illness or surgery) or abrupt cessation of glucocorticoid therapy. Patients with adrenal insufficiency secondary to
hypopituitarism can also experience acute cortisol deficiency, but circulatory collapse is less likely because their
renin–angiotensin–aldosterone axis is intact.
If possible, collect blood samples to measure plasma glucose and electrolyte concentrations before starting
treatment. In a patient with suspected adrenal crisis but no previous diagnosis of primary adrenal insufficiency,
also collect samples to measure plasma cortisol, adrenocorticotrophic hormone (ACTH) and renin concentrations.
However, it is essential that treatment with intravenous glucocorticoid therapy begins quickly; do not delay
treatment to wait for laboratory results, or if phlebotomy is delayed or not available.
Start glucocorticoid treatment immediately; do not delay treatment to wait for results of laboratory tests.
For an adult, start treatment with:
hydrocortisone 100 mg intravenously, initially, then 50 mg intravenously, every 6 hours

until stable and tolerating oral intake.
If intravenous access is not established or if parenteral glucocorticoid therapy is not immediately available, an oral
glucocorticoid can be used:
prednis(ol)one 40 mg orally.
For a neonate or child within the normal weight range for their age [Note 6], use:
hydrocortisone
neonate or child up to 6 weeks: 25 mg intravenously or intramuscularly, initially, then 5 to
10 mg intravenously or intramuscularly, 6-hourly until stable and tolerating oral intake
child 6 weeks to 3 years: 25 mg intravenously or intramuscularly, initially, then 10 mg
intravenously or intramuscularly, 6-hourly until stable and tolerating oral intake
child 3 to 7 years: 50 mg intravenously or intramuscularly, initially, then 12.5 mg
child 7 to 12 years: 50 mg intravenously or intramuscularly, initially, then 25 mg
intravenously or intramuscularly, 6-hourly until stable and tolerating oral intake.
hydrocortisone 50 to 75 mg/m2 intravenously or intramuscularly, initially, then 12.5 to

18.75 mg/m2 intravenously or intramuscularly, 6-hourly until stable and tolerating oral
intake [Note 7].
Intravenous sodium chloride 0.9% is required to correct hypovolaemia. If present, prompt correction of
hypoglycaemia and severe hyperkalaemia are also important. Hyperkalaemia usually responds to intravenous
fluids and hydrocortisone therapy—do not use intravenous insulin and glucose.
Once the patient is stable and tolerating oral intake, patients with pre-existing adrenal insufficiency can resume
their usual oral glucocorticoid at the dose used for intercurrent illness. If the patient is recovering well, reduce the
dose to the usual maintenance dose over 2 to 3 days.
After an episode of adrenal crisis, patients who were not already known to have adrenal insufficiency should be
assessed to establish the cause and guide further management.
Adrenal insufficiency during pregnancy and lactation

The principles of managing adrenal insufficiency during pregnancy are the same as those for nonpregnant patients.
Specialist input is recommended before conception and during pregnancy.
Hydrocortisone is the preferred glucocorticoid in pregnancy, but cortisone acetate and prednis(ol)one are also
suitable; it is not necessary to switch stable treatment to hydrocortisone. Dexamethasone can cross the placenta and
suppress fetal adrenal glands, so should not be used in pregnancy.
Most women with pre-existing adrenal insufficiency can continue their usual glucocorticoid and
mineralocorticoid replacement doses throughout pregnancy. Some women require a gradual increase of their
glucocorticoid dose during the third trimester, particularly those taking a maintenance dose at the lower end of the
usual range.
New-onset or previously undiagnosed adrenal insufficiency in a pregnant woman is rare. Diagnosis is difficult
—during the first trimester, symptoms of adrenal insufficiency or adrenal crisis (eg vomiting, nausea, fatigue) can
be incorrectly attributed to pregnancy. In addition, the plasma total cortisol concentration increases during a
healthy pregnancy (related to an increase in corticosteroid binding globulin), so a concentration within the
reference range does not exclude adrenal insufficiency during pregnancy. If in doubt, seek advice to interpret the
results. More specific symptoms, such as salt craving and hyperpigmentation in skin creases or mucous
membranes, can help identify adrenal insufficiency. If adrenal insufficiency is diagnosed during pregnancy,
glucocorticoid and mineralocorticoid replacement should be started; seek specialist advice.
Women with persistent vomiting may require parenteral hydrocortisone. Use:
hydrocortisone 100 mg intravenously or intramuscularly, then 50 mg every 6 hours until

oral therapy can be tolerated. A higher oral maintenance dose than usual may be required.
If vomiting persists despite parenteral therapy, seek specialist advice.
An increased glucocorticoid dose may also be required during labour.
Glucocorticoid and mineralocorticoid therapy should continue during breastfeeding.
Other considerations in adrenal insufficiency

Drugs that affect steroid dose requirements
Some drugs, for example rifampicin, phenytoin and carbamazepine, increase steroid metabolism in the liver,
increasing glucocorticoid and mineralocorticoid dose requirements.
Other drugs, such as some azole antifungals and some protease inhibitors, decrease steroid metabolism in the liver
and reduce glucocorticoid and mineralocorticoid dose requirements.
Long-term use of a nonsteroidal anti-inflammatory drug (NSAID) predisposes the patient to hyperkalaemia, and
can exacerbate the fluid retention and elevated blood pressure caused by fludrocortisone.
Hypertension and heart failure associated with adrenal insufficiency

Hypertension or oedema in a patient with adrenal insufficiency may be due to overtreatment with fludrocortisone.
A low plasma renin concentration indicates an excessive fludrocortisone dose.
If a patient with hypertension and adrenal insufficiency has a plasma renin concentration at the lower end of the
normal range or below, reduce the fludrocortisone dose. If the plasma renin concentration is in the upper part of the
normal range or elevated, and the patient does not have any other signs that suggest mineralocorticoid excess (eg
oedema, hypokalaemia), start antihypertensive therapy. Angiotensin II (a potent vasoconstrictor) is usually
elevated in these patients, so angiotensin converting enzyme inhibitors and angiotensin II receptor blockers are
effective. Dihydropyridine calcium channel blockers cause vasodilation, so are also effective. Diuretics should be
avoided, and aldosterone antagonists (eg spironolactone, eplerenone) are contraindicated.
A patient with heart failure and adrenal insufficiency can be treated with most of the usual drugs for heart failure
(eg an angiotensin converting enzyme inhibitor, a beta blocker), but an aldosterone antagonist should not be used.
Instead, the fludrocortisone dose should be reduced, or even stopped, to reduce the mineralocorticoid effect.
Key references
Principles of managing adrenal insufficiency
Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, et al. Diagnosis and treatment of primary
adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2016;101(2):364–89.
Patient education for adrenal insufficiency
Glucocorticoid replacement for adrenal insufficiency
Brunton L, Chabner B, Knollman B. Goodman & Gillman's the pharmacological basis of therapeutics. 12th ed. New
York: McGraw-Hill Education; 2011.
Patti G, Guzzeti C, Di Iorgi N, Maria Allegri AE, Napoli F, Loche S, et al. Central adrenal insufficiency in children and
adolescents. Best Pract Res Clin Endocrinol Metab 2018;32(4):425–44.
Glucocorticoid replacement during intercurrent illness and surgery
Broersen LH, Pereira AM, Jorgensen JO, Dekkers OM. Adrenal insufficiency in corticosteroids use: systematic review
and meta-analysis. J Clin Endocrinol Metab 2015;100(6):2171–80.
Maguire AM, Craig ME, Cowell CT. Management of adrenal insufficiency during the stress of medical illness and
surgery.Comment. Med J Aust 2008;189(6):350.
Stewart PM, Biller BM, Marelli C, Gunnarsson C, Ryan MP, Johannsson G. Exploring inpatient hospitalizations and
morbidity in patients with adrenal insufficiency. J Clin Endocrinol Metab 2016;101(12):4843–50.
Royal Children's Hospital (RCH) Melbourne. Clinical practice guidelines: adrenal crisis and acute adrenal insufficiency.
Melbourne: RCH. Last Updated: March 2016.
https://www.rch.org.au/clinicalguide/guideline_index/Adrenal_crisis_and_acute_adrenal_insufficiency/
White K, Arlt W. Adrenal crisis in treated Addison's disease: a predictable but under-managed event. Eur J Endocrinol
2010;162(1):115–20.
Adrenal crisis
Adrenal insufficiency during pregnancy and lactation
Demey-Ponsart E, Foidart JM, Sulon J, Sodoyez JC. Serum CBG, free and total cortisol and circadian patterns of
adrenal function in normal pregnancy. J Steroid Biochem 1982;16(2):165–9.
Ozdemir I, Demirci F, Yucel O, Simsek E, Yildiz I. A case of primary Addison's disease with hyperemesis gravidarum
and successful pregnancy. Eur J Obstet Gynecol Reprod Biol 2004;113(1):100–2.
Yuen KC, Chong LE, Koch CA. Adrenal insufficiency in pregnancy: challenging issues in diagnosis and management.
Endocrine 2013;44(2):283–92.
Adrenocortical suppression
Glucocorticoid therapy suppresses the release of adrenocorticotrophic hormone (ACTH) from the pituitary
gland. This can cause gradual atrophy of ACTH–dependent tissue in the adrenal cortex, leading to
adrenocortical suppression and subsequent dependence on exogenous glucocorticoid therapy. A patient who
is dependent on exogenous glucocorticoid therapy is at risk of cortisol deficiency if the glucocorticoid is
stopped or the dose is reduced quickly. They are also at risk of cortisol deficiency during periods of stress,
such as surgery or illness, because the usual response of increased adrenal cortisol production does not occur.
The dose and duration of treatment likely to cause clinically relevant adrenocortical suppression is not clear,
and varies significantly between patients. Oral prednis(ol)one at a dose of 10 mg or more daily (or the
equivalent dose of another glucocorticoid—see Table 19.6) for more than 3 weeks could be expected to cause
suppression. A high dose of an inhaled, topical or intra-articular glucocorticoid can also cause adrenocortical
suppression (see Table 9.12 for high doses of inhaled glucocorticoids).
A single morning cortisol concentration within the reference range does not exclude adrenocortical
suppression. However, an ambulatory morning cortisol concentration above 400 nanomol/L makes clinically
significant adrenocortical suppression unlikely, provided the patient is not taking a drug that can interfere
with the test (eg oestrogen therapy). The morning cortisol should be measured before 9am and at least 24
hours after the last dose of glucocorticoid. A normal response to short Synacthen test definitively excludes
adrenocortical suppression.
To prevent glucocorticoid deficiency in a patient who has, or is at risk of, adrenocortical suppression:
slowly taper the glucocorticoid dose if stopping treatment, allowing at least 1 week between each dose
reduction
increase the dose of glucocorticoid therapy during periods of stress (see Glucocorticoid replacement
during intercurrent illness and surgery for recommended doses). If the patient’s regular dose is equal to
or higher than the dose recommended for their illness or surgery, the dose does not need to be increased
further.
Key references
Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM. Adrenal insufficiency in corticosteroids use: systematic
review and meta-analysis. J Clin Endocrinol Metab 2015;100(6):2171–2180. .
Hägg E, Asplund K, Lithner F. Value of basal plasma cortisol assays in the assessment of pituitary-adrenal
insufficiency. Clin Endocrinol (Oxf) 1987;26(2):221–226. .
Jung C, Inder WJ. Management of adrenal insufficiency during the stress of medical illness and surgery. Med J
Aust 2008;188(7):409–413. .
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia is the most common cause of adrenal dysfunction in children, typically presenting
with features of androgen excess. It is a genetic condition that causes deficiency of an enzyme essential in the
biosynthesis of cortisol and aldosterone; the enzyme most commonly affected is 21-hydroxylase. While this results
in cortisol and aldosterone deficiency, androgen excess also occurs because the low cortisol concentration leads to
excess release of adrenocorticotrophic hormone (ACTH) from the pituitary gland (due to lack of negative
feedback), causing increased synthesis of adrenal precursor hormones. These precursor hormones, which would
normally be converted to cortisol, aldosterone and androgens, are converted primarily to androgens.
Congenital adrenal hyperplasia is usually diagnosed in infancy or early childhood. Females usually present as
neonates with virilisation of their genitalia. Infants of either sex can present with failure to thrive. They can also
present with vomiting and dehydration as part of a life-threatening, salt-losing crisis, which is an endocrine
emergency; seek urgent specialist advice.
Milder deficiencies of the enzymes responsible for cortisol and aldosterone biosynthesis can present in later
childhood or adulthood, also with symptoms of androgen excess.
At diagnosis, screening of all siblings is recommended. Antenatal diagnosis is available if the genetic mutation for
the family is known.
Lifelong glucocorticoid and mineralocorticoid therapy is required for congenital adrenal hyperplasia.
Dosing of glucocorticoid therapy for congenital adrenal hyperplasia in children is difficult—specialist management
is required. A higher maintenance dose is often required than for primary adrenal insufficiency, because the aim is
to achieve adrenal suppression rather than just cortisol replacement. If the glucocorticoid dosage is insufficient,
androgenic effects continue, including growth acceleration (with bone age advancement and potential for
premature growth plate closure and short stature), acne and advanced puberty. Excessive glucocorticoid dosage
can cause slow growth, Cushingoid features and maturational delay.
Mineralocorticoid replacement allows use of a lower glucocorticoid dose, minimising the impact of glucocorticoid
therapy on growth.
For a child or a prepubertal teenager, usual maintenance doses to achieve adrenal suppression in congenital adrenal
hyperplasia are:
1 hydrocortisone 12 to 15 mg/m2 orally, daily in 3 divided doses [Note 1]
OR
2 cortisone acetate 15 to 25 mg/m2 orally, daily in 3 divided doses [Note 1]
fludrocortisone 50 to 200 micrograms orally, daily.
Infants may need a higher fludrocortisone dose in the first few months of life.
Prednis(ol)one and dexamethasone have a greater propensity to inhibit growth than hydrocortisone and cortisone
acetate. They are occasionally used under specialist guidance if other drugs have not been effective.If
prednis(ol)one is used, it may need to be given in divided doses.
Monitoring of congenital adrenal hyperplasia treatment is highly specialised, involving measurement of 17-
hydroxyprogesterone concentration and either plasma renin concentration or plasma renin activity. Monitoring
growth can help to identify over-suppression.
During intercurrent illness or surgery, a temporary increase in glucocorticoid therapy is necessary, as for primary
adrenal insufficiency. See Glucocorticoid replacement during intercurrent illness and surgery for details.
Nonclassical congenital adrenal hyperplasia is caused by a partial deficiency of the 21-hydroxylase enzyme,
leading to androgen excess without symptoms of glucocorticoid deficiency. In females, it usually presents as
hirsutism and menstrual irregularity, and may be clinically indistinguishable from polycystic ovary syndrome.
Nonclassical congenital adrenal hyperplasia can be asymptomatic and can go undiagnosed, particularly in men, in
whom symptoms of androgen excess can be less obvious.
Treatment is a combined oestrogen and progestin preparation, with or without an antiandrogen. Glucocorticoids
are not used for routine maintenance therapy, but are sometimes used to suppress adrenal androgen production if
fertility is desired. Specialist management is required.
Key references
Auchus RJ, Arlt W. Approach to the patient: the adult with congenital adrenal hyperplasia. J Clin Endocrinol Metab
2013;98(7):2645–55.
Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, et al. Congenital adrenal hyperplasia due to
steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab
2018;103(11):4043–88.
Witchel SF, Azziz R. Nonclassic congenital adrenal hyperplasia. Int J Pediatr Endocrinol 2010;2010:625105.
Primary aldosteronism
Primary aldosteronism (excess production of aldosterone) is usually caused by an aldosterone-secreting
adenoma (Conn syndrome). The features of primary aldosteronism are elevated blood pressure, hypokalaemia
(present in about 50% of cases), aldosterone excess and suppressed plasma renin activity.
A plasma aldosterone-to-renin ratio is the initial screening test for suspected primary aldosteronism. An
elevated aldosterone-to-renin ratio is a positive result; refer patients with an elevated aldosterone-to-renin
ratio to a specialist for further tests to confirm the diagnosis.
The aldosterone-to-renin ratio is susceptible to interference by many blood pressure–lowering drugs, as well
as nonsteroidal anti-inflammatory drugs (NSAIDs)—the effects of common drugs on aldosterone, renin, and
aldosterone-to-renin ratio are shown in Table 19.7. Patients are often taking one or more blood pressure–
lowering drugs before a diagnosis of primary aldosteronism is considered. The initial aldosterone-to-renin
ratio can be performed while the patient is taking a blood pressure–lowering drug, but expert advice is
recommended to interpret the result, with consideration of the effect of the drug. For example, beta blockers
increase the aldosterone-to-renin ratio, so a normal aldosterone-to-renin ratio in a patient taking a beta blocker
makes the diagnosis of primary aldosteronism unlikely.
Blood pressure–lowering drugs that do not affect the aldosterone-to-renin ratio include diltiazem, verapamil,
prazosin and hydralazine. Hydralazine can cause reflex tachycardia; this can be prevented by starting
verapamil before the hydralazine.
Effect of common drug classes on aldosterone-to-renin ratio (Table 19.7) [NB1] [NB2]
Effect on aldosterone Effect on renin Effect on aldosterone-to- False-positive or false-

renin ratio negative screening result
for primary
aldosteronism
beta blockers
centrally acting antiadrenergic drugs (methyldopa, clonidine)
nonsteroidal anti-inflammatory drugs (NSAIDs)

↓ ⇊ ↑ false positive
angiotensin converting enzyme inhibitors
angiotensin receptor blockers

↓ ⇈ ↓ false negative
all diuretics
↑ ⇈ ↓ false negative
dihydropyridine calcium channel blockers
↓ or neutral ↑ ↓ false negative
NB1: Hypokalaemia can suppress aldosterone and cause a false-negative result for primary aldosteronism; ensure the patient is potassium replete
before testing.
NB2: The impact of the effect of these drugs on the interpretation of the result depends on the aldosterone-to-renin ratio threshold used, which
varies among centres.
Primary aldosteronism caused by an aldosterone-secreting adenoma (Conn syndrome) is usually treated with
adrenalectomy.
If adrenalectomy is contraindicated or the patient has bilateral adrenal hypersecretion, an aldosterone

antagonist is first-line treatment. An aldosterone antagonist is also used in preparation for an adrenalectomy.
Use:
spironolactone 25 mg orally, once daily. Adjust dose according to blood pressure,

serum potassium concentration and plasma renin concentration.
Spironolactone also blocks androgen receptors, which can lead to gynaecomastia and erectile dysfunction in
males. If these adverse effects occur, amiloride is a suitable alternative. Use:
amiloride 5 mg orally, twice daily. Adjust dose according to blood pressure and serum
potassium concentration.
Eplerenone rarely causes gynaecomastia or erectile dysfunction. It can be considered instead of

spironolactone, but at the time of writing, it is not approved by the Australian Therapeutic Goods
Administration (TGA) for treating primary aldosteronism [Note 1].
Familial dexamethasone-suppressible primary aldosteronism is an uncommon variant of primary

aldosteronism. Usual treatment is low-dose dexamethasone, spironolactone or amiloride.
Note 1: See the Therapeutic Goods Administration website for current information.
Key references
Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, et al. The management of primary
aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J Clin
Endocrinol Metab 2016;101(5):1889–916.
Mulatero P, Rabbia F, Milan A, Paglieri C, Morello F, Chiandussi L, et al. Drug effects on aldosterone/plasma renin
activity ratio in primary aldosteronism. Hypertension 2002;40(6):897–902.
Stowasser M, Taylor PJ, Pimenta E, Ahmed AH, Gordon RD. Laboratory investigation of primary aldosteronism.
Clin Biochem Rev 2010;31(2):39–56.
Cushing syndrome
Cushing syndrome
Cushing syndrome refers to the signs and symptoms that result from excess cortisol. These include central
obesity, facial puffiness or roundness, peripheral oedema, thinning of the skin, and weakness, as well as
complications such as diabetes, elevated blood pressure, dyslipidaemia and osteoporosis. In children, cortisol
excess can also cause growth failure and delay of maturation (except in children with coincident androgen
excess).
Cushing syndrome can be caused by:
exogenous administration of glucocorticoids (most common cause in children)

endogenous production of cortisol by an adrenal adenoma or carcinoma
bilateral nodular adrenal hyperplasia (rare)
overstimulation of both adrenal glands by excess adrenocorticotrophic hormone (ACTH) production
from:
a pituitary adenoma (Cushing disease)
an ectopic ACTH-producing tumour.
Initial screening tests for Cushing syndrome include the 1 mg overnight dexamethasone suppression test, and
measurements of free cortisol (24-hour urinary cortisol and late-night salivary cortisol). Some drugs can cause
a false-positive result for Cushing syndrome on the 1 mg overnight dexamethasone suppression test; see Table
19.8.
Drugs that can cause a false-positive result for Cushing syndrome on the 1 mg overnight
dexamethasone suppression test (Table 19.8)
Drug Mechanism of effect

Oestrogen-containing preparations (eg oral oestrogen stimulates cortisol binding globulin,
contraceptive pill, menopausal hormone therapy) causing increased total cortisol concentration
[NB1]
cytochrome P450 3A4 (CYP3A4) inducers (eg increased hepatic clearance of dexamethasone
rifampicin, carbamazepine, phenytoin,
phenobarbitone, bosentan, modafinil, St. John’s wort,
efavirenz, enzalutamide, mitotane)
NB1: Oestrogen-containing preparations do not interfere with measurements of free cortisol (24-hour urinary cortisol or late-night salivary
cortisol).
Adrenal and pituitary tumours are treated by surgical removal. Pituitary tumours can usually be removed
transsphenoidally. A unilateral adrenal adenoma can cause suppression of the adjacent adrenal gland, so
following successful surgery to remove an adrenal tumour, or an ACTH-producing pituitary adenoma, the
patient will be transiently glucocorticoid deficient. Use glucocorticoid replacement until the pituitary–adrenal
axis recovers (typically several months, and up to 1 year), then gradually withdraw the glucocorticoid.
Mineralocorticoid replacement is not required.
Pharmacological blockade of adrenal corticosteroid production is used if:
the source of ACTH excess is unclear

preoperative control of cortisol excess is required
surgical resection has been unsuccessful.
Pharmacological blockade should be managed in a specialist centre with experience in managing Cushing
syndrome.
Key references
Cushing syndrome
Lodish M, Dunn SV, Sinaii N, Keil MF, Stratakis CA. Recovery of the hypothalamic-pituitary-adrenal axis in
children and adolescents after surgical cure of Cushing's disease. J Clin Endocrinol Metab 2012;97(5):1483–91.
Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, et al. The diagnosis of Cushing's
syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2008;93(5):1526–40.
Phaeochromocytoma
Introduction to phaeochromocytoma
Phaeochromocytoma is an adrenomedullary tumour that produces catecholamines. It often presents with features
of catecholamine excess such as paroxysmal hypertension, with episodes of headache, palpitations and sweating.
However, the presentation is highly variable, and many phaeochromocytomas are identified on biochemical
screening. Up to 5% of patients with incidentally discovered adrenal masses (‘incidentalomas’) have
phaeochromocytoma. Most catecholamine-secreting tumours are in the adrenal gland, but approximately 10% are
extra-adrenal (paragangliomas). Secretory paragangliomas are usually found in the chest, abdomen and pelvis,
while head and neck paragangliomas are usually nonsecretory.
The recommended screening test for phaeochromocytoma is plasma free metanephrines and normetanephrines, or
urine total metanephrines. Some drugs can cause a false-positive result for phaeochromocytoma on these tests; see
Table 19.9. Metanephrine testing can be performed in patients taking these drugs, but expert advice is
recommended to interpret the results.
Drugs that can cause a false-positive result for phaeochromocytoma on metanephrine testing
(Table 19.9)
Drug class Mechanism of effect

tricyclic antidepressants
inhibition of noradrenaline reuptake and increased normetanephrine
noradrenaline reuptake inhibitors
concentration
serotonin–norepinephrine reuptake inhibitors
increased metabolism of catecholamines to metanephrines and
monoamine oxidase inhibitors
increased normetanephrine and metanephrine concentrations
increased catecholamine release and increased normetanephrine and
indirect sympathomimetics
metanephrine concentrations
alpha and beta blockers blockade of adrenoceptors with compensatory increased
noradrenaline production and increased normetanephrine
tetracyclic antidepressants concentration
If a patient is diagnosed with phaeochromocytoma, take a family history for hypertension, stroke, sudden death,
and head and neck tumours (possible paragangliomas). Genetic testing is recommended in patients presenting with
phaeochromocytoma or paraganglioma regardless of family history—about 30% have a genetic mutation.
Management of phaeochromocytoma
For management of phaeochromocytoma in children, seek specialist advice.
Phaeochromocytoma in adults is treated by surgical removal. Once the diagnosis is confirmed, start drug therapy to
control blood pressure and to ensure alpha-adrenergic blockade before surgery. This minimises the risk of a
hypertensive crisis during surgery, as well as postoperative hypotension. Drug therapy is also appropriate if
surgery is contraindicated. For management of a hypertensive crisis associated with phaeochromocytoma, see here.
Treatment as an outpatient for at least 2 weeks is usually required to achieve adequate preoperative control.
Phenoxybenzamine, a noncompetitive alpha-adrenergic blocker, has traditionally been preferred to competitive
blockers such as prazosin, which can be displaced from alpha receptors by a rise in concentration of endogenous
catecholamines. However, some studies have shown similar perioperative outcomes with either class of drug. Use:
1 phenoxybenzamine 10 mg orally, twice daily initially. Increase the dose by 10 mg every 2

to 3 days to a target blood pressure of 120/80 mmHg with 20/10 mmHg postural drop.
Usual daily dose 1 mg/kg in 2 or 3 divided doses
OR
2 prazosin 0.5 mg orally, twice daily initially. Gradually increase the dose to 2 to 5 mg, 2 or
3 times daily. Increase the dose to a target blood pressure of 120/80 mmHg with 20/10
mmHg postural drop.
Alpha-adrenergic blockade can be considered adequate when:
episodic symptoms resolve

blood pressure reduces to the desired target
postural drop is at least 20/10 mmHg (major symptomatic postural hypotension indicates overtreatment).
Reflex tachycardia is common with alpha-adrenergic blockade, and a beta blocker is usually required to control
heart rate. Do not start a beta blocker before establishing alpha blockade. Use of a beta blocker in a patient without
adequate alpha-adrenergic blockade is contraindicated in a patient with phaeochromocytoma; unopposed alpha
receptor–mediated vasoconstriction can cause an extreme rise in blood pressure.
Do not start beta blockade in a patient with phaeochromocytoma until alpha blockade has been established.
If beta-blocker therapy is required, use:
1 atenolol 50 mg orally, twice daily initially. Increase the dose as required to a target heart
rate of 60 beats per minute. Maximum dose 100 mg twice daily
OR
1 bisoprolol 2.5 mg orally, twice daily initially. Increase the dose as required to a target
heart rate of 60 beats per minute. Maximum dose 5 mg twice daily
OR
1 metoprolol 50 mg orally, twice daily initially. Increase the dose as required to a target
heart rate of 60 beats per minute. Maximum dose 100 mg twice daily.
Key references
Introduction to phaeochromocytoma
Davison AS, Jones DM, Ruthven S, Helliwell T, Shore SL. Clinical evaluation and treatment of phaeochromocytoma.
Ann Clin Biochem 2018;55(1):34–48.
Eisenhofer G, Goldstein DS, Walther MM, Friberg P, Lenders JW, Keiser HR, et al. Biochemical diagnosis of
pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab 2003;88(6):2656–
66.
Eisenhofer G, Peitzsch M. Laboratory evaluation of pheochromocytoma and paraganglioma. Clin Chem

2014;60(12):1486–99.
Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al. Pheochromocytoma and
paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2014;99(6):1915–42.
Neary NM, King KS, Pacak K. Drugs and pheochromocytoma-don't be fooled by every elevated metanephrine. N Engl
J Med 2011;364(23):2268–70.
Whiting MJ, Doogue MP. Advances in biochemical screening for phaeochromocytoma using biogenic amines. Clin
Biochem Rev 2009;30(1):3–17.
Management of phaechromocytoma
Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al. Pheochromocytoma and
paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2014;99(6):1915–42.
Neary NM, King KS, Pacak K. Drugs and pheochromocytoma-don't be fooled by every elevated metanephrine. N Engl
J Med 2011;364(23):2268–70.
Randle RW, Balentine CJ, Pitt SC, Schneider DF, Sippel RS. Selective versus non-selective alpha-blockade prior to
laparoscopic adrenalectomy for pheochromocytoma. Ann Surg Oncol 2017;24(1):244–50.
Weingarten TN, Cata JP, O'Hara JF, Prybilla DJ, Pike TL, Thompson GB, et al. Comparison of two preoperative
medical management strategies for laparoscopic resection of pheochromocytoma. Urology 2010;76(2):508 e6–11.
Introduction to pituitary disorders
The hormones secreted by the anterior pituitary gland are:
adrenocorticotrophic hormone (ACTH)

thyroid stimulating hormone (TSH)
growth hormone
prolactin
follicle stimulating hormone
luteinising hormone.
The hormones secreted by the posterior pituitary gland are:
arginine vasopressin (also known as antidiuretic hormone)

oxytocin.
Pituitary disorders are most commonly caused by sellar or parasellar masses, the majority of which are
pituitary adenomas. Refer patients with a sellar or parasellar mass to an endocrinologist for a differential
diagnosis, and assessment of pituitary function.
Other causes of pituitary disorders include surgery, radiation, infection, trauma, congenital defects and certain
drugs. A disorder of the hypothalamus can cause a secondary pituitary disorder. In children, craniofacial
dysmorphic features and eye anomalies (especially midline clefts and optic nerve hypoplasia) suggest
problems with hypothalamic–pituitary development.
The signs and symptoms of a pituitary disorder can be related to an excess or insufficient secretion of
pituitary hormones, as well as pressure effects of a mass (eg headache, visual disturbances). The onset can be
acute or insidious.
The resilience of the individual pituitary cell types to the various causes of pituitary disorders varies. In
hypopituitarism related to pituitary compression, the order of diminished pituitary hormone reserve is usually
growth hormone, follicle stimulating hormone, luteinising hormone, thyroid stimulating hormone then
adrenocorticotrophic hormone. Prolactin deficiency is rare, except in patients with complete pituitary
disruption or genetic syndromes. Prolactin secretion is under tonic inhibitory control, so any disruption
typically causes hyperprolactinaemia.
Management of pituitary disorders depends on the aetiology and severity of the disorder, and should usually
be determined by a specialist.
For a pituitary mass causing altered hormone secretion or pressure effects, transsphenoidal surgery is usually
indicated; craniotomy is rarely indicated. Nonfunctioning adenomas can often be observed without
intervention if they are not a threat to vision and if pituitary function is normal. Some disorders, such as
prolactinoma, are typically managed with drug therapy.
For a pituitary disorder causing hormone deficiency, replacement therapy can be required short term (eg
before surgical correction), or indefinitely. Some deficiencies do not require immediate intervention, but
prompt replacement therapy is required for:
cortisol deficiency (caused by adrenocorticotrophic hormone deficiency)

thyroid hormone deficiency (caused by thyroid stimulating hormone deficiency)
diabetes insipidus (caused by arginine vasopressin deficiency).
Key references
Kim SY. Diagnosis and treatment of hypopituitarism. Endocrinol Metab (Seoul) 2015;30(4):443–55.
Hypopituitarism
Overview of hypopituitarism
Hypopituitarism refers to a deficiency of pituitary hormones. For a list of hormones secreted by the pituitary gland,
and information about common aetiologies of pituitary disorders, see Introduction to pituitary disorders.
Hypopituitarism typically has nonspecific symptoms and an insidious onset. Acute hypopituitarism can occur if
hormone deficiency remains untreated. In adults, symptoms of hypopituitarism include:
amenorrhoea
sexual dysfunction
fatigue
depression
altered mental state
cold intolerance
postural light-headedness.
Physical signs of hypopituitarism in adults include:
marked pallor
loss or lack of body hair
fine wrinkling of the face
delay in return of reflexes
testicular atrophy
orthostatic hypotension.
The symptoms and signs of hypopituitarism in children are different to those in adults, and depend on the age at
presentation; they include:
hypoglycaemia—due to combined adrenocorticotrophic hormone (ACTH) and growth hormone deficiency

prolonged neonatal jaundice (giant-cell hepatitis)
micropenis
undescended testes in infancy
growth failure
delayed puberty.
Biochemical findings suggestive of hypopituitarism include:
low serum thyroxine (T4) concentration in the absence of elevated serum thyroid stimulating hormone
(TSH) concentration
in adults, low serum oestrogen or androgen concentrations without elevated serum luteinising hormone or
follicle stimulating hormone concentration.
In adults, hypopituitarism is commonly caused by a pituitary adenoma. The clinical history can be useful to
identify hypopituitarism due to other causes—prior cranial radiotherapy increases the risk of hypopituitarism,
often occurring years after radiotherapy. Head injury, subarachnoid haemorrhage and major postpartum
haemorrhage can all precipitate hypopituitarism, for which the diagnosis is sometimes initially missed.
Genetic causes of hypopituitarism are usually detected during childhood. Hypopituitarism in a child can also occur
following surgery or radiotherapy.
Chronic hypopituitarism
Treatment of chronic hypopituitarism aims to correct hormone deficiency. Specialist management is recommended.
Glucocorticoid replacement and thyroid hormone replacement are usually required indefinitely. Gonadal hormone
replacement is indicated indefinitely in men, and at least up to the age of 50 years in women. Growth hormone
replacement and arginine vasopressin replacement are used on an individual basis.
Adults with a congenital cause of hypopituitarism require similar management to those with acquired
hypopituitarism, although they tend to have more marked hormone deficiency, as patients with acquired
hypopituitarism often retain some basal hormone secretion.
A woman with hypopituitarism who is pregnant or planning pregnancy should be referred to an endocrinologist for
specialist antenatal care, including serial ultrasound for fetal growth assessment during pregnancy.
Glucocorticoid replacement in hypopituitarism

For patients with adrenal insufficiency secondary to hypopituitarism, the adrenal hormone cortisol is replaced,
rather than the pituitary hormone, adrenocorticotrophic hormone (ACTH). Lifelong glucocorticoid replacement is
needed for patients with ACTH deficiency.
The principles of glucocorticoid replacement in hypopituitarism are the same as for primary adrenal insufficiency,
although patients with hypopituitarism often have a lower dose requirement. For detail about glucocorticoid
replacement for adrenal insufficiency, see here.
Patients with adrenal insufficiency secondary to hypopituitarism do not require mineralocorticoid replacement
because aldosterone secretion is principally controlled by the renin–angiotensin system, not by ACTH.
Thyroid hormone replacement in hypopituitarism

For patients with hypothyroidism secondary to hypopituitarism, the thyroid hormone thyroxine (T4) is replaced
rather than the pituitary hormone, thyroid stimulating hormone (TSH). Lifelong thyroid replacement therapy is
needed for patients with TSH deficiency.
Do not start thyroid replacement therapy before excluding or correcting coexisting glucocorticoid deficiency—
levothyroxine increases the clearance of cortisol, and can precipitate adrenal crisis in a patient with low
glucocorticoid reserve.
To avoid adrenal crisis, do not start thyroxine replacement therapy in hypopituitarism before correcting coexisting glucocorticoid
deficiency.
The principles of initial replacement of T4 are the same as those in primary hypothyroidism, but the dose of
levothyroxine must be adjusted based on clinical features and serum T4 concentration, not serum TSH
concentration. A low serum TSH concentration is an expected finding in hypothyroidism secondary to
hypopituitarism, and is not a basis for reducing the levothyroxine dose. Aim for a serum T4 concentration in the
upper half of the reference range. For doses and information about starting thyroxine replacement therapy in
adults, see here, and for children, see here.
Gonadal hormone replacement in hypopituitarism

Hypogonadism is common in patients with hypopituitarism. Replacement therapy is required to restore muscle,
bone and sexual function. The target gland hormones are replaced, rather than the pituitary hormone (with the
exception of gonadotrophin therapy for induction of fertility). In men, gonadal hormone replacement is indicated
indefinitely. In women, it is indicated at least up to the age of 50 years, after which the need for continued therapy
can be re-assessed on an individual basis.
Hormone replacement therapy in premenopausal women with hypopituitarism constitutes physiological

replacement, and has not been associated with the adverse effects seen in postmenopausal women (eg breast
cancer).
Transdermal oestrogen has a lower risk of venous thromboembolism than oral oestrogen. It also preserves growth
hormone sensitivity compared with oral oestrogen, allowing the use of a lower dose of somatropin to treat
coexisting growth hormone deficiency.
For detailed information about gonadal hormone replacement therapy, see Female hypogonadism and Male
hypogonadism.
Growth hormone replacement in hypopituitarism

For information about short stature and growth hormone deficiency in children, see here.
The diagnosis of growth hormone deficiency may require testing in a specialist endocrinology unit. For a patient
with fewer than three pituitary hormone deficiencies, but with risk factors for growth hormone deficiency (eg
pituitary lesion, head injury, subarachnoid haemorrhage) and symptoms suggestive of growth hormone deficiency,
testing is required for diagnosis. The gold-standard test is the insulin tolerance test; the glucagon stimulation test
and arginine stimulation test are suitable alternatives. For a patient with three or more pituitary hormone
deficiencies (eg thyroid, adrenal and gonadal deficiencies) and a low plasma insulin-like growth factor 1 (IGF-1)
concentration, testing is not necessary (although is required to access treatment on the Pharmaceutical Benefits
Scheme [PBS]).
In an adult with growth hormone deficiency, somatropin (recombinant human growth hormone) can improve body
composition, bone density and sense of wellbeing, and can possibly reduce long-term cardiovascular disease risk.
Somatropin is accessible through the PBS for symptomatic adult growth hormone deficiency via the Australian
growth hormone program [Note 1]. Its use is limited by strict eligibility criteria, and it can only be started by a
specialist.
For growth hormone replacement therapy in an adult, use:
somatropin 0.2 to 0.4 mg subcutaneously, daily. Adjust dose every 2 to 3 months

according to plasma insulin-like growth factor 1 concentration.
Titrate the somatropin dose to achieve a plasma insulin-like growth factor 1 concentration in the middle of the age-
adjusted reference range.
Women typically need a higher somatropin dose than men to achieve a normal plasma insulin-like growth factor 1
concentration. Concomitant use of oral oestrogen therapy (eg for coexisting hypogonadism) decreases sensitivity
to growth hormone, increasing the dose requirement further. Encourage women taking oral oestrogen to switch to a
transdermal oestrogen preparation, which does not affect growth hormone sensitivity.
No data are available to indicate that growth hormone therapy is beneficial or safe in the management of normal
ageing without proven growth hormone deficiency. Use of growth hormone therapy in this setting is not
recommended.
Note 1: See information about the growth hormone program on the Department of Health website.
Arginine vasopressin replacement and diabetes insipidus in

hypopituitarism
Overview of diabetes insipidus
Diabetes insipidus is defined by a reduced reabsorption of water from the kidneys back into the circulation, leading
to polyuria, polydipsia and electrolyte imbalances (particularly hypernatraemia). If untreated, it can cause severe
dehydration and seizures. Diabetes insipidus can be caused by arginine vasopressin (AVP) deficiency due to
hypopituitarism (central diabetes insipidus), or by reduced sensitivity to arginine vasopressin in the kidneys
(nephrogenic diabetes insipidus).
Central diabetes insipidus most commonly occurs as a transient complication of pituitary surgery, although it can
be ongoing. Patients with uncomplicated pituitary adenomas rarely develop diabetes insipidus—its presence
without a history of pituitary surgery (or other acute cause such as head injury or stroke) suggests a sellar or
parasellar mass other than an adenoma (eg craniopharyngioma, metastatic malignancy, germinoma, inflammatory
disorder such as lymphocytic hypophysitis or Langerhans cell histiocytosis).
Refer patients with new-onset diabetes insipidus without an obvious precipitant to an endocrinologist for a water
deprivation test to confirm the diagnosis. A water deprivation test involves measurement of the response of plasma
and urine osmolality to desmopressin during closely supervised water deprivation. The urine osmolality will
increase in response to desmopressin if the patient has central diabetes insipidus, but not nephrogenic diabetes
insipidus.
New-onset diabetes insipidus with an obvious acute precipitant (eg head injury, pituitary surgery) does not require
a water deprivation test to confirm the diagnosis.
Management of chronic diabetes insipidus

Diabetes insipidus causing mild polyuria (up to 3 litres per day) can safely be left untreated, provided the patient
has ready access to water.
Diabetes insipidus causing moderate to severe polyuria can cause hypernatraemia. Mild hypernatraemia can
usually be managed with increased water intake (see here for more information about management of
hypernatraemia if required).
For ongoing management of polyuria, desmopressin (a synthetic analogue of arginine vasopressin) may be
required. To minimise the risk of hyponatraemia associated with desmopressin, use the minimum effective dose
required to control polyuria. Advice from an endocrinologist may be necessary to guide management decisions.
In adults, oral desmopressin is preferred over intranasal desmopressin, as it is less likely to cause symptomatic
hyponatraemia. For arginine vasopressin replacement in an adult, use:
1 desmopressin 100 micrograms orally, 2 to 3 times daily. Adjust the dose according to
response (symptoms and electrolytes). Maintenance dose is usually between 100 and 200
micrograms orally, 2 to 3 times daily
OR
2 desmopressin 5 to 10 micrograms intranasally, once or twice daily. Adjust the dose

according to response (symptoms and electrolytes). Maintenance dose is usually between
10 and 20 micrograms, once or twice daily.
During pregnancy, the desmopressin dose usually needs to be increased because the clearance of arginine
vasopressin increases.
Treatment of central diabetes insipidus in neonates, infants and children is difficult, and desmopressin should only
be started and adjusted by a specialist. For arginine vasopressin replacement in children, a reasonable regimen is:
1 desmopressin intranasally
child between 1 month and 2 years: 2.5 to 5 micrograms, once or twice daily, adjusted
according to response (symptoms and electrolytes)
child older than 2 years: 5 to 20 micrograms, once or twice daily, adjusted according to
response (symptoms and electrolytes)
OR
1 desmopressin orally
child between 1 month and 2 years: 10 micrograms, 2 to 3 times daily, adjusted according
to response (symptoms and electrolytes)
child older than 2 years: 50 to 100 micrograms, 2 to 3 times daily, adjusted according to
response (symptoms and electrolytes).
Intranasal desmopressin solution can be given orally if small doses are needed for infants. Hydrochlorothiazide
and infant formula with a low renal solute load can also be used in infants under specialist management.
The desmopressin intranasal solution is delivered by a tube (rhinyle) or spray. The tube delivers fractional doses
from 5 micrograms upwards; the spray delivers a fixed 10 microgram dose. For doses below 5 micrograms,
dilution by a paediatric pharmacist is required. The dose conversion between the nasal and oral formulations is not
clear. One 10 microgram nasal spray may equate to 400 micrograms of the tablet formulation. The dose should be
retitrated if switching between formulations.
Patients with adequate thirst perception should be instructed to drink to thirst. Patients without adequate thirst
perception require a fluid intake plan, developed by an endocrinologist, with consideration of factors such as
gender, body mass, and climate (eg temperature, humidity).
Patients with adequate thirst perception should be instructed to drink to thirst; other patients require a fluid intake plan.
Management of acute diabetes insipidus
For acute diabetes insipidus (eg after pituitary or hypothalamic surgery, after head injury), use parenteral
desmopressin or argipressin once the diagnosis has been confirmed. If urine output is high (eg above 250 mL/hour
for more than 2 consecutive hours), measure serum sodium concentration and urine and plasma osmolality before
starting treatment. Diabetes insipidus following an acute cause is commonly transient, often only requiring a single
dose of desmopressin or argipressin therapy. The dose can be repeated if polyuria recurs, and depending on
electrolytes and osmolality.
To treat acute diabetes insipidus in an adult, use:
1 desmopressin 1 to 2 micrograms intramuscularly or intravenously. Repeat the dose as

required, based on urine output and osmolality, usually 12- to 18-hourly
OR
1 argipressin 5 to 10 units subcutaneously or intramuscularly. Repeat the dose as required,
based on urine output and osmolality, usually 6- to 8-hourly.
For a child, seek specialist advice.
Increasing the desmopressin dose increases the duration of its effect on water excretion, rather than the intensity of
effect.
Argipressin has a shorter duration of action than desmopressin, so may be preferred in acute diabetes insipidus to
reduce the risk of iatrogenic hyponatraemia. Intravenous administration of argipressin is not recommended,
because it can cause pressor effects.
Using intravenous fluids during desmopressin or argipressin therapy can lead to hyponatraemia resulting from
impaired water excretion. Hyponatraemia can be avoided by ensuring that fluid intake does not exceed urine output
in each 6- or 8-hour period.
Acute hypopituitarism
Management of acute hypopituitarism
Acute hypopituitarism can be precipitated by intercurrent illness (eg vomiting, dehydration), infection or trauma in
patients with hypopituitarism. Other causes of acute hypopituitarism include acute head injury, Sheehan syndrome
(pituitary infarction associated with peripartum blood loss) and pituitary apoplexy.
Common presenting features of acute hypopituitarism include:
altered mental state

orthostatic hypotension
fever
hyponatraemia
hypoglycaemia.
Collect samples for measuring plasma glucose and serum electrolyte concentrations before starting treatment. For
patients with severe signs or symptoms, start glucocorticoid replacement without waiting for laboratory results.
For adults, use:
hydrocortisone 100 mg intravenously, then 50 mg every 6 hours until stable and tolerating
oral intake.
Acute hypopituitarism is rare in children. For a neonate or child within the normal weight range for their age [Note
2], use:
hydrocortisone
neonate or child up to 6 weeks: 25 mg intravenously or intramuscularly, initially, then 5 to
10 mg intravenously or intramuscularly, 6-hourly until stable and tolerating oral intake
child 6 weeks to 3 years: 25 mg intravenously or intramuscularly, initially, then 10 mg
child 3 to 7 years: 50 mg intravenously or intramuscularly, initially, then 12.5 mg
child 7 to 12 years: 50 mg intravenously or intramuscularly, initially, then 25 mg
intravenously or intramuscularly, 6-hourly until stable and tolerating oral intake.
hydrocortisone 50 to 75 mg/m2 intravenously or intramuscularly, initially, then 12.5 to

18.75 mg/m2 intravenously or intramuscularly, 6-hourly until stable and tolerating oral
intake [Note 3].
Switch to oral therapy when oral intake is tolerated. For patients with a pre-existing diagnosis of hypopituitarism,
reduce the dose to the usual maintenance dose over 2 to 3 days (see glucocorticoid replacement for information
about maintenance dosing). Patients without a pre-existing diagnosis should be assessed to establish the cause and
guide further management.
Fluid replacement with intravenous sodium chloride 0.9%, and correction of hypoglycaemia (if present) are
important aspects of management. Severe hyponatraemia can also occur, usually as a consequence of
glucocorticoid deficiency; see Hyponatraemia for management advice.
Pituitary apoplexy
Pituitary apoplexy is a syndrome caused by haemorrhage or infarction of the pituitary gland, usually affecting a
pituitary adenoma. Precipitating factors include high blood pressure, major surgery, pregnancy and head injury.
The syndrome is associated with rapid onset of:
severe headache (the presentation may be confused with a subarachnoid haemorrhage)

neck stiffness
visual field defect
diplopia from cranial nerve palsies
hypopituitarism (adrenocorticotrophic hormone [ACTH] deficiency is the most common deficiency).
Patients should be referred at diagnosis to a multidisciplinary team including an endocrinologist and a

neurosurgeon.
If pituitary apoplexy has caused visual loss, surgical decompression is often required—it should be performed
within 8 days of onset to avoid irreversible visual loss. Urgent neurosurgical management is rarely necessary.
Visual defects (visual loss or diplopia) resulting from apoplexy involving a prolactinoma can respond to acute
dopamine agonist therapy (see Dopamine agonist therapy for prolactinoma). If visual defects do not resolve,
surgical decompression can still be undertaken within 8 days of onset.
Diplopia from compression of the upper cranial nerves passing through the cavernous sinus often resolves
spontaneously and is not an indication for immediate surgery.
For acute glucocorticoid replacement in a patient with pituitary apoplexy associated with a pituitary adenoma,
hydrocortisone is preferred. Use:
hydrocortisone 100 mg intravenously as an initial dose
FOLLOWED BY
1 hydrocortisone 50 mg intravenously or intramuscularly, 6-hourly
OR
1 hydrocortisone 2 to 4 mg/hour by intravenous infusion.
Dexamethasone can be used to reduce oedema in pituitary apoplexy. Use:
dexamethasone 4 mg intravenously, 6 to 12 hourly.
Key references
Hypopituitarism
Albani A, Ferrau F, Angileri FF, Esposito F, Granata F, Ferreri F, et al. Multidisciplinary management of pituitary
apoplexy. Int J Endocrinol 2016;2016:7951536.
Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, et al. Hormonal replacement in
hypopituitarism in adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2016;101(11):3888–
921.
Kim SY. Diagnosis and treatment of hypopituitarism. Endocrinol Metab (Seoul) 2015;30(4):443–55.
Littley MD, Shalet SM, Beardwell CG, Ahmed SR, Applegate G, Sutton ML. Hypopituitarism following external
radiotherapy for pituitary tumours in adults. Q J Med 1989;70(262):145–60.
Rajasekaran S, Vanderpump M, Baldeweg S, Drake W, Reddy N, Lanyon M, et al. UK guidelines for the management
of pituitary apoplexy. Clin Endocrinol (Oxf) 2011;74(1):9–20.
Pituitary adenomas
Overview of pituitary adenomas
Pituitary adenomas are the most common intracranial neoplasm, and make up the vast majority of sellar masses.
Pituitary adenomas can cause pressure effects, such as headaches and visual impairment. Clinically nonfunctioning
pituitary macroadenomas (10 mm or more in diameter) can also cause varying degrees of hypopituitarism, while
functioning adenomas present with features related to excess of a specific hormone (with or without pressure
effects). Functioning adenomas include:
prolactinomas—causing hyperprolactinaemia
growth hormone–secreting adenomas—causing acromegaly
adrenocorticotrophic hormone (ACTH)-secreting adenomas—causing Cushing disease.
With increased availability and frequency of neuroimaging, incidental discovery of pituitary adenomas is
becoming more common. Refer patients with a sellar or parasellar mass to an endocrinologist for a differential
diagnosis, and assessment of pituitary function.
Although uncommon, genetic mutations can play a role in pituitary adenomas. Genetic testing for multiple
endocrine neoplasia type 1 (MEN1) should be considered if the patient has coexisting primary
hyperparathyroidism or pancreatic neuroendocrine tumours.
Prolactinomas are the most common type of functioning adenomas; they are treated with drug therapy first line.
Most other functioning adenomas are managed by surgical removal by an experienced neurosurgeon. Treatment of
a nonfunctioning pituitary adenoma is not always necessary, depending on the size of the adenoma, the degree of
suprasellar extension, and the age and comorbidities of the patient. It may be appropriate to monitor a
nonfunctioning adenoma with serial magnetic resonance imaging (MRI) scans, intervening only if signs of
adenoma growth that threaten the optic apparatus appear, or if hypopituitarism develops.
Before surgery on any pituitary mass, coexisting hypopituitarism must be managed (see Chronic hypopituitarism).
During pregnancy, the high concentration of oestrogen induces growth of normal prolactin-secreting cells, leading
to pituitary enlargement. Although existing adenomas and other masses rarely enlarge symptomatically during
pregnancy, enlargement of the pituitary gland can precipitate or aggravate symptoms of an existing mass by
causing displacement. See also Prolactinoma during pregnancy.
Prolactinomas and hyperprolactinaemia

Overview
Prolactinomas are prolactin-secreting adenomas, which cause hyperprolactinaemia. In women, the main symptoms
of hyperprolactinaemia are menstrual disturbance, infertility and galactorrhoea; men can experience erectile
dysfunction and diminished libido. In children, hyperprolactinaemia can cause pubertal delay.
Most prolactinomas are less than 10 mm in diameter (microprolactinomas). Prolactinomas that are 10 mm or more
in diameter (macroprolactinomas) can cause pressure effects, such as headache and visual impairment, in addition
to hyperprolactinaemia. Males tend to have larger and more aggressive prolactinomas than females.
A pregnancy test is mandatory in women of reproductive age with amenorrhoea and hyperprolactinaemia.
Prolactinomas (and other pituitary adenomas) can occasionally expand during pregnancy, and the risks associated
with expansion must be carefully assessed before attempting to conceive. See Prolactinomas during pregnancy.
Prolactinomas are usually treated with dopamine agonist therapy.
Serum prolactin concentration can be elevated by mechanisms other than prolactinomas (see Box 19.2).
Causes of hyperprolactinaemia (Box 19.2) [NB1]
Hyperprolactinaemia can be caused by:
a prolactinoma
disruption of the pituitary stalk (trauma, surgery, tumour)
pregnancy
a hypothalamic disorder, including:
tumour (craniopharyngioma, glioma)
infiltration (sarcoidosis)
radiotherapy
certain drugs, including:
antipsychotics [NB2]
methyldopa
metoclopramide
domperidone
opioids
selective serotonin reuptake inhibitors (SSRIs)
tricyclic antidepressants
cannabis
oral contraceptive pills
a systemic disorder, including:
hypothyroidism
kidney disease
liver failure
epileptic seizures
a neurogenic cause, including:
breast stimulation and lactation
chest wall trauma or lesion
stress
pseudohyperprolactinaemia.
NB1: Hyperprolactinaemia is occasionally idiopathic, with no pituitary adenoma or other cause apparent.
NB2: For antipsychotic-induced hyperprolactinaemia, aripiprazole can be useful; see Management of antipsychotic adverse effects for more
information.
Dopamine agonist therapy for a prolactinoma
The goals of dopamine agonist therapy for a prolactinoma are to normalise the serum prolactin concentration,
restore normal gonadal function, and reduce or stabilise prolactinoma size. Use:
1 cabergoline 0.5 mg orally, weekly in one or two doses, increasing according to response
by 0.5 mg in monthly intervals, up to a maximum total weekly dose of 3 mg
OR
2 bromocriptine 1.25 mg orally, daily at night, increasing according to response by 1.25 mg

every 3 to 7 days up to a maximum of 15 mg daily in 2 or 3 divided doses
OR
3 quinagolide 25 micrograms orally, daily at night for 3 days, then 50 micrograms daily at
night for 3 days, then 75 micrograms daily at night, then increase the dose according to
response at intervals of at least 1 week, up to a maximum of 300 micrograms once daily.
Tailor the dose according to the prolactin concentration and pituitary imaging.
In women of reproductive age, ovulation can be restored soon after starting dopamine agonist therapy. Provide
advice on contraception if pregnancy is not desired. In some patients, restoring gonadal function can take several
months, particularly for males with larger or more resistant prolactinomas.
Allow around 6 months of therapy to determine if the normalisation of serum prolactin concentration has restored
adequate endogenous testosterone secretion in men, or menstrual cyclicity in women. If hypogonadism persists,
replacement testosterone or oestrogen/progestin therapy is indicated; see Male hypogonadism and Female
hypogonadism.
Consider a trial of drug withdrawal after about 3 years if:
symptoms have resolved

the size of the prolactinoma has reduced markedly
the serum prolactin concentration is well controlled with cabergoline 0.5 mg once a week (or a similar dose
of another dopamine agonist).
If relapse occurs in a woman with a microprolactinoma, restart treatment and continue until their natural
menopause. If relapse occurs in a woman with a macroprolactinoma, or in a man, restart treatment and continue
lifelong.
Other therapy for a prolactinoma
The combined oral contraceptive pill can be used instead of dopamine agonist therapy for a woman with a
microprolactinoma who does not desire fertility and who does not have distressing symptoms (eg galactorrhoea).
The oestrogen provides skeletal protection against the effects of secondary amenorrhoea.
Pituitary surgery for prolactinomas is generally reserved for patients who cannot tolerate or are resistant to
dopamine agonists (ie require a high dose without complete biochemical control). It may also be useful in selected
cases, such as noninvasive adenomas in women desiring fertility. The majority of surgical studies show low rates
of postoperative biochemical remission.
Radiotherapy is reserved for prolactinomas that continue to expand despite surgical and drug therapy.
Radiotherapy usually arrests growth of a prolactinoma, but rarely normalises prolactin concentration.
Prolactinomas during pregnancy
During pregnancy, most prolactinomas remain stable and only require clinical monitoring; however, occasionally
they enlarge and cause symptoms. The risk of symptomatic enlargement depends on the size of the prolactinoma
before pregnancy. A microprolactinoma or small macroprolactinoma (eg contained within the sella) is unlikely to
expand symptomatically, particularly if it has previously been treated with surgery or radiotherapy; the risk is
around 3 to 5%. For a large macroprolactinoma, the risk of symptomatic enlargement is much higher—up to 30%
if the prolactinoma has not been previously treated with surgery or radiotherapy.
In a woman with a microprolactinoma or small macroprolactinoma who is taking dopamine agonist therapy,
stop therapy when pregnancy is confirmed. Although bromocriptine and cabergoline have not been associated with
miscarriage or congenital malformations, stopping therapy is reasonable because the risk of prolactinoma
enlargement in these patients is small. Quinagolide should not be used during pregnancy or prescribed to any
woman planning pregnancy.
If dopamine agonist therapy is stopped, assess the woman regularly throughout pregnancy for signs of
prolactinoma enlargement (eg headache, visual disturbance). Serum prolactin concentration does not reliably rise
with prolactinoma enlargement, so should not be used for monitoring. Formal assessment of visual fields is
recommended each trimester for a woman with a macroprolactinoma, but is not necessary for a woman with a
microprolactinoma. Magnetic resonance imaging (MRI) is only recommended if the patient becomes symptomatic.
If the patient has evidence of prolactinoma enlargement on MRI, treatment with a dopamine agonist can be
restarted. Bromocriptine is preferred during pregnancy; cabergoline is suitable second line (see Dopamine agonist
therapy for prolactinoma for doses).
For a woman with a large macroprolactinoma, provide counselling about the high risk of prolactinoma
enlargement during pregnancy. Surgical debulking before pregnancy greatly reduces this risk, but can affect
fertility. Specialist consultation before pregnancy is necessary. If a woman with a large macroprolactinoma
becomes pregnant, use bromocriptine therapy throughout the pregnancy. Surgery or early delivery may be
necessary if the prolactinoma does not respond to dopamine agonist therapy.
Prolactinomas during breastfeeding and postpartum
Women with a prolactinoma can safely breastfeed—no evidence suggests that suckling stimulates prolactinoma
growth.
If possible, delay starting or resuming dopamine agonist therapy in a woman who wishes to breastfeed, as it
suppresses lactation. If treatment cannot be delayed, and the woman is able to produce breastmilk, breastfeeding
may be continued with caution—monitor the infant for adverse effects such as drowsiness, insomnia, dry mouth or
constipation.
After pregnancy, the serum prolactin concentration can decrease or normalise; reduction in prolactinoma size can
also occur. Reassess serum prolactin concentration 2 months after cessation of breastfeeding, or, if not
breastfeeding, 2 months after delivery.
Normoprolactinaemic galactorrhoea
If a patient with galactorrhoea is found to have a normal serum prolactin concentration (ie normoprolactinaemic
galactorrhoea), further investigation (eg measurement of other hormones) is not required. If the symptoms do not
bother the patient, treatment is not necessary; for bothersome symptoms, a single dose of cabergoline is usually
effective. Use:
cabergoline 1 mg orally, as a single dose.
Acromegaly
Overview of acromegaly
Acromegaly is a rare condition caused by excessive growth hormone secretion by a pituitary adenoma. Clinical
features include:
acral overgrowth (enlarged extremities [eg nose, ears, jaw, hands, feet])
soft tissue changes
increased sweating
impaired glucose tolerance
neuropathy
arthritis
hypertension
cardiomyopathy
sleep apnoea
gigantism (children).
A diagnosis of acromegaly is confirmed by an increased serum growth hormone concentration that does not
suppress during an oral glucose tolerance test, and an elevated plasma insulin-like growth factor 1 (IGF-1)
concentration. An adenoma is usually identified with pituitary magnetic resonance imaging (MRI). Specialist
advice is required to confirm the diagnosis and to guide management.
The aim of therapy for acromegaly is to reduce the plasma insulin-like growth factor 1 concentration to within the
normal range for age and to lower the serum growth hormone concentration to less than 2.5 micrograms/L [Note
1]. Some studies show a further benefit in reducing serum growth hormone concentration to less than 1
microgram/L.
Transsphenoidal surgery is usually first-line management.
If growth hormone excess persists after surgery, or if a patient is unsuitable for surgery, drug therapy can be used
(see Drug therapy for acromegaly). Radiotherapy is an alternative option.
In addition to management of the adenoma, optimise management of cardiovascular disease risk factors. Good
blood pressure control is particularly important. A baseline echocardiogram should be done routinely, as well as a
sleep study to assess for sleep apnoea, if clinically indicated. A baseline colonoscopy is required, given the
increased risk of colonic neoplasia (polyps and carcinoma).
Note 1: Laboratories throughout Australia and New Zealand are adopting micrograms/L reporting for growth
hormone concentrations; 2.5 micrograms/L is equivalent to 7.5 × 10−3 international units/L.
Drug therapy for acromegaly
Somatostatin analogues for acromegaly
Somatostatin analogues are the treatment of choice for patients who are unsuitable for surgery or who did not
respond to surgery. They lower growth hormone secretion and reduce adenoma size in up to two-thirds of patients.
The starting dose of somatostatin analogue therapy depends on the individual patient and is determined by a
specialist. Subsequent dosing is titrated according to symptoms, and serum growth hormone and plasma insulin-
like growth factor 1 concentrations. An appropriate dose regimen is:
1 lanreotide modified-release injection (autogel) 60, 90 or 120 mg by deep subcutaneous

injection, every 4 weeks
if well controlled on 60 mg every 4 weeks, consider changing to 120 mg every 8 weeks
if well controlled on 90 mg every 4 weeks, consider changing to 120 mg every 6 weeks
OR
1 octreotide modified-release injection (LAR) 10, 20 or 30 mg by deep intramuscular

injection, every 4 weeks.
Pasireotide is an alternative somatostatin analogue. It is available on the Pharmaceutical Benefits Scheme (PBS)
for patients whose serum growth hormone and plasma insulin-like growth factor 1 concentrations did not
normalise with maximum dose lanreotide or octreotide therapy [Note 2]. It reduces serum growth hormone and
plasma insulin-like growth factor 1 concentrations, and shrinks adenoma size. The usual dosage regimen is:
pasireotide modified-release 40 mg by deep intramuscular injection, every 4 weeks. If

serum growth hormone or plasma insulin-like growth factor 1 concentrations have not
normalised after 3 months, increase to a maximum dose of 60 mg every 4 weeks.
Pasireotide can cause bradycardia and QT-interval prolongation; baseline electrocardiogram (ECG) is
recommended before starting therapy. Monitor pituitary and adrenal hormone concentrations during treatment with
pasireotide.
Note 2: See the Pharmaceutical Benefits Scheme website for current information.
Dopamine agonists for acromegaly
Dopamine agonists can reduce growth hormone secretion in up to 50% of patients with acromegaly. Adding a
dopamine agonist to a somatostatin analogue is useful if the somatostatin analogue alone does not completely
normalise serum growth hormone and plasma insulin-like growth factor 1 concentrations. Some studies suggest
that patients with prolactin and growth hormone co-secretion are more likely to respond to dopamine agonist
therapy than patients with only growth hormone secretion. However, dopamine agonist therapy may also be
effective in normoprolactinaemic patients. The usual dosage regimen is:
1 cabergoline 0.5 mg orally, twice weekly, increasing according to response up to a

maximum of 2 mg twice weekly
OR
2 bromocriptine 1.25 mg orally, daily at night, increasing according to response up to 5 to

30 mg orally, daily in 2 or 3 divided doses.
Pegvisomant for acromegaly
Pegvisomant, a growth hormone–receptor antagonist, is highly effective in normalising plasma insulin-like growth
factor 1 concentration. Cases of adenoma enlargement have been reported when it has been used as monotherapy;
however, a study of long-term safety with monotherapy showed low rates of enlargement [Note 3].
Pegvisomant monotherapy is available on the PBS for patients whose serum growth hormone and plasma insulin-
like growth factor 1 concentrations did not normalise with maximum dose somatostatin analogue therapy [Note 4].
Pegvisomant can also be used in combination with a somatostatin analogue, although at the time of writing this
combination is not subsidised by the PBS [Note 4]. Some studies show it can be given less frequently if used in
combination with a somatostatin analogue.
The usual dosage regimen is:
pegvisomant 80 mg subcutaneously as a loading dose under specialist supervision,

followed by 10 mg subcutaneously, daily, increasing by 5 mg every 4 to 6 weeks until
plasma insulin-like growth factor 1 concentration is normalised, up to a maximum of 30
mg daily.
Pegvisomant does not reduce serum growth hormone concentration so plasma insulin-like growth factor 1
concentration is used for monitoring instead.
Note 3: Freda PU, Gordon MB, Kelepouris N, Jonsson P, Koltowska-Haggstrom M, van der Lely AJ. Long-term
treatment with pegvisomant as monotherapy in patients with acromegaly: experience from ACROSTUDY.
Endocr Pract 2015;21(3):264-74. [URL]
Note 4: See the Pharmaceutical Benefits Scheme website for current information.
Cushing disease
Cushing disease refers to Cushing syndrome caused by an adrenocorticotrophic hormone (ACTH)-secreting
pituitary adenoma. Transsphenoidal removal of the adenoma is the optimal treatment for Cushing disease.
Following successful surgery, the patient will be transiently glucocorticoid deficient. Use glucocorticoid
replacement as for hypopituitarism until the pituitary–adrenal axis recovers (typically several months, and up to a
year), then gradually withdraw the glucocorticoid. Remission rates vary between 65 and 90% for microadenomas
and up to 65% for macroadenomas; up to 25% of patients who have initial remission will experience recurrence
within 10 years.
Radiotherapy can also be used to treat Cushing disease, but it can take several months to years to achieve
biochemical normalisation. Drug therapy to block cortisol production is used in the interim.
See also Cushing syndrome.
Key references
Prolactinomas and hyperprolactinaemia
Christin-Maitre S, Delemer B, Touraine P, Young J. Prolactinoma and estrogens: pregnancy, contraception and
hormonal replacement therapy. Ann Endocrinol (Paris) 2007;68(2-3):106–12.
Huang W, Molitch ME. Evaluation and management of galactorrhea. Am Fam Physician 2012;85(11):1073–80.
Karaca Z, Tanriverdi F, Unluhizarci K, Kelestimur F. Pregnancy and pituitary disorders. Eur J Endocrinol
2010;162(3):453–75.
Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, et al. Diagnosis and treatment of
hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96(2):273–88.
Molitch ME. Prolactinoma in pregnancy. Best Pract Res Clin Endocrinol Metab 2011;25(6):885–96.
Acromegaly
Beckers A. Does preoperative somatostatin analog treatment improve surgical cure rates in acromegaly? A new look
at an old question. J Clin Endocrinol Metab 2008;93(8):2975–7.
Cuevas-Ramos D, Fleseriu M. Pasireotide: a novel treatment for patients with acromegaly. Drug Des Devel Ther
2016;10:227–39.
Feenstra J, de Herder WW, ten Have SM, van den Beld AW, Feelders RA, Janssen JA, et al. Combined therapy with
somatostatin analogues and weekly pegvisomant in active acromegaly. Lancet 2005;365(9471):1644–6.
Freda PU, Gordon MB, Kelepouris N, Jonsson P, Koltowska-Haggstrom M, van der Lely AJ. Long-term treatment with
pegvisomant as monotherapy in patients with acromegaly: experience from ACROSTUDY. Endocr Pract
2015;21(3):264–74.
Karavitaki N, Turner HE, Adams CB, Cudlip S, Byrne JV, Fazal-Sanderson V, et al. Surgical debulking of pituitary
macroadenomas causing acromegaly improves control by lanreotide. Clin Endocrinol (Oxf) 2008;68(6):970–5.
Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK. American Association of Clinical
Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly: 2011 update.
Endocr Pract 2011;17(Suppl 4):1-44.
Pita-Gutierrez F, Pertega-Diaz S, Pita-Fernandez S, Pena L, Lugo G, Sangiao-Alvarellos S, et al. Place of

preoperative treatment of acromegaly with somatostatin analog on surgical outcome: a systematic review and meta-
analysis. PLoS One 2013;8(4):e61523.
Sandret L, Maison P, Chanson P. Place of cabergoline in acromegaly: a meta-analysis. J Clin Endocrinol Metab
2011;96(5):1327–35.
Cushing disease
Lodish M, Dunn SV, Sinaii N, Keil MF, Stratakis CA. Recovery of the hypothalamic-pituitary-adrenal axis in children
and adolescents after surgical cure of Cushing's disease. J Clin Endocrinol Metab 2012;97(5):1483–91.
Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, et al. The diagnosis of Cushing's
syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2008;93(5):1526–40.
Lymphocytic hypophysitis
Lymphocytic hypophysitis is a rare autoimmune disease characterised by inflammation of the pituitary gland
and sometimes the pituitary stalk. It can occur in association with other autoimmune disorders, including
immunoglobulin G4 (IgG4) disorders. It is often misdiagnosed as a pituitary adenoma. The typical
presentation is headache and hypopituitarism, particularly diabetes insipidus and adrenocorticotrophic
hormone (ACTH) deficiency (which can occur in isolation). Visual disturbance can also occur.
Lymphocytic hypophysitis is more common in pregnant women and the early postpartum period, although it
can occur in women at any time, as well as men and children.
Immune checkpoint inhibitors (eg ipilimumab, tremelimumab, pembrolizumab, nivolumab, pidilizumab),

which are used in cancer immunotherapy, can cause an autoimmune hypophysitis. Patients receiving immune
checkpoint inhibitor therapy who present with headache, fatigue and hyponatraemia should be investigated
for autoimmune hypophysitis with full biochemical assessment of pituitary function and pituitary magnetic
resonance imaging (MRI).
Urgently refer any patient with suspected lymphocytic hypophysitis to an endocrinologist.
Evidence to guide the management of lymphocytic hypophysitis is limited. Management involves

replacement for pituitary hormone deficiencies (see Hypopituitarism), and treatment for pressure effects (eg
severe headache, optic chiasm compression or other cranial nerve palsies). Spontaneous resolution of
pituitary enlargement and improved pituitary function have been reported in some patients receiving hormone
replacement and symptomatic management only.
Treatment with high-dose glucocorticoids can reduce the inflammatory process. It is important to measure
IgG4 concentration before starting glucocorticoid therapy. Relapse following initially successful
glucocorticoid treatment can be treated with a repeat course. An alternative immunosuppressant drug, such as
azathioprine, can be used instead of the repeat course of glucocorticoid treatment, or in combination with the
repeat course. Stereotactic radiotherapy can also be beneficial following relapse or unsuccessful
glucocorticoid therapy.
Surgery is indicated for patients with ongoing evidence of optic chiasm compression, or for histological
confirmation of the diagnosis in patients with an unresponsive lesion.
Key references
Angelousi A, Chatzellis E, Kaltsas G. New molecular, biological, and immunological agents inducing
hypophysitis. Neuroendocrinology 2018;106(1):89–100.
Faje A. Hypophysitis: evaluation and management. Clin Diabetes Endocrinol 2016;2:15.
Iglesias P. Cancer immunotherapy-induced endocrinopathies: clinical behavior and therapeutic approach. Eur J
Intern Med 2018;47:6–13.
Sznol M, Postow MA, Davies MJ, Pavlick AC, Plimack ER, Shaheen M, et al. Endocrine-related adverse events
associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev
2017;58:70–6.
Osteoporosis and minimal-trauma fracture
Introduction to osteoporosis and minimal-trauma fracture
Osteoporosis is characterised by low bone mineral density (BMD) and microarchitectural deterioration of bone
tissue, leading to bone fragility and increased fracture risk. Together with falls and older age, osteoporosis is an
important risk factor for minimal-trauma fracture (a fracture resulting from trauma no greater than a fall from a
standing height).
Common sites of minimal-trauma fracture include the vertebral bodies, distal radius, proximal humerus, pelvis and
proximal femur. Fractures of the fingers, toes, face and skull are usually not related to osteoporosis.
Minimal-trauma fractures remain a major cause of morbidity in Australia, and mortality is increased after minimal-
trauma fractures in adults older than 60 years. Prevention of fractures is important; fractures cause pain and
disability to the patient, and have a high health economic burden.
Consider osteoporosis in any patient older than 50 years who sustains a minimal-trauma fracture.
Although many effective treatments for osteoporosis are available, fewer than 20% of patients who present with a
minimal-trauma fracture are investigated for osteoporosis or treated to prevent secondary fracture. Consider
osteoporosis in any patient older than 50 years who sustains a minimal-trauma fracture. For assessment of bone
status, see here. The decision to start osteoporosis treatment is based on multiple factors, including fracture site,
BMD and the presence of other risk factors for fracture (see Considerations before treating osteoporosis,
Management of osteoporosis following minimal-trauma fracture and Management of osteoporosis in the absence
of fracture for treatment decisions).
For information about osteoporosis during pregnancy and breastfeeding, see here. For information about
osteoporosis and bone health in children, see here.
Assessing and interpreting bone status

Bone mineral density
Overview of bone mineral density
Measurement of bone mineral density (BMD) provides information about the severity of osteoporosis and the
effectiveness of treatment. BMD is measured by scanning the axial skeleton with dual energy X-ray
absorptiometry (DXA). BMD should be measured:
if the result will influence the decision to treat

as a baseline measurement before treatment.
In adults, BMD measurement at the total hip, lumbar spine or femoral neck give the best indication of fracture risk.
The total hip is the preferred site because total hip BMD has good precision (less affected by positioning) and is
less likely to be affected by factors that can interfere with BMD measurement. Spine BMD measurement can be
spuriously elevated by osteoarthritis, arterial calcification and vertebral fractures.
Forearm BMD can be measured if total hip or lumbar spine cannot be assessed or interpreted, in a patient with
hyperparathyroidism, and in obese patients who are over the weight limit for DXA machine. Measurement at other
sites (including Ward’s area [a specific region of the hip] and total body) should not be used to diagnose
osteoporosis.
Repeat BMD measurements should be performed on the same machine because BMD measurements are not
standardised between machines and facilities. Facilities providing DXA should adhere to international standards
[Note 1], and the DXA report should:
identify the skeletal site for each BMD measurement

contain a single diagnosis for the patient, rather than a different diagnosis for each site measured
for serial measurements, only report a change in BMD if it meets the ‘least significant change’ threshold
(specific to each facility).
Assessment of BMD with transmission ultrasound of bone or computed tomography (CT)-BMD is not routinely
recommended.
Note 1: Lewiecki EM, Binkley N, Morgan SL, Shuhart CR, Camargos BM, Carey JJ, et al. Best practices for dual-energy x-ray absorptiometry
measurement and reporting: International Society for Clinical Densitometry Guidance. J Clin Densitom 2016;19(2):127-40. [URL]
T-scores and Z-scores
The T-score is the number of standard deviations by which a patient’s BMD varies from the young adult mean for
their sex, as measured by DXA. Relative fracture risk approximately doubles for each standard deviation decrease
in T-score. The World Health Organization classifies low BMD according to T-score as either osteoporosis or
osteopenia (see Table 19.10); these definitions only apply to BMD measurements taken at the lumbar spine, total
hip or femoral neck.
Word Health Organization categorisation by T-score (Table 19.10)
T-score Interpretation
–1 or higher normal
between –1 and –2.5 osteopenia or low bone density
–2.5 or lower osteoporosis
The Z-score is the number of standard deviations a person’s BMD varies from the age- and sex-matched mean
BMD. A Z-score below –2.0 is below the expected range and warrants investigation for a secondary cause of low
bone density. Z-scores are recommended for reporting BMD in premenopausal women, men younger than 50
years, and children.
Other investigations in osteoporosis assessment

Plain X-rays can be used to identify fractures but not to diagnose osteoporosis.
Vertebral fractures are painless in 70% of cases, but may be suspected in patients with significant height loss (3 cm
or more) or kyphosis (curvature of the spine). X-rays can be used to confirm fracture in these patients.
Bone-turnover markers may be used by specialists to monitor osteoporosis treatment, but their routine use in
general practice is not yet recommended. The most commonly used bone turnover markers are:
serum fasting collagen type 1 cross-linked C-telopeptide (CTX), an indicator of bone resorption
fasting spot urine N-terminal telopeptide to creatinine ratio (uNTx/Cr), an indicator of bone resorption
serum fasting type 1 procollagen (N-terminal) (P1NP), an indicator of bone formation.
Risk factors for minimal-trauma fracture

Falls and low bone mineral density (BMD) are significant risk factors for minimal-trauma fracture. Most other risk
factors for minimal-trauma fracture contribute to falls risk or BMD loss. See Table 19.11 for a list of risk factors
for minimal-trauma fracture.
Women have a lower peak BMD than men and their BMD decreases in association with menopause, so they have
a higher lifetime risk of osteoporosis and fracture than men.
Age increases the incidence of minimal-trauma fractures at all sites; the incidence of proximal femoral fractures
increasing exponentially in elderly people.
Absolute fracture risk can be calculated using an online calculator (eg Fracture Risk Assessment Tool [FRAX],
Garvan Institute Fracture Risk Calculator). The role of absolute fracture risk calculators in practice is evolving;
they are particularly useful to identify patients at low fracture risk who do not require drug therapy.
Risk factors for minimal-trauma fracture (Table 19.11)
Nonmodifiable factors
previous minimal-trauma fracture
female sex
postmenopause
early menopause
late menarche
ageing
family history of osteoporosis

Modifiable factors
Falls and factors that increase the risk of falls, including:
balance disorder
visual impairment
muscle weakness and sarcopenia
sedating drugs
antihypertensive drugs
Drugs that affect bone homeostasis or density, including:
glucocorticoids
androgen deprivation therapy for prostatic cancer
aromatase inhibitors for breast cancer
excessive thyroid hormone replacement
long-term heparin
selective serotonin reuptake inhibitors
antiepileptic drugs, particularly hepatic enzyme inducers (modest effect)
thiazolidinediones (modest effect)
proton pump inhibitors (modest effect)
Lifestyle and nutrition factors, including:
smoking
hazardous alcohol consumption
physical inactivity
immobilisation
low calcium intake
vitamin D deficiency
low protein intake
Disorders that affect bone homeostasis or density, including:
endocrine disorders:
sex hormone deficiency
Cushing syndrome
hyperthyroidism
hyperparathyroidism
diabetes mellitus
malabsorption syndromes:
coeliac disease
gastric or bowel resection
bariatric surgery
chronic disorders (eg liver, kidney or cardiopulmonary diseases)
low body weight and weight loss, including anorexia nervosa
rheumatoid arthritis and other connective tissue diseases
haematological disorders (eg multiple myeloma, myeloproliferative disorders)
Prevention of minimal-trauma fracture

Overview of prevention of minimal-trauma fracture
Many people who experience a minimal-trauma fracture have modifiable risk factors. For primary and secondary
prevention of minimal-trauma fracture, address all modifiable risk factors, including preventing falls, optimising
the management of comorbidities, and minimising the use of drugs (if possible) that affect bone homeostasis or
density.
Advise and assist all patients at risk of minimal-trauma fracture to:
implement strategies to prevent falls

increase weight-bearing exercise and balance training
ensure adequate calcium intake
ensure vitamin D sufficiency
stop smoking
limit alcohol intake to two standard drinks per day
maintain ideal body weight.
For information about when to use drug therapy for primary or secondary prevention of minimal-trauma fracture,
see Management of osteoporosis following minimal-trauma fracture and Management of osteoporosis in the
absence of fracture, as well as Glucocorticoid-induced osteoporosis.
Preventing falls
Measures to prevent falls and thereby reduce the incidence and severity of fractures include:
improving vision
adjusting drug therapy if possible (eg drugs causing sedation, altered gait or postural hypotension)
minimising household risks (preferably under the guidance of an occupational therapist)
providing aids for daily living (eg walking aids, rails)
minimising periods of immobilisation
promoting exercise to maintain mobility, balance and strength.
Consider referral to a falls prevention clinic.
Exercise to prevent minimal-trauma fracture
Exercise has a positive effect on two of the major risk factors for minimal-trauma fracture—falls and low BMD.
Exercise maintains muscle strength, muscle mass, flexibility, mobility and balance, which can reduce the
frequency and severity of falls. Exercise can also prevent the loss of, or even increase, BMD, although evidence
that exercise reduces the incidence of fractures is lacking.
The benefits of exercise vary according to the type of exercise:
A combination of weight-bearing and high-impact exercise has the most significant benefit on BMD, and
also improves muscle strength. The intensity of exercise should be progressively increased as the patient
gains fitness.
Balance training and muscle strengthening exercises can reduce the risk of falls, and can also be beneficial
for BMD.
Tai Chi, and group and home-based exercise programs have been shown to reduce falls in older people.
Non–weight-bearing exercise (eg swimming, cycling) does not increase bone density, but has other health
benefits, and can improve or maintain muscle strength.
Advise and assist all patients to exercise, with individualised exercise plans that consider the patient’s abilities and
fracture risk. Consider referral to an exercise physiologist or physiotherapist for an individualised plan, particularly
for a patient with existing osteoporosis or prior minimal-trauma fracture.
For more detail about exercises to prevent osteoporosis and fractures, including patient information, see the
Osteoporosis Australia website. Videos for patients are available from the Osteoporosis Canada website.
Calcium and osteoporosis

Optimising calcium intake has been shown to achieve a small increase in bone mineral density (BMD), but data
demonstrating a correlation between fracture risk and calcium intake alone are lacking. In most studies of
treatments for osteoporosis, adequate calcium (and vitamin D) were entry requirements.
The Australian recommended daily intake of calcium is:
1300 mg in patients taking drug therapy for osteoporosis

1300 mg in women older than 50 years and men older than 70 years
1000 mg in women 50 years or younger and men 70 years or younger.
This intake should ideally be achieved from dietary sources. Encourage patients with a low dietary calcium intake
to increase their intake of calcium-rich foods, rather than taking a supplement. Calcium supplements can cause
bloating and constipation, and, in some studies, have been associated with a small increase in the risk of
myocardial infarction (although this finding is not supported by other studies).
Dairy food is the main dietary source of calcium [Note 2]. Most milks contain approximately 1000 mg of calcium
per litre. Concentrated low-fat and skim milks have a slightly higher calcium content. To achieve a daily intake of
1000 to 1300 mg of calcium, three servings of dairy products are recommended per day. Dairy foods are also a
good source of protein, which may independently contribute to good bone health.
If a person’s daily calcium requirement cannot be met through dietary intake, an oral calcium supplement can be
considered.
Only consider an oral calcium supplement if dietary intake is insufficient.
Calcium carbonate tablets are a reasonable first choice of supplement, based on their low cost and acceptable
absorption in most people if taken after meals. Calcium citrate tablets are a reasonable alternative. Calcium citrate
does not require gastric acidity for absorption, so may be better absorbed than calcium carbonate in people taking a
proton pump inhibitor.
Limit the dose from a supplement to 500 to 600 mg of elemental calcium daily. Use:
1 calcium carbonate 1.25 to 1.5 g (elemental calcium 500 to 600 mg) orally, daily with food
OR
2 calcium citrate 2.38 g (elemental calcium 500 mg) orally, daily.
The elemental calcium content of the supplement is the most important factor—there is no evidence that complex
mineral preparations are more beneficial than simple preparations, and often they contain less elemental calcium.
Note 2: For a list of the calcium content of selected foods, see the Osteoporosis Australia website.
For a calcium intake calculator, see the International Osteoporosis Foundation website.
Vitamin D and osteoporosis

Vitamin D plays an important role in bone mineralisation and maintaining calcium homeostasis.
In most studies of treatments for osteoporosis, adequate vitamin D (and calcium) were entry requirements.
Observational data in postmenopausal women taking alendronate, risedronate and raloxifene showed that women
who were vitamin D deficient were more likely to have a fracture than those who were vitamin D replete. In
patients taking drug therapy for osteoporosis, maintain a serum 25-hydroxyvitamin D concentration above 50
nanomol/L.
For advice on vitamin D supplementation, see Vitamin D deficiency.
Considerations before treating osteoporosis

Before starting drug therapy for osteoporosis, consider the possibility of a secondary cause of bone loss or fracture
(see Table 19.11 for a list of conditions that can cause bone loss), and factors that can interfere with bone mineral
density (BMD) measurement. Up to 30% of postmenopausal women and 50% of men with osteoporosis have a
secondary cause.
Osteoporosis in premenopausal women and young men (less than 50 years) is uncommon and its presence should
prompt investigation for a secondary cause. Seek specialist advice to guide management.
Optimising the management of a secondary cause can minimise fracture risk and avoid unnecessary treatment with
antiresorptive drugs. However, specific osteoporosis treatment may still be required despite management of a
secondary cause.
Patient history and clinical examination can help to identify secondary causes of bone loss. Features that suggest
that a secondary cause may be responsible for bone loss or fracture include:
a Z-score lower than –2.0

severe osteoporosis (eg T-score below –3.0)
multiple fractures
bone loss or minimal-trauma fracture in a young patient or a patient with no other apparent risk factors
history of a medical condition or use of a drug that affects bone homeostasis or density (see Table 19.11)
unusual persistence of pain at the fracture site
features of systemic illness (eg weight loss)
unusual fracture patterns or radiological findings.
Investigations to detect common secondary causes may be reasonable; consider testing:
serum calcium concentration

serum phosphate concentration
serum alkaline phosphatase concentration
serum 25-hydroxyvitamin D concentration
serum thyroid stimulating hormone concentration
liver biochemistry
kidney function.
If a specific secondary cause is suspected, other tests can be performed as indicated; for example:
serum parathyroid hormone concentration

urinary calcium excretion
serum and urine protein electrophoresis
erythrocyte sedimentation rate
coeliac serology
serum testosterone concentration in men
serum follicle stimulating hormone and oestradiol concentrations in women
24-hour urinary free cortisol test, overnight dexamethasone suppression test or late-night salivary free
cortisol test.
Also consider the possibility of a metabolic bone disease other than osteoporosis (eg osteomalacia), particularly in
patients with a malabsorption disorder or kidney disease.
Specialist input is required for management of osteoporosis in patients with a secondary cause of osteoporosis,
women of child-bearing potential and pregnant women, post-transplant osteoporosis and patients with osteoporosis
and chronic kidney disease (particularly creatinine clearance less than 35 mL/min).
Management of osteoporosis following minimal-trauma fracture

After acute management of a fracture in hospital, refer the patient to their general practitioner or a fracture liaison
service for follow-up. Consider starting drug therapy for osteoporosis in any patient older than 50 years who has a
minimal-trauma fracture at any site (excluding skull, face, fingers and toes).
Following a minimal-trauma fracture, measure bone mineral density (BMD). The decision to treat is based on
fracture site, BMD and ongoing risk of fracture. The majority of minimal-trauma fractures occur in patients with a
T-score in the osteopenic range (see Table 19.10 for World Health Organization categorisation by T-score).
If the T-score is in the osteopenic or osteoporotic range, start drug therapy for osteoporosis.
If the T-score is within the normal range, consider further investigations based on patient history and clinical
examination to exclude other causes of fracture. See Considerations before treating osteoporosis for more
information. If other causes of fracture are excluded, the decision to treat depends on the fracture site:
For a patient who had a minimal-trauma hip fracture, start treatment.

A patient who had a minimal-trauma vertebral fracture is unlikely to have normal bone density. A T-score
above –1 is much more likely to be attributable to a problem with the radiographic technique or other
interference (see Assessment of bone status for more information). Although drugs for osteoporosis have not
been studied in patients with normal BMD and a vertebral fracture, consider starting treatment in these
patients, particularly in those with other risk factors for fracture. Specialist advice is recommended.
For a patient who had a minimal-trauma fracture at another site (not a hip or vertebral fracture), evidence
to guide management is not available. Treatment could be considered in patients with other risk factors for
fracture. Specialist advice is recommended.
If BMD cannot be measured (eg dual energy X-ray absorptiometry [DXA] machine is not accessible), start drug
therapy for osteoporosis in any patient who has a minimal-trauma hip or vertebral fracture. Measure BMD when
possible to allow subsequent monitoring.
If treatment is warranted, see Choice of drug therapy for osteoporosis for information about choosing the right
treatment for each patient.
If treatment is not yet warranted or desired, repeated measurement of BMD after 2 years and regular risk
assessment is reasonable to monitor ongoing fracture risk.
For all patients, ensure calcium intake is sufficient and they are vitamin D replete. Provide advice about lifestyle
measures to prevent minimal-trauma fracture.
Management of osteoporosis in the absence of fracture
Management of osteoporosis in the absence of fracture is based on individual fracture risk assessment; see Risk
factors for minimal-trauma fracture. Measure bone mineral density (BMD) if the patient has significant risk factors
for osteoporosis or minimal-trauma fracture. Measurement of BMD in patients 70 years and older (regardless of
other risk factors) is also recommended.
Measure BMD in patients with significant risk factors for fracture, and in patients 70 years and older.
Absolute fracture risk can be calculated using an online calculator (eg Fracture Risk Assessment Tool [FRAX],
Garvan Institute Fracture Risk Calculator). The role of fracture risk calculators in practice is evolving; they are
particularly useful to identify and reassure patients at low fracture risk who do not require drug therapy.
For patients aged 70 years and older, drug therapy for osteoporosis can be started for primary fracture prevention if
the T-score is –2.5 or less. For younger patients, consider all risk factors for fracture—younger patients with a
declining BMD or a high risk of fracture may benefit from treatment; seek specialist advice. For treatment
decisions in patients taking glucocorticoid therapy, see Glucocorticoid-induced osteoporosis.
See Choice of drug therapy for osteoporosis for information about choosing the right treatment for each patient.
If a patient has risk factors for fracture but treatment is not yet warranted or desired, repeated measurement of
BMD after 2 years and regular risk assessment is reasonable to monitor ongoing fracture risk.
For all patients, ensure calcium intake is sufficient and they are vitamin D replete. Provide advice about lifestyle
Choice of drug therapy for osteoporosis

For information about when to use drug therapy for osteoporosis, see Management of osteoporosis following
minimal-trauma fracture and Management of osteoporosis in the absence of fracture. See also Considerations
before treating osteoporosis.
For treatment of osteoporosis, the most commonly used drugs are antiresorptive drugs (ie an oral or intravenous
bisphosphonate, or denosumab). The choice of antiresorptive drug is guided by comorbidities, patient preference
and potential adverse effects. See Table 19.12 for considerations to guide antiresorptive drug choice.
Treatment of premenopausal women and young patients (eg younger than 50 years) usually requires specialist
input; an oral bisphosphonate is often favoured.
Use of teriparatide is limited by strict Pharmaceutical Benefits Scheme (PBS) funding criteria; it is usually
reserved as a second-line treatment for patients who experience a fracture while on antiresorptive therapy.
Hormone therapy can be useful in some women with osteoporosis. Oestrogen and tibolone can be considered in
postmenopausal women younger than 60 years, particularly those who have another indication for hormone
therapy (eg menopausal symptoms). Raloxifene can be considered in young postmenopausal women with spinal
osteoporosis, particularly if they have risk factors for breast cancer.
For patients with a secondary cause of osteoporosis, osteoporosis in women of child-bearing potential and
pregnant women, post-transplant osteoporosis, and patients with osteoporosis and chronic kidney disease
(particularly creatinine clearance less than 35 mL/min), seek specialist advice to guide management.
For current information about drugs for osteoporosis listed on the PBS, see the PBS website.
Considerations to guide choice of antiresorptive drugs for osteoporosis (Table 19.12)
Advantages Disadvantages
alendronate
can cause or exacerbate upper gastrointestinal tract irritation
oral dosing absorption reduced by food, antacids, calcium, magnesium and iron
low cost requires more frequent dosing than intravenous options
not recommended in severe kidney disease

risedronate
oral dosing can cause or exacerbate upper gastrointestinal tract irritation
low cost absorption reduced by food, antacids, calcium, magnesium and iron
enteric-coated formulation requires more frequent dosing than intravenous options

available (may have a lower
incidence of gastrointestinal not recommended in severe kidney disease
adverse effects, and absorption
less affected by food, antacids, enteric-coated formulation only available as a weekly dose (non–enteric-coated
calcium, magnesium and iron) formulation available as a monthly dose)
zoledronic acid
intravenous administration not acceptable to some patients
not recommended in severe kidney disease

intravenous administration avoids
gastrointestinal adverse effects can cause transient influenza-like symptoms
yearly dosing can improve can cause uveitis (uncommon)

adherence
can cause hypocalcaemia (particularly in patients with impaired kidney
function [estimated glomerular filtration rate less than 35 mL/min/1.73 m2],
vitamin D deficiency or a malabsorption disorder)
denosumab
subcutaneous dosing not acceptable to some patients
subcutaneous administration adherence to 6-monthly dosing regimen is essential to prevent loss of bone
avoids gastrointestinal adverse mineral density between doses
effects
therapy must be either indefinite, or replaced by a bisphosphonate if stopped
dose adjustment not required in
kidney disease withdrawal or interruption of treatment (dose delayed by more than 4 weeks) is
associated with an increased risk of multiple spontaneous vertebral fracture
6-monthly dosing can improve
compliance can cause hypocalcaemia (particularly in patients with impaired kidney
function [creatinine clearance 30 mL/min or less], vitamin D deficiency or a
malabsorption disorder)
Antiresorptive drugs for osteoporosis

Bisphosphonates
Bisphosphonate regimens
Bisphosphonates slow bone loss and improve bone mineral density (BMD) by inhibiting osteoclasts. They reduce
vertebral, nonvertebral and hip fracture rates.
Suitable regimens are:
1 alendronate 70 mg orally, once weekly on an empty stomach
OR
1 risedronate 35 mg orally, once weekly on an empty stomach [Note 3]
OR
1 risedronate 150 mg orally, once a month on an empty stomach
OR
1 zoledronic acid 5 mg by intravenous infusion over at least 15 minutes, once a year.
Oral bisphosphonates (except enteric-coated formulations) must be taken on an empty stomach, and at least 2
hours apart from calcium, iron, magnesium and antacids, which can limit efficacy by significantly reducing
absorption.
Throughout therapy, ensure the patient’s calcium intake is sufficient and they are vitamin D replete.
Zoledronic acid can cause hypocalcaemia, particularly in patients with risk factors for hypocalcaemia such as
vitamin D deficiency, kidney disease or a malabsorption disorder. Before the first dose, measure kidney function,
serum corrected calcium concentration and serum 25-hydroxyvitamin D concentration. In patients at risk of
hypocalcaemia, these parameters should also be measured before each subsequent dose. Intravenous
administration of zoledronic acid in primary care is safe provided that:
serum 25-hydroxyvitamin D concentration is greater than 50 nanomol/L

serum calcium concentration corrected for albumin is in the normal range (2.10 to 2.60 mmol/L)
estimated glomerular filtration rate (eGFR) is greater than 35 mL/min/1.73 m2
the patient is well hydrated.
Intravenous zoledronic acid can cause transient influenza-like symptoms. This most often occurs after the first dose
and is less likely to occur with subsequent doses. To reduce the severity of the reaction, advise patients to take
paracetamol before and for several days after the infusion.
Less frequent administration of zoledronic acid may be considered with specialist advice. In a study of women
aged over 65 years with osteopenia, administration of zoledronic acid every 18 months reduced the incidence of
fractures compared to placebo [Note 4].
Note 3: This dose is also available in an enteric-coated formulation, which does not need to be taken on an empty
stomach.
Note 4: Reid IR, Horne AM, Mihov B, Stewart A, Garratt E, Wong S, et al. Fracture prevention with zoledronate
in older women with osteopenia. N Engl J Med 2018;379(25):2407-16. [URL]
Duration of bisphosphonate therapy
Bisphosphonates are retained in the skeleton after treatment withdrawal. The beneficial effects on BMD persist for
several years after stopping alendronate and zoledronic acid. In contrast, BMD decreases within one year of
stopping risedronate.
Long-term bisphosphonate therapy has been linked to an increased risk of skeletal adverse effects such as
osteonecrosis of the jaw and atypical fracture of the femur, although the absolute risk remains low. Limiting the
duration of bisphosphonate therapy may reduce the incidence of these effects.
In patients not at high risk of minimal-trauma fracture, consider stopping therapy after 5 years of an oral
bisphosphonate or 3 years of an intravenous bisphosphonate. Bisphosphonate treatment can be continued for up to
10 years (oral) or 6 years (intravenous) for patients at high risk of minimal-trauma fracture, including patients:
age 75 years and older

with a previous hip or vertebral fracture
who had minimal-trauma fracture after starting treatment (after exclusion of other causes of fracture)
with hip T-score of –2.5 or lower.
Evidence to guide oral bisphosphonate treatment beyond 10 years is not available, so treatment needs to be
individualised according to patient needs. Consider specialist input.
After stopping treatment, consider measuring BMD after 2 to 3 years—treatment can be restarted if BMD has
decreased significantly (eg decreased by 5% or by 0.05 grams/cm2 at lumbar spine, hip or femoral neck).
Treatment can also be restarted if the patient has a minimal-trauma fracture after stopping treatment, or has new or
worsening risk factors for fracture (eg increased falls risk).
For information about monitoring therapy, see here.
Denosumab
Denosumab reversibly inhibits bone resorption by reducing osteoclast formation and differentiation and increasing
osteoclast apoptosis. Denosumab increases BMD at the lumbar spine and hip, and reduces vertebral, nonvertebral
and hip fractures.
Before starting denosumab, discuss with the patient the importance of adhering to a 6-monthly regimen, and
explain that denosumab therapy must either be continued indefinitely (at the time of writing, the use of denosumab
for more than 10 years has not been studied), or be replaced by bisphosphonate therapy if stopped.
Withdrawal of denosumab has been associated with multiple spontaneous vertebral fractures.
Recent studies have demonstrated an increased incidence of multiple spontaneous vertebral fractures when
denosumab is stopped or a dose is delayed for more than 4 weeks (ie it has been more than 7 months since the last
dose). The risk of multiple vertebral fractures is particularly high in patients with a prior vertebral fracture. Unlike
bisphosphonates, which have a long skeletal half-life, stopping denosumab leads to a rapid increase in bone
turnover and loss of BMD. If denosumab is stopped, a replacement drug (typically a bisphosphonate) must be
started to prevent rapid bone loss and vertebral fracture. At the time of writing, the optimal choice of
bisphosphonate (oral or intravenous) to replace denosumab is not known; the optimal time to start the
bisphosphonate after stopping denosumab, and how long it should be continued, are also not known. A suggested
regimen based on limited clinical trial data is to start oral alendronate no more than 6 months after the last dose of
denosumab, and continue for 12 to 24 months.
Serious skeletal adverse effects such as osteonecrosis of the jaw and atypical fracture of the femur have been rarely
reported with denosumab.
If denosumab is suitable, use:
denosumab 60 mg subcutaneously, every 6 months.
Throughout therapy, ensure the patient’s calcium intake is sufficient and they are vitamin D replete.
Denosumab can cause hypocalcaemia, particularly in patients with risk factors for hypocalcaemia such as vitamin
D deficiency, kidney disease or a malabsorption disorder. Before the first dose, measure kidney function, serum
corrected calcium concentration and serum 25-hydroxyvitamin D concentration. In patients at risk of
hypocalcaemia, these parameters should also be measured before each subsequent dose. Administration of
denosumab is safe provided that:

serum total calcium concentration corrected for albumin is in the normal range (2.10 to 2.60 mmol/L)
creatinine clearance is greater than 30 mL/min.
For information about monitoring therapy, see here.
Skeletal adverse effects of antiresorptive drugs
Osteonecrosis of the jaw
Antiresorptive drugs (bisphosphonates and denosumab) are associated with a small increase in the incidence of
osteonecrosis of the jaw, known as medication-related osteonecrosis of the jaw when associated with drug therapy.
This is a rare complication that has mainly occurred in patients who had dental surgery during treatment with a
high-dose intravenous bisphosphonate for multiple myeloma or metastatic cancer. The incidence of medication-
related osteonecrosis of the jaw in patients taking an antiresorptive drug for osteoporosis ranges from fewer than 1
to 150 per 100 000 patient-years [Note 5]. Although medication-related osteonecrosis of the jaw has significant
consequences for the patient and can be difficult to treat, the benefit of antiresorptive therapy in preventing
fractures far outweighs the low risk of medication-related osteonecrosis of the jaw in most patients.
The benefit of antiresorptive therapy in preventing fractures far outweighs the low risk of medication-related osteonecrosis of the
jaw in most patients.
The risk of medication-related osteonecrosis of the jaw is highest following dental extractions and dental implant
insertion, and in periodontal disease. Advise patients starting an antiresorptive drug that ideally, they should have a
dental review, and to notify the dentist that they are starting (or have recently started) antiresorptive therapy. Early
dental assessment and initiation of dental treatment reduces the incidence of medication-related osteonecrosis of
the jaw. Any necessary dental treatment should be completed before or shortly after starting antiresorptive therapy
(eg within 6 months)—the risk of medication-related osteonecrosis of the jaw in osteoporotic patients remains low
in the early stage of treatment.
To help prevent the need for an invasive dental procedure during antiresorptive treatment, advise patients to
maintain good oral hygiene, have regular dental health reviews, and to seek early management of any oral or
dental concerns. See also Maintaining optimal oral health for information about prevention of medication-related
osteonecrosis of the jaw. Other factors that increase the risk of medication-related osteonecrosis of the jaw include
smoking, glucocorticoid therapy, immune compromise, diabetes, anaemia, hyperthyroidism and dialysis.
Bisphosphonate therapy for more than 4 years also increases the risk of medication-related osteonecrosis of the
jaw.
If an invasive dental procedure is necessary, discuss the patient’s risk of medication-related osteonecrosis of the
jaw, as well as the risk associated with the procedure, with the treating dentist. See Risk assessment for
medication-related osteonecrosis of the jaw for a guide to stratifying the risk of medication-related osteonecrosis of
the jaw. For a patient at higher risk of medication-related osteonecrosis of the jaw, referral to an oral maxillofacial
surgeon for the procedure is appropriate.
Recommendations for patients taking an antiresorptive drug who require an invasive dental procedure vary among
international and local guidelines [Note 6]. Interruption of antiresorptive therapy (a ‘drug holiday’), or timing of
the procedure to coincide with a low serum drug concentration, have been suggested to reduce the risk of
medication-related osteonecrosis of the jaw. These practices are based on extrapolation of the drug
pharmacokinetics in the serum and on bone physiology; however, outcome data to support them are not available.
Interruption is never appropriate for denosumab, as this leads to a rapid increase in bone turnover and loss of
BMD, and increases the risk of spontaneous vertebral fracture (see Denosumab). See also Drug holidays and
scheduling of procedures for more information.
Note 5: Patient-years are used to express incidence, which is the number of new cases observed during a
specified period. An incidence of 150 per 100 000 patient-years means 150 new cases occur for every 100 000
patients taking the drug for 1 year.
Note 6: Ebeling P, Center J, Clifton-Bligh R, Cooper M, Ewald D, Singh M, et al. Osteoporosis prevention, diagnosis and management in
postmenopausal women and men over 50 years of age. 2nd ed. Melbourne: The Royal Australian College of General Practitioners; 2017. [URL]
Hellstein JW, Adler RA, Edwards B, Jacobsen PL, Kalmar JR, Koka S, et al. Managing the care of patients receiving antiresorptive therapy for
prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific
Affairs. J Am Dent Assoc 2011;142(11):1243-51. [URL]
Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O’Ryan F, et al. Diagnosis and management of osteonecrosis of the jaw: a
systematic review and international consensus. J Bone Miner Res 2015;30(1):3-23. [URL]
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons position
paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg 2014;72(10):1938-56. [URL]
Atypical fractures of the femur
Atypical subtrochanteric or diaphyseal femoral fractures are rare. Antiresorptive therapy increases the risk of
atypical femoral fractures. The risk increases with duration of therapy, although the absolute incidence remains
low (113 per 100 000 patient-years [Note 7] after 8 to 10 years of treatment). The risk appears to decline after
stopping bisphosphonate therapy. The benefit of antiresorptive therapy in preventing fractures outweighs the low
risk of atypical femoral fractures. About 7% of cases of atypical femoral fractures occur without exposure to either
a bisphosphonate or denosumab.
A prodrome of thigh, groin or hip pain occurs in around 70% of patients with an atypical femoral fracture. Advise
patients receiving prolonged bisphosphonate or denosumab therapy (more than 3 years) to report unexplained
thigh or groin pain. If these symptoms develop, perform femoral shaft x-ray. An isotope bone scan or magnetic
resonance imaging (MRI) may also be needed. Up to 40% of atypical femoral fractures are bilateral, so both
femurs should be imaged. If an atypical femoral fracture is confirmed, stop the bisphosphonate or denosumab and
urgently refer the patient to a specialist centre with bone and orthopaedic expertise.
Note 7: Patient-years are used to express incidence, which is the number of new cases observed during a specified period. An incidence of 113 per 100
000 patient-years means 113 new cases occur for every 100 000 patients taking the drug for 1 year.
Other drugs for osteoporosis

Teriparatide
Teriparatide is a synthetic form of human parathyroid hormone. At the time of writing, it is the only osteoporosis
treatment that increases bone formation. Teriparatide reduces the incidence of vertebral and nonvertebral fractures
in postmenopausal women with osteoporosis. Teriparatide has been shown to increase bone mineral density
(BMD) in men, but it has not been studied for fracture prevention in men.
Teriparatide’s use is limited by strict eligibility criteria for Pharmaceutical Benefits Scheme (PBS) subsidy—
therapy must be started by a specialist, and the patient must have a T-score of –3 or less, and at least two minimal-
trauma fractures, including a fracture after at least one year of antiresorptive therapy [Note 8].
Do not use teriparatide in patients:
younger than 25 years (especially children)

with known or suspected Paget disease of bone
who have previously had radiotherapy involving bone
with pre-existing hypercalcaemia, malignancy, severe kidney disease or primary hyperparathyroidism.
If teriparatide is indicated, a suitable regimen is:
teriparatide 20 micrograms subcutaneously, once daily.
The maximum lifetime duration of teriparatide is 24 months [Note 9]. Following a course of teriparatide, start
antiresorptive therapy (ie a bisphosphonate or denosumab) to increase BMD further and maintain the antifracture
effect.
Teriparatide caused bone osteosarcomas in rats, but this effect has not been observed in humans.
Note 8: See the Pharmaceutical Benefits Scheme website for current information on eligibility criteria for teriparatide.
Note 9: At the time of writing, teriparatide is only available on the Pharmaceutical Benefits Scheme (PBS) for a total lifetime duration of 18 months.
See the PBS website for current information.
Oestrogen therapy
In postmenopausal women, oestrogen therapy reduces bone resorption and BMD loss, and reduces the incidence of
fractures. However, its use is limited by the risk of adverse effects with long-term use (eg some cancers). Evidence
suggests that the risk of harm is lower when oestrogen therapy is started in younger women than in older women,
with a low absolute risk of harm if oestrogen is used within 10 years of menopause. Lower risk is also observed in
women who take oestrogen alone (ie women who have had a hysterectomy) rather than combined therapy.
Discuss the harms and benefits of therapy with the patient. Oestrogen therapy is typically used in postmenopausal
women who are younger than 60 years, particularly those who have another indication for oestrogen therapy
(usually menopausal hormone therapy).
Oral oestradiol or oestradiol valerate (2 mg per day), or the equivalent dose of transdermal oestradiol (delivering
50 micrograms per 24 hours) are thought to be adequate for bone protection (see Table 5.35 for oestrogen
preparations). However, lower oestrogen doses may also reduce bone loss. Women with an intact uterus treated
with oestrogen therapy must also take adjuvant progestogen therapy, to prevent endometrial hyperplasia (see Table
5.36 for progestogen preparations).
In a woman with premature ovarian insufficiency, oestrogen therapy is required (in the absence of
contraindications) until the typical age of menopause, regardless of BMD status (see Premature menopause and
early menopause).
Selective oestrogen receptor modulators
Raloxifene is a selective oestrogen receptor modulator that reduces postmenopausal bone loss. Raloxifene reduces
vertebral fracture risk in women who are more than 3 years postmenopause, but does not appear to reduce
nonvertebral (including hip) fracture risk. It reduces the risk of breast cancer, but increases the risk of venous
thromboembolism, and causes a small increase in the risk of death after stroke. It also increases hot flushes.
Raloxifene is most appropriate for treating younger postmenopausal women (younger than 60 years) with spinal
osteoporosis, and may be a particularly suitable choice in women at high risk of breast cancer. Use:
raloxifene 60 mg orally, once daily.
A combination formulation (known as a tissue-selective oestrogen complex) containing conjugated oestrogens and
the selective oestrogen receptor modulator bazedoxifene is also available for management of menopausal
symptoms. This formulation improves hip and vertebral BMD. The effect on fracture risk has not been studied;
however, studies of bazedoxifene alone showed a reduction in vertebral fracture risk similar to raloxifene. It is
typically used for women younger than 60 years who have menopausal symptoms. At the time of writing, this
formulation is not available on the Pharmaceutical Benefits Scheme (PBS); see the PBS website for current
information.
Tibolone
Tibolone has oestrogenic effects on bone and reduces the risk of fracture in postmenopausal women to a similar
extent to oestrogen therapy. It is typically used for women younger than 60 years who have menopausal symptoms.
The safety profile of tibolone is less extensively studied than that of oestrogen, but it appears to increase the
recurrence of breast cancer in patients previously treated for breast cancer. It may increase the risk of stroke,
particularly in women older than 60 years.
If tibolone is suitable, use:
tibolone 2.5 mg orally, daily.
Tibolone has progestogenic effects, so does not need to be given with progestogen therapy.
Monitoring osteoporosis treatment

To monitor osteoporosis treatment, use actual bone mineral density (BMD) values; T-scores and Z-scores are not
appropriate.
In patients treated for osteoporosis, consider measuring BMD at the lumbar spine and hip:
2 years after starting treatment

1 to 2 years after a significant change in treatment.
Consider more frequent measurement of BMD (but not more often than once a year) in patients with severe
osteoporosis or high risk of bone loss, including those taking high-dose glucocorticoid therapy.
If BMD is stable or improving, subsequent measurement is not required for at least 2 years; an interval of up to 5
years may be reasonable.
If BMD decreases by more than by 5% or 0.05 grams/cm2 at any major site, or if a fracture occurs, consider
investigation for new or unrecognised risk factors, and check adherence to therapy. A change of therapy may be
appropriate.
For more information about measurement of BMD, and information about alternative methods to monitor
treatment (eg bone-turnover markers), see Assessing bone status.
Glucocorticoid-induced osteoporosis
Glucocorticoids can reduce bone mineral density (BMD) in both men and women. They reduce bone formation
and increase bone resorption by reducing osteoblast function and intestinal calcium absorption, and causing
osteocyte dysfunction, hypercalciuria and gonadal suppression. Glucocorticoids also increase fracture risk
independent of BMD, so a patient taking a glucocorticoid has a higher fracture risk than a patient not taking a
glucocorticoid who has the same BMD.
The highest rate of bone loss occurs within the first 3 to 6 months of treatment; a slower decline continues with
ongoing use. The extent of bone loss is related to the dose and the duration of glucocorticoid therapy. A
prednis(ol)one dose of at least 7.5 mg per day, or an equivalent dose of another glucocorticoid (see Table 19.6), is
associated with the greatest risk. However, an increase in bone loss and fracture risk has been observed with
prednis(ol)one doses as low as 2.5 mg daily.
Before starting glucocorticoid therapy that is expected to continue long term, assess the patient’s risk of fracture,
and measure their BMD. For all patients, ensure their calcium intake is sufficient and they are vitamin D replete.
Also optimise the management of any other risk factors for fracture (see Table 19.11), and provide advice on
prevention of minimal-trauma fracture.
In patients who will receive at least 7.5 mg prednis(ol)one per day (or an equivalent dose of another glucocorticoid
[see Table 19.6]) for at least 3 months, and who have a baseline T-score lower than –1.5, consider drug therapy to
prevent glucocorticoid-induced osteoporosis. Clinical judgement is necessary when assessing fracture risk; in
addition to baseline BMD and glucocorticoid dose, factors such as patient age and comorbidities affect the
decision to treat and choice of therapy.
Bisphosphonates prevent fractures in patients taking glucocorticoid therapy, and are considered first-line treatment.
Denosumab can also prevent fracture in these patients, but at the time of writing it is not available on the
Pharmaceutical Benefits Scheme (PBS) for this indication [Note 10]. Teriparatide is more effective than
alendronate in reducing vertebral fractures in patients taking glucocorticoids, but strict eligibility criteria for PBS
funding apply [Note 11]. Oestrogen therapy can prevent or reduce glucocorticoid-induced bone loss in
postmenopausal women.
If no other risk factors are present, preventive drug therapy may only be required for the duration of glucocorticoid
treatment.
Consider measuring BMD every 12 to 24 months for the first few years of glucocorticoid treatment. If BMD
results are stable and acceptable, further BMD measurement can be less frequent.
Note 10: See the Pharmaceutical Benefits Scheme website for current information on eligibility criteria for
denosumab.
Note 11: See the Pharmaceutical Benefits Scheme website for current information on eligibility criteria for
teriparatide.
Osteoporosis and pregnancy and lactation

Osteoporotic fractures are rare during pregnancy and lactation, but the increased structural and metabolic stress
placed on the skeleton in this period can exacerbate pre-existing low bone mineral density (BMD) or skeletal
fragility. Although pregnancy and lactation do not increase the long-term risk of low BMD or fracture, they do
cause loss of BMD in the short term (particularly during lactation). Bone resorption is increased to meet the
calcium requirement of the fetus during pregnancy and the infant during lactation. BMD usually returns to the
prepregnancy level 12 months after stopping breastfeeding.
Osteoporotic fractures during pregnancy usually involve the spine or the hip. The patient usually presents with
lower thoracic or lumbar pain during the third trimester or puerperium. Back pain is common during pregnancy
and the postpartum, so fractures often go undiagnosed. Severe, persistent pain that is uncharacteristic of
musculoskeletal pain, warrants specialist referral for further investigation.
Rest and simple analgesia are the mainstay of treatment, as the pain usually resolves over several weeks and the
BMD normalises without intervention.
Drug therapy for osteoporosis is reserved for severe cases such as multiple vertebral fractures, persistent disabling
pain, or if BMD does not increase as expected after stopping breastfeeding.
Transient osteoporosis of pregnancy is a rare demineralising condition that usually affects the hip, but can affect
other joints. The mechanism of bone loss is not known. Symptomatic transient osteoporosis of pregnancy should
be distinguished from the asymptomatic physiological loss of bone mass that occurs in all women during
pregnancy and lactation. Transient osteoporosis of pregnancy classically presents in the third trimester of
pregnancy as severe atraumatic anterolateral groin pain with anterior thigh radiation. The onset can be acute or
insidious. The BMD can be significantly reduced in the hip compared with the lumbar spine. Transient
osteoporosis of pregnancy is a self-limiting condition that usually resolves 2 to 6 months postpartum. Specialist
assessment and management is required.
Osteoporosis and bone health in children

Osteoporosis in a young patient requires specialist management. Paediatric osteoporosis can be diagnosed:
following a vertebral fracture not related to local disease or significant trauma

in a child or adolescent with both:
a clinically significant fracture history (at least two long bone fractures by 10 years, or at least three
long bone fractures before 19 years), and
a height-adjusted Z-score of –2 or below (see here for information about Z-scores).
To interpret bone mineral density (BMD) measurements in young patients, use paediatric reference data, and the
height-adjusted Z-score; do not use T-scores to assess BMD in children.
Osteoporosis in young people is usually related to a secondary cause, such as reduced mobility and chronic
inflammatory disorders (eg neurodevelopmental disorders, neuromuscular disorders, disorders requiring
glucocorticoid therapy). Other causes include malabsorption syndromes (eg coeliac disease, Crohn disease, cystic
fibrosis), poor nutrition, anorexia nervosa, hypogonadism, malignancy and transplantation. Secondary osteoporosis
is being increasingly recognised in childhood. Primary osteoporosis in children is rare, and is usually related to a
genetic condition (eg Osteogenesis imperfecta).
Educate patients and carers about lifestyle measures that can optimise BMD. The principles of fracture prevention
are similar to those in adults; see here. Maintaining healthy gonadal and pubertal status is also essential to
optimising bone health in young people.
Bisphosphonate therapy can be used in children and adolescents with osteoporosis. Treatment should only be
started by a specialist—the doses and frequency of administration differ significantly from those used in adults.
The Australian Paediatric Working Group provides more detailed information about the use of bisphosphonates in
young people [Note 12].
Note 12: Simm PJ, Biggin A, Zacharin MR, Rodda CP, Tham E, Siafarikas A, et al. Consensus guidelines on the
use of bisphosphonate therapy in children and adolescents. J Paediatr Child Health 2018;54(3):223-33. [URL]
Adverse effects of cancer therapy on bones

Breast cancer
Women newly diagnosed with breast cancer can have unrecognised abnormalities of bone and mineral metabolism
such as vitamin D deficiency, osteopenia, osteoporosis and primary hyperparathyroidism.
Aromatase inhibitors are often used to treat oestrogen receptor–positive breast cancer. Women treated with an
aromatase inhibitor require a baseline bone mineral density (BMD) measurement before starting treatment,
because aromatase inhibitors cause a rapid and profound decline in serum oestradiol concentration, resulting in
rapid bone loss and fractures. A bisphosphonate or denosumab should be considered in women with any of the
below:
prevalent or incident clinical or morphometric fractures

reduced BMD (T-score lower than –2 at the hip or spine)
annual bone loss of 5% or more.
Tamoxifen treatment for breast cancer usually stabilises or increases BMD in postmenopausal women, but causes
bone loss in premenopausal women.
Ensure the patient’s calcium intake is sufficient and they are vitamin D replete, and provide advice about lifestyle
More detailed information about the management of bone health in women with oestrogen receptor–positive breast
cancer can be found in the joint position statement of the Endocrine Society of Australia, the Australian and New
Zealand Bone and Mineral Society, the Australasian Menopause Society, and the Clinical Oncology Society of
Australia [Note 13].
Note 13: Grossmann M, Ramchand SK, Milat F, Vincent A, Lim E, Kotowicz MA, et al. Assessment and
management of bone health in women with oestrogen receptor-positive breast cancer receiving endocrine
therapy: Position statement of the Endocrine Society of Australia, the Australian and New Zealand Bone and
Mineral Society, the Australasian Menopause Society and the Clinical Oncology Society of Australia. Clin
Endocrinol (Oxf) 2018;89(3):280-96. [URL]
Prostate cancer
Androgen deprivation therapy is often used to treat prostate cancer. This rapidly reduces serum testosterone
concentration, increasing bone loss and risk of fractures. All men should have a baseline assessment of fracture
risk and BMD before starting therapy.
Ensure the patient’s calcium intake is sufficient and that they are vitamin D replete, and provide advice on lifestyle
All men with prostate cancer who receive androgen deprivation therapy and who have a history of minimal-trauma
fracture should start therapy with a bisphosphonate or denosumab. Therapy should also be considered in men with
a reduced BMD (T-score lower than or equal to –2) at the hip or spine.
Key references
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Prevention of minimal-trauma fracture
Bolland MJ, Leung W, Tai V, Bastin S, Gamble GD, Grey A, et al. Calcium intake and risk of fracture: systematic
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Gillespie LD, Robertson MC, Gillespie WJ, Sherrington C, Gates S, Clemson LM, et al. Interventions for preventing
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Considerations before treating osteoporosis
Management of osteoporosis following minimal-trauma fracture
Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, et al. Zoledronic acid and clinical
fractures and mortality after hip fracture. N Engl J Med 2007;357(18):1799–809.
Scottish Intercollegiate Guidelines Network (SIGN). Management of osteoporosis and the prevention of fragility
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prevention-of-fragility-fractures.html
Management of osteoporosis in the absence of fracture
Reid IR, Horne AM, Mihov B, Stewart A, Garratt E, Wong S, et al. Fracture prevention with zoledronate in older
women with osteopenia. N Engl J Med 2018;379(25):2407–16.
Shepstone L, Lenaghan E, Cooper C, Clarke S, Fong-Soe-Khioe R, Fordham R, et al. Screening in the community to
reduce fractures in older women (SCOOP): a randomised controlled trial. Lancet 2018;391(10122):741–7.
Sheu A, Diamond T. Secondary osteoporosis. Aust Prescr 2016;39(3):85–7.
Choice of drug therapy for osteoporosis
Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D, Lamy O. Severe spontaneous vertebral fractures after denosumab
discontinuation: three case reports. Osteoporos Int 2016;27(5):1923–5.
Eastell R, Rosen CJ, Black DM, Cheung L, Murad MH, Shoback D. Pharmacological management of osteoporosis in
postmenopausal women: an Endocrine Society guideline. J Clin Endocrinol Metab 2019;104:[epub 25 March 2019
ahead of print]. https://www.endocrine.org/guidelines-and-clinical-practice/clinical-practice-guidelines/osteoporosis-in-
postmenopausal-women
Lamy O, Gonzalez-Rodriguez E, Stoll D, Hans D, Aubry-Rozier B. Severe rebound-associated vertebral fractures after
denosumab discontinuation: 9 clinical cases report. J Clin Endocrinol Metab 2017;102(2):354–8.
Popp AW, Zysset PK, Lippuner K. Rebound-associated vertebral fractures after discontinuation of denosumab-from
clinic and biomechanics. Osteoporos Int 2016;27(5):1917–21.
Antiresorptive drugs for osteoporosis
Bisphosphonates
Adler RA, El-Hajj Fuleihan G, Bauer DC, Camacho PM, Clarke BL, Clines GA, et al. Managing osteoporosis in patients
on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research.
J Bone Miner Res 2016;31(1):16–35.
Reid IR, Horne AM, Mihov B, Stewart A, Garratt E, Wong S, et al. Fracture prevention with zoledronate in older
women with osteopenia. N Engl J Med 2018;379(25):2407–16.
Denosumab
Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical features of 24 patients with
rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J
Bone Miner Res 2017;32(6):1291–6.
Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D, Lamy O. Severe spontaneous vertebral fractures after denosumab
discontinuation: three case reports. Osteoporos Int 2016;27(5):1923–5.
Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, et al. 10 years of denosumab treatment in
postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label
extension. Lancet Diabetes Endocrinol 2017;5(7):513–23.
Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, et al. Vertebral fractures after discontinuation
of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone
Miner Res 2018;33(2):190–8.
Freemantle N, Satram-Hoang S, Tang ET, Kaur P, Macarios D, Siddhanti S, et al. Final results of the DAPS
(Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with
alendronate in postmenopausal women. Osteoporos Int 2012;23(1):317–26.
Lamy O, Gonzalez-Rodriguez E, Stoll D, Hans D, Aubry-Rozier B. Severe rebound-associated vertebral fractures after
denosumab discontinuation: 9 clinical cases report. J Clin Endocrinol Metab 2017;102(2):354–8.
Leder BZ. An Essential Warning. J Bone Miner Res 2018;33(2):188–9.
Lewiecki EM. New and emerging concepts in the use of denosumab for the treatment of osteoporosis. Ther Adv
Musculoskelet Dis 2018;10(11):209–23.
Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, et al. Effect of denosumab on bone density
and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of
therapy: a randomized blinded phase 2 clinical trial. Bone 2008;43(2):222–9.
Popp AW, Zysset PK, Lippuner K. Rebound-associated vertebral fractures after discontinuation of denosumab-from
clinic and biomechanics. Osteoporos Int 2016;27(5):1917–21.
Reid IR, Horne AM, Mihov B, Gamble GD. Bone loss after denosumab: only partial protection with zoledronate. Calcif
Tissue Int 2017;101(4):371–4.
Tsourdi E, Langdahl B, Cohen-Solal M, Aubry-Rozier B, Eriksen EF, Guanabens N, et al. Discontinuation of

Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone 2017;105:11–7.
Skeletal adverse effects of antiresorptive drugs
Damm DD, Jones DM. Bisphosphonate-related osteonecrosis of the jaws: a potential alternative to drug holidays. Gen
Dent 2013;61(5):33–8.
Guidance Development Group. Oral health management of patients at risk of medication-related osteonecrosis of the
jaw [Dental clinical guidance]. Dundee, Scotland: Scottish Dental Clinical Effectiveness Programme; 2017.
http://www.sdcep.org.uk/published-guidance/medication-related-osteonecrosis-of-the-jaw/
Hellstein JW, Adler RA, Edwards B, Jacobsen PL, Kalmar JR, Koka S, et al. Managing the care of patients receiving
antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the
American Dental Association Council on Scientific Affairs. J Am Dent Assoc 2011;142(11):1243–51.
Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O'Ryan F, et al. Diagnosis and management of
osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 2015;30(1):3–23.
Milat F, Ebeling PR. Osteoporosis treatment: a missed opportunity. Med J Aust 2016;205(4):185–90.
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and
Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw-2014 update. J Oral Maxillofac
Surg 2014;72(10):1938–56.
Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, et al. Atypical subtrochanteric and diaphyseal
femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner
Res 2014;29(1):1–23.
Other drugs for osteoporosis
Barbehenn EK, Lurie P, Wolfe SM. Osteosarcoma risk in rats using PTH 1-34. Trends Endocrinol Metab
2001;12(9):383.
Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, et al. Effects of raloxifene on cardiovascular
events and breast cancer in postmenopausal women. N Engl J Med 2006;355(2):125–37.
Cranney A, Papaioannou A, Zytaruk N, Hanley D, Adachi J, Goltzman D, et al. Parathyroid hormone for the treatment
of osteoporosis: a systematic review. CMAJ 2006;175(1):52–9.
Cummings SR, Ettinger B, Delmas PD, Kenemans P, Stathopoulos V, Verweij P, et al. The effects of tibolone in older
postmenopausal women. N Engl J Med 2008;359(7):697–708.
Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, et al. Efficacy of raloxifene on vertebral fracture
risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin
Kenemans P, Bundred NJ, Foidart JM, Kubista E, von Schoultz B, Sismondi P, et al. Safety and efficacy of tibolone in
breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol
2009;10(2):135–46.
Lindsay R, Gallagher JC, Kagan R, Pickar JH, Constantine G. Efficacy of tissue-selective estrogen complex of
bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril
2009;92(3):1045–52.
Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, et al. Menopausal hormone therapy
and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative
randomized trials. JAMA 2013;310(13):1353–68.
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathyroid hormone (1-34) on
fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344(19):1434–
41.
Pinkerton JV, Harvey JA, Lindsay R, Pan K, Chines AA, Mirkin S, et al. Effects of bazedoxifene/conjugated estrogens
on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab 2014;99(2):E189–98.
Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, et al. Effect of hormone replacement therapy
on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012;345:e6409.
Glucocorticoid-induced osteoporosis
Buckley L, Guyatt G, Fink HA, Cannon M, Grossman J, Hansen KE, et al. 2017 American College of Rheumatology
guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheumatol
2017;69(8):1521–37.
Saag KG, Wagman RB, Geusens P, Adachi JD, Messina OD, Emkey R, et al. Denosumab versus risedronate in
glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy, non-
inferiority study. Lancet Diabetes Endocrinol 2018;6(6):445–54.
Osteoporosis and pregnancy and lactation
Kovacs CS. Osteoporosis presenting in pregnancy, puerperium, and lactation. Curr Opin Endocrinol Diabetes Obes
2014;21(6):468–75.
Lakhanpal S, Ginsburg WW, Luthra HS, Hunder GG. Transient regional osteoporosis. a study of 56 cases and review
of the literature. Ann Intern Med 1987;106(3):444–50.
Osteoporosis and bone health in children
Bianchi ML, Leonard MB, Bechtold S, Hogler W, Mughal MZ, Schonau E, et al. Bone health in children and
adolescents with chronic diseases that may affect the skeleton: the 2013 ISCD pediatric official positions. J Clin
Densitom 2014;17(2):281–94.
Simm PJ, Biggin A, Zacharin MR, Rodda CP, Tham E, Siafarikas A, et al. Consensus guidelines on the use of
bisphosphonate therapy in children and adolescents. J Paediatr Child Health 2018;54(3):223–33.
The International Society for Clinical Densitometry (ISCD). 2013 ISCD combined official positions. Middletown, CT:
ISCD; 2014. https://www.iscd.org/official-positions/2nd-iscd-pediatric-position-development-conference/
Adverse effects of cancer therapy on bones
Grossmann M, Ramchand SK, Milat F, Vincent A, Lim E, Kotowicz MA, et al. Assessment and management of bone
health in women with oestrogen receptor-positive breast cancer receiving endocrine therapy: position statement of the
Endocrine Society of Australia, the Australian and New Zealand Bone & Mineral Society, the Australasian Menopause
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Published June 2019. Amended December 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Vitamin D deficiency
Introduction to vitamin D deficiency
The main source of vitamin D (colecalciferol or vitamin D3) in humans is ultraviolet B radiation from the sun
acting on 7-dehydrocholesterol in the skin. Vitamin D3 is converted in the liver to 25-hydroxyvitamin D, the form
of vitamin D that is measured in the serum. 25-hydroxyvitamin D is converted in the kidneys to the active form of
vitamin D, 1,25-dihydroxyvitamin D (calcitriol), which promotes absorption of calcium and phosphate from the
gut, and assists bone mineralisation by interacting with parathyroid hormone. Dietary sources provide less than
10% of total requirements of vitamin D.
Adequate exposure to sunlight is the best way to prevent vitamin D deficiency. The amount of exposure required
depends on the season, the location (ie distance from the equator) and the person’s skin tone. Suggested exposure
times depending on location in Australia can be found on the Osteoporosis Australia website.
Vitamin D deficiency can be classified by severity, as shown in Table 19.13. Serum 25-hydroxyvitamin D
concentration can vary seasonally by up to 20 nanomol/L, so measurements should always be interpreted in the
context of the season.
Vitamin D deficiency is usually asymptomatic, but can present with mild bone pain and muscle weakness. Severe
deficiency can cause defects in bone mineralisation leading to osteomalacia in adults or rickets in children.
Classification of vitamin D deficiency by severity (Table 19.13) [NB1]
Severity of vitamin D deficiency Serum 25-hydroxyvitamin D concentration

mild 30 to 49 nanomol/L
moderate 12.5 to 29 nanomol/L
severe lower than 12.5 nanomol/L
NB1: Serum 25-hydroxyvitamin D concentration can vary seasonally by up to 20 nanomol/L, so measurements should always be interpreted in the
context of the season.
Who should have their vitamin D measured?

Routine screening for vitamin D deficiency in healthy people with no risk factors for deficiency is not
recommended; it is likely to identify people with mild, often seasonal, deficiency who are unlikely to benefit from
supplementation. Screening is only funded by the Medicare Benefits Schedule for select patients [Note 1].
Routine screening for vitamin D deficiency in healthy people with no risk factors for deficiency is not recommended.
Measure serum 25-hydroxyvitamin D concentration in people at increased risk of vitamin D deficiency, such as
those who:
are institutionalised or housebound (eg chronic illness, disability)

wear clothing that covers most of the skin (eg for cultural or occupational reasons)
have dark skin (Fitzpatrick skin types V and VI [Note 2])
have a medical condition (eg end-stage liver disease, kidney disease, hyperparathyroidism) or take a drug
(eg rifampicin, antiepileptics) that affects vitamin D metabolism and storage in the liver
have fat malabsorption (eg due to cystic fibrosis, coeliac disease or inflammatory bowel disease) or
gastrectomy.
If a patient is found to be vitamin D replete on testing, repeated (eg annual) testing is not recommended—it is
unlikely to reveal subsequent deficiency unless the patient’s risk factors have changed substantially.
Women with a risk factor for deficiency who become pregnant should have their serum 25-hydroxyvitamin D
concentration measured at their first antenatal visit.
Note 1: See the Medicare Benefits Schedule website for current information.
Note 2: Australian Radiation Protection and Nuclear Safety Agency (ARPANSA). Fitzpatrick skin type [chart]. Canberra: ARPANSA; 2019. [URL]
Who should be treated with vitamin D?
Vitamin D supplementation is recommended for people who:
have uncomplicated moderate or severe vitamin D deficiency (serum 25-hydroxyvitamin D concentration

lower than 30 nanomol/L), particularly if symptomatic
are starting drug therapy for osteoporosis and have a serum 25-hydroxyvitamin D concentration lower than
50 nanomol/L (see also Vitamin D and osteoporosis)
have osteomalacia or rickets.
In patients with mild vitamin D deficiency without symptoms or complications (ie not associated with rickets,
osteomalacia or hyperparathyroidism), evidence that vitamin D supplementation improves outcomes is limited and
inconsistent. Lifestyle changes to improve sun exposure are usually sufficient; however, supplementation for mild
deficiency is also reasonable and unlikely to cause harm.
Healthy people with a serum 25-hydroxyvitamin D concentration above 50 nanomol/L are not deficient, and there
is no evidence that vitamin D supplements prevent long-term disease in these people.
The use of vitamin D to improve outcomes not related to bone or muscle health is not recommended. In a large
randomised placebo-controlled study, vitamin D supplementation did not result in a lower incidence of cancer or
cardiovascular events [Note 3].
If a patient is found to be vitamin D deficient, also review calcium intake and supplement if needed. See here for
information on calcium intake.
Note 3: Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D supplements and prevention of cancer and cardiovascular
disease. N Engl J Med 2019;380(1):33-44. [URL]
Vitamin D treatment regimens

Evidence to support a specific target serum 25-hydroxyvitamin D concentration to improve outcomes is lacking. A
reasonable target of vitamin D supplementation is a serum 25-hydroxyvitamin D concentration of 50 nanomol/L or
more.
Vitamin D absorption is affected by many factors (eg weight, medical conditions, drugs) so the dose required to
meet this target varies, even between patients with similar baseline serum 25-hydroxyvitamin D concentration.
For patients with vitamin D deficiency complicated by osteomalacia or rickets, see Osteomalacia and rickets.
For children with vitamin D deficiency, use the same colecalciferol doses as those used for Rickets caused by
vitamin D deficiency.
For adults with uncomplicated mild vitamin D deficiency, consider lifestyle measures to increase exposure to
sunlight first line. If supplementation is preferred, use:
1 colecalciferol 25 to 50 micrograms (1000 to 2000 international units) orally, daily
OR
1 colecalciferol 175 to 350 micrograms (7000 to 14 000 international units) orally, weekly.
To treat uncomplicated moderate to severe vitamin D deficiency, higher doses are used, although long-term safety
data for these doses is not available. A suitable regimen is:
colecalciferol 75 to 125 micrograms (3000 to 5000 international units) orally, daily for 6
to 12 weeks, followed by 25 to 50 micrograms (1000 to 2000 international units) orally,
daily.
Consider using a higher dose in obese patients, and patients taking a drug that alters metabolism and storage of 25-
hydroxyvitamin D in the liver (eg rifampicin or some antiepileptics). Very high doses (eg 1250 micrograms [50
000 international units] weekly) are sometimes used to treat patients with known fat malabsorption disorders (eg
due to cystic fibrosis, coeliac disease or inflammatory bowel disease) or gastrectomy, or severe symptomatic
deficiency, although safety data for these doses is not available.
Higher doses taken less frequently (eg taking the total monthly dose once a month) can be considered to improve
adherence. These regimens may increase the risk of dosing errors, so are not routinely recommended first line.
Megadose therapy with 7500 to 12 500 micrograms (300 000 to 500 000 international units) is occasionally used
for patients with severe deficiency and poor adherence; however, safety data are limited and it is associated with an
increased risk of falls in older people.
Measure the serum 25-hydroxyvitamin D concentration after 6 months in patients with baseline mild deficiency,
and 3 months in patients with baseline moderate to severe deficiency. Earlier testing can be considered in patients
with particularly severe deficiency or persistent symptoms, and those with fat malabsorption or gastrectomy. After
reaching the target serum 25-hydroxyvitamin D concentration, no further testing is needed unless risk factors
change. Most patients need ongoing low-dose (ie colecalciferol 25 to 50 micrograms [1000 to 2000 international
units]) treatment.
The formulations of colecalciferol available in Australia are unlikely to cause vitamin D toxicity. However, if
toxicity from colecalciferol occurs, see Hypercalcaemia caused by vitamin D toxicity.
Key references
Vitamin D deficiency
Australian Radiation Protection and Nuclear Safety Agency (ARPANSA). Fitzpatrick skin type [chart]. Canberra:
ARPANSA; 2019. https://www.arpansa.gov.au/services/monitoring/ultraviolet-radiation-monitoring/ultraviolet-radiation-
dose/ultraviolet
Lucas R, Neale R. What is the optimal level of vitamin D? - separating the evidence from the rhetoric. Aust Fam
Physician 2014;43(3):119–22.
Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D supplements and prevention of
cancer and cardiovascular disease. N Engl J Med 2019;380(1):33–44.
Nowson CA, McGrath JJ, Ebeling PR, Haikerwal A, Daly RM, Sanders KM, et al. Vitamin D and health in adults in
Australia and New Zealand: a position statement. Med J Aust 2012;196(11):686–7.
Nowson CA, McGrath JJ, Ebeling PR, Haikerwal A, Daly RM, Sanders KM, et al. Update to vitamin D and health in
adults in Australia and New Zealand: a position statement from the Endocrine Society of Australia (ESA). Sydney:
ESA; 2013. https://www.endocrinesociety.org.au/position-statements.asp
The Royal College of Pathologists of Australasia (RCPA). The Royal College of Pathologists of Australasia: tests,
treatments and procedures clinicians and consumers should question [Choosing Wisely recommendation]. Sydney:
NPS MedicineWise; Last reviewed 22 April 2015 http://www.choosingwisely.org.au/recommendations/rcpa
Working Group of the Australian and New Zealand Bone and Mineral Society and the Endocrine Society of Australia
and Osteoporosis Australia. Vitamin D and adult bone health in Australia and New Zealand: a position statement. Med
J Aust 2005;182:281–85. https://www.anzbms.org.au/policies.asp
Hypocalcaemia
Introduction to hypocalcaemia
Hypocalcaemia is often asymptomatic, but patients may present with generalised signs of neuromuscular
irritability such as tetany (often including positive Chvostek and Trousseau signs).
Hypocalcaemia is diagnosed on the basis of a low serum total calcium concentration corrected for albumin (normal
range 2.10 to 2.60 mmol/L). If the albumin concentration is significantly abnormal, serum ionised calcium should
be measured directly.
Common causes of hypocalcaemia are listed in Box 19.3.
Common causes of hypocalcaemia (Box 19.3)
Severe vitamin D deficiency [NB1]
Autoimmune hypoparathyroidism
Parathyroid injury following thyroidectomy or parathyroidectomy
Hypoparathyroidism related to congenital disorders (eg DiGeorge syndrome)
Hypomagnesaemia (including in association with malabsorption, alcohol abuse and proton pump inhibitors)
Antiresorptive drugs (bisphosphonates and denosumab)
Autosomal dominant hypocalcaemia
Neonate of a mother with hypercalcaemia
Vitamin D–dependent rickets type 1 or 2 [NB2]
NB1: Severe vitamin D deficiency in children with nutritional deficiency is the most common cause of hypocalcaemia in children.
NB2: Vitamin D–dependent rickets type 1 is a deficiency of the enzyme that catalyses the conversion of 25-hydroxyvitamin D to 1,25-
dihydroxyvitamin D. Vitamin D–dependent rickets type 2 is a mutation of the vitamin D receptor gene, leading to resistance to 1,25-
dihydroxyvitamin D.
Acute severe hypocalcaemia

Acute severe hypocalcaemia can cause tetany, laryngospasm and seizures. Depending on the severity of associated
seizures, hypocalcaemia can be life-threatening; arrange immediate transport to hospital by ambulance for
management in a high-dependency ward. In children, acute severe hypocalcaemia can cause neuronal damage and
intellectual impairment if left untreated.
Severe symptomatic hypocalcaemia of any cause should be treated initially with a slow intravenous injection of
calcium. In adults, this is followed by a continuous intravenous calcium infusion. In children, the slow intravenous
injection can be repeated as required; calcium infusions are not usually used in children. The goal is to control
symptoms by maintaining the serum calcium concentration within the normal range.
Extravasation of calcium can cause localised skin necrosis; ensure intravenous access is secure and monitored.
Calcium gluconate is preferred to calcium chloride as it is less toxic to peripheral veins. Calcium should never be
administered by intramuscular or subcutaneous injection.
Extravasation of intravenous calcium can cause severe tissue damage.
The parenteral calcium formulations available in Australia are:
calcium gluconate 10%, available as a 10 mL vial containing 2.2 mmol of elemental calcium
calcium chloride 10%, available as a 10 mL vial containing 6.8 mmol of elemental calcium.
For an adult, use:
1 calcium gluconate 10% 20 mL (4.4 mmol elemental calcium) in sodium chloride 0.9%
100 mL intravenously over 20 minutes; repeat if required
FOLLOWED BY
calcium gluconate 10% 100 mL (22 mmol elemental calcium) in sodium chloride 0.9%
900 mL by intravenous infusion at an initial rate of 50 mL/hour (1.1 mmol elemental
calcium/hour). Titrate to maintain a corrected serum total calcium concentration of 2.0 to
2.3 mmol/L
OR
2 calcium chloride 10% 5 mL (3.4 mmol elemental calcium) in sodium chloride 0.9% 100
mL intravenously over 20 minutes; repeat if required
FOLLOWED BY
calcium chloride 10% 30 mL (20.4 mmol elemental calcium) in sodium chloride 0.9% 970
mL by intravenous infusion at an initial rate of 50 mL/hour (1.02 mmol elemental
calcium/hour). Titrate to maintain a corrected serum total calcium concentration of 2.0 to
2.3 mmol/L.
For a child, use:
calcium gluconate 10% 0.5 mL/kg (0.11 mmol elemental calcium/kg) up to a maximum of
20 mL (4.4 mmol elemental calcium), diluted in sodium chloride 0.9%, intravenously over
30 to 60 minutes; repeat as required.
Measure serum calcium concentration every 3 to 4 hours, and monitor cardiac function for the duration of
intravenous therapy.
Once the patient is stable and can tolerate oral intake, start an oral calcium supplement. If hypocalcaemia is caused
by severe vitamin D deficiency or hypoparathyroidism, or if hypocalcaemia is difficult to control with the infusion,
also start oral calcitriol (an active vitamin D compound). See Moderate hypocalcaemia for calcium and calcitriol
doses. The infusion can be stopped once adequate oral therapy has been established.
It may be necessary to correct coexisting hypomagnesaemia (see Hypomagnesaemia), especially in patients with:
severe postoperative hypoparathyroidism

malabsorption due to short bowel syndrome
hypocalcaemia associated with alcohol abuse
proton pump inhibitor–induced hypomagnesaemia.
Long-term therapy may be necessary if the cause of hypocalcaemia is permanent (eg damaged parathyroid gland);
see Long-term management of hypocalcaemia.
Moderate hypocalcaemia
Moderate hypocalcaemia usually presents with muscle cramps, spasms or paraesthesia. It is typically caused by
hypoparathyroidism.
In an adult, hypocalcaemia can be corrected with an oral calcium supplement. Patients with hypoparathyroidism
usually also require oral calcitriol. Patients with vitamin D deficiency should be treated with oral colecalciferol
(see Vitamin D treatment regimens for doses). In children, calcium and calcitriol are usually used together.
For an adult with moderate hypocalcaemia, a reasonable initial regimen is:
1 calcium carbonate 1.25 to 1.5 g (elemental calcium 500 to 600 mg) orally, twice daily,
with food
OR
1 calcium citrate 2.38 g (elemental calcium 500 mg) orally, twice daily
PLUS with either of the above regimens in patients with hypoparathyroidism
calcitriol 0.25 to 0.5 micrograms orally, twice daily.
For a child with moderate hypocalcaemia, a reasonable initial regimen is:
calcium carbonate 100 mg/kg (elemental calcium 40 mg/kg) orally, daily in 4 to 6 divided
doses; increase as required (doses up to 300 to 500 mg/kg [elemental calcium 120 to 200
mg/kg] may be required)
PLUS
calcitriol 0.015 micrograms/kg orally, daily.
Review the patient's symptoms, and measure serum calcium and phosphate concentrations every 1 to 2 weeks.
Adjust the dose or frequency of treatment as needed, until therapy is stabilised. Calcitriol raises the serum calcium
concentration over 1 to 2 days and the dose requirement varies significantly among patients. Once stable, measure
24-hour urine calcium excretion to check for hypercalciuria. If hypercalciuria is present, reduce the dose of
calcitriol slightly.
Long-term therapy may be necessary if the cause of hypocalcaemia is permanent (eg damaged parathyroid gland);
see Long-term management of hypocalcaemia.
Long-term management of hypocalcaemia

Long-term treatment for hypocalcaemia with an oral calcium supplement, and a vitamin D supplement (calcitriol
or colecalciferol) if appropriate, may be necessary if the cause of hypocalcaemia is permanent (eg damaged
parathyroid gland). Clinical and biochemical monitoring every 6 months is usually sufficient for these patients.
Aim for a serum calcium concentration at the lower limit or slightly below the reference range to avoid hypercalciuria and
nephrocalcinosis.
The primary aim of ongoing therapy is to maintain symptom control, rather than achieve a target serum calcium
concentration. A concentration at the lower limit of or slightly below the reference range is reasonable—
attempting to normalise the serum calcium concentration can cause hypercalciuria and nephrocalcinosis. Kidney
ultrasound to screen for nephrocalcinosis is recommended for all children who require ongoing therapy, and for
adults if clinically indicated.
Discourage patients from consuming food or drink with a high phosphate content (eg soft drinks, sparkling water).
Although some dairy products (eg milk) contain phosphate, moderate consumption is safe and a normal dietary
calcium intake, as well as a high water intake, should be encouraged.
Management of hypocalcaemia during pregnancy and breastfeeding

In pregnant and breastfeeding women with pre-existing hypoparathyroidism, test serum ionised calcium
concentration and serum total calcium concentration corrected for albumin regularly, aiming to maintain the
concentrations at the lower limit of the normal range.
During pregnancy, calcitriol and calcium requirements do not usually change appreciably, but if titration is
required, adjust the calcitriol dose rather than the calcium dose.
During breastfeeding, bone resorption and reabsorption of calcium from the kidneys increases, so the calcitriol
dose requirement usually decreases.
Key references
Hypocalcaemia
Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, van Biesen W, et al. European Society of
Endocrinology clinical guideline: treatment of chronic hypoparathyroidism in adults. Eur J Endocrinol 2015;173(2):G1–
20.
Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008;336(7656):1298–302.
Paxton GA, Teale GR, Nowson CA, Mason RS, McGrath JJ, Thompson MJ, et al. Vitamin D and health in pregnancy,
infants, children and adolescents in Australia and New Zealand: a position statement. Med J Aust 2013;198(3):142–3.
Turner J, Gittoes N, Selby P, Society for Endocrinology Clinical Committee. Society For Endocrinology endocrine
emergency guidance: emergency management of acute hypocalcaemia in adult patients. Endocr Connect
2016;5(5):G7–G8.
Hypercalcaemia
Introduction to hypercalcaemia
Hypercalcaemia is diagnosed on the basis of an elevated serum total calcium concentration, corrected for albumin
(normal range 2.10 to 2.60 mmol/L). If the albumin concentration is significantly abnormal, serum ionised calcium
should be measured directly.
Hypercalcaemia may be detected incidentally, or present with a variety of nonspecific symptoms (eg failure to
thrive in an infant, abdominal pain, constipation, polyuria, polydipsia). Cardiac rhythm abnormalities can also
occur.
Hypercalcaemia has many causes (see Box 19.4), but 80 to 90% of cases in adults result from primary
hyperparathyroidism or malignancy (see the Palliative Care guidelines for management of hypercalcaemia of
malignancy).
Hypercalcaemia is classified as parathyroid-dependent or parathyroid-independent, by simultaneously measuring

serum calcium and parathyroid hormone concentrations. In parathyroid-dependent hypercalcaemia, the parathyroid
hormone concentration is usually above or at the upper end of the normal range.
Causes of hypercalcaemia (Box 19.4)
Most common causes
primary hyperparathyroidism
hypercalcaemia of malignancy
Less common causes
thiazide diuretic drugs [NB1]
vitamin D toxicity
sarcoidosis or other granulomatous disorders
severe hyperthyroidism
milk alkali syndrome
renal osteodystrophy with tertiary hyperparathyroidism
primary adrenal insufficiency
familial hypocalciuric hypercalcaemia (familial benign hypercalcaemia)
prolonged immobilisation [NB2]
cytochrome P450 24A1 (CYP24A1) gene mutation
idiopathic hypercalcaemia of infancy
neonatal subcutaneous fat necrosis
neonatal severe hyperparathyroidism
infantile hypophosphatasia
William syndrome
NB1: Patients who develop hypercalcaemia after starting a thiazide diuretic usually have primary hyperparathyroidism, which may have been
previously undiagnosed.
NB2: Immobilisation during states of high bone turnover (eg adolescence, Paget disease of bone) can cause hypercalcaemia.
Acute severe hypercalcaemia

Initial rehydration
Acute severe hypercalcaemia (serum total calcium concentration corrected for albumin above 3.0 mmol/L) often
causes dehydration and electrolyte depletion, leading to a deterioration in kidney function that increases the serum
calcium concentration further. Rehydration with a sodium chloride infusion is essential; it can be expected to
reduce the serum calcium concentration, but not necessarily to normalise it. A reasonable infusion rate for an adult
is:
sodium chloride 0.9% 4 to 6 litres by intravenous infusion over 24 hours.
Rehydration in a child is determined by weight and degree of dehydration.
Monitor cardiac function until serum calcium is reduced to a safe concentration (ie within or slightly above the
normal range). Hypercalcaemia increases the risk of cardiac complications, particularly in older people and
patients with a history of cardiac disease.
Intravenous frusemide can be used under specialist supervision to treat fluid overload following rehydration. Do
not use frusemide for primary treatment of hypercalcaemia because it can deplete intravascular volume further.
Additional treatment
If severe hypercalcaemia in a child does not respond adequately to rehydration, seek specialist advice.
In an adult with severe hypercalcaemia (of any cause) that has not responded to rehydration, consider using an
intravenous bisphosphonate infusion to temporarily lower the serum calcium concentration. Before starting a
bisphosphonate, take a blood sample to measure the patient’s parathyroid hormone concentration to help determine
the cause of hypercalcaemia. For the bisphosphonate infusion, use:
1 zoledronic acid 4 mg by intravenous infusion over at least 15 minutes
OR
2 pamidronate 60 to 90 mg by intravenous infusion over 4 hours; starting dose depends on

total serum calcium concentration corrected for albumin.
Patients must be well hydrated before receiving bisphosphonate therapy.
The bisphosphonate infusion can cause transient influenza-like symptoms. This most often occurs after the first
dose, and is less likely to occur with subsequent doses. To reduce the severity of the reaction, advise patients to
take paracetamol before and for several days after the infusion.
In acute life-threatening hypercalcaemia, consider parenteral salcatonin (salmon calcitonin) in addition to the
bisphosphonate to achieve a more rapid effect. Salcatonin becomes less effective with repeated doses and is
usually ineffective after several days of use. Use:
salcatonin 100 international units subcutaneously, intramuscularly or intravenously, every

8 to 12 hours.
Glucocorticoids may be required in refractory hypercalcaemia caused by malignancy, vitamin D toxicity or

sarcoidosis. Severe hypercalcaemia complicated by kidney failure can require dialysis. Seek specialist advice.
Hypercalcaemia caused by vitamin D toxicity

Hypercalcaemia can be caused by vitamin D toxicity, usually from an exogenous source (ie calcitriol or high-dose
colecalciferol therapy).
If vitamin D toxicity is caused by calcitriol therapy, stop the calcitriol (as well as any concurrent calcium
supplement). The hypercalcaemia usually settles within 1 or 2 days.
The formulations of colecalciferol available in Australia are unlikely to cause vitamin D toxicity. However, if
toxicity from colecalciferol occurs, stopping treatment might not lead to rapid resolution because colecalciferol is
stored extensively in fat. In addition to rehydration, oral glucocorticoids can be effective in severe or protracted
vitamin D toxicity. A suitable regimen is:
prednis(ol)one 30 to 60 mg orally, once daily; starting dose depends on total serum

calcium concentration corrected for albumin.
Continue prednis(ol)one therapy until the total serum calcium concentration corrected for albumin is within the
normal range and hypercalciuria is significantly reduced. Withdraw therapy by tapering the dose to avoid adrenal
insufficiency (see Adrenocortical suppression).
Hypercalcaemia caused by sarcoidosis or other granulomatous

disorders
Hypercalcaemia caused by sarcoidosis or other granulomatous disorders is associated with an inappropriately high
concentration of 1,25-dihydroxyvitamin D (calcitriol). Seek expert advice for management. In addition to
rehydration, prednis(ol)one is effective. A suitable regimen is:
prednis(ol)one 15 to 30 mg orally, once daily; starting dose depends on total serum

calcium concentration corrected for albumin.
Continue prednis(ol)one therapy until the total serum calcium concentration corrected for albumin is within the
normal range and hypercalciuria has resolved. Withdraw therapy by tapering the dose to avoid adrenal
insufficiency (see Adrenocortical suppression).
Hypercalcaemia and pregnancy

Hypercalcaemia is uncommon in pregnancy. Mild degrees of hypercalcaemia can be masked by the physiological
decline of serum total (not ionised) calcium in normal pregnancy. Severe hypercalcaemia can cause hyperemesis,
dehydration, premature contractions and neuromuscular effects, threatening both the mother and neonate. In a
pregnant woman with hypercalcaemia, exclude any factors that could be contributing to hypercalcaemia (eg
supplements containing vitamin D).
Evidence to guide management of hypercalcaemia secondary to hyperparathyroidism (usually due to a parathyroid

adenoma) during pregnancy is lacking. Mild, asymptomatic cases can be managed conservatively with hydration
and correction of electrolyte abnormalities. Bisphosphonates should not be used during pregnancy. In symptomatic
or severe cases, surgical removal of a parathyroid adenoma during the second trimester is indicated.
Hypercalcaemia in pregnancy can also be caused by pseudohyperparathyroidism, a rare cause of hypercalcaemia

that results from physiological release of parathyroid hormone–related protein from the placenta and breasts during
pregnancy. The increased parathyroid hormone–related protein stimulates skeletal resorption.
Psuedohyperparathyroidism is usually asymptomatic, with mild hypercalcaemia and suppressed parathyroid
hormone on testing. Management is similar to that for primary hyperparathyroidism.
In pregnant women with hyperparathyroidism or pseudohyperparathyroidism, the fetal serum calcium

concentration is even higher than the maternal concentration, and can result in suppression of fetal parathyroid
function in utero. The neonate is at risk of hypocalcaemia secondary to suppressed parathyroid activity, so must be
assessed for hypocalcaemia on delivery and treated if necessary.
Key references
Hypercalcaemia
Bilezikian JP, Bandeira L, Khan A, Cusano NE. Hyperparathyroidism. Lancet 2018;391(10116):168–78.
Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, et al. Guidelines for the management of
asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin
Brandi ML, Bilezikian JP, Shoback D, Bouillon R, Clarke BL, Thakker RV, et al. Management of hypoparathyroidism:
summary statement and guidelines. J Clin Endocrinol Metab 2016;101(6):2273–83.
Hypophosphataemia
Hypophosphataemia
Hypophosphataemia is defined as a serum phosphate concentration lower than 0.8 mmol/L (normal range is
0.8 to 1.5 mmol/L).
Treatment is not always necessary, depending on the severity and the rate of decline of serum phosphate
concentration.
Moderate hypophosphataemia (serum phosphate concentration 0.5 to 0.8 mmol/L) is often seen with
primary hyperparathyroidism, tumour-induced osteomalacia, vitamin D deficiency, iron infusions and antacid
abuse. It usually resolves when the cause is treated or stopped, so oral phosphate replacement is rarely
needed.
Severe hypophosphataemia (serum phosphate concentration lower than 0.5 mmol/L) can be caused by
alcohol withdrawal syndrome, refeeding syndrome (anorexia nervosa, starvation), trauma and sepsis, and
occurs in around 1% of hospitalised patients. It is often asymptomatic, but presenting symptoms can be:
neuromuscular—ranging from progressive myopathy to paralysis, confusion and seizures

cardiorespiratory—respiratory muscular failure, left ventricular dysfunction with heart failure and
arrhythmias
haematological—haemolysis, thrombocytopenia and impaired leucocyte function.
Management of acute hypophosphataemia in critically ill patients is guided by the severity of the
deficiency. For patients with severe hypophosphataemia and normal kidney function, use:
potassium dihydrogen phosphate 13.6% 2 to 10 mmol elemental phosphate/hour by

intravenous infusion, for 4 hours.
Measure serum calcium and phosphate concentrations hourly and adjust the dose as necessary. Monitor
cardiac and kidney function during the infusion. Phosphate replacement is usually required until the cause has
been treated.
Chronic hypophosphataemia can occur in patients with conditions such as familial X-linked
hypophosphataemic rickets and tumour-induced osteomalacia. It can be treated with a combination of:
oral elemental phosphorus (sodium acid phosphate, monobasic sodium phosphate)

calcitriol (usually only used for children and adolescents).
The aim of treatment is to maintain a normal serum phosphate concentration. Use:
elemental phosphorus 500 to 1000 mg orally, 3 times daily. Starting dose depends on
serum phosphate concentration.
Elemental phosphorous can cause diarrhoea, which may limit the dose.
Milk is rich in phosphate and regular consumption can reduce the dose requirement of elemental
phosphorous.
Key references
Hypophosphataemia
Disorders of serum minerals (Section V). In: Favus MJ. Primer on the metabolic bone diseases and disorders of
mineral metabolism. 6th ed. Washington, DC: American Society for Bone and Mineral Research; 2006. p. 176–
242.
Hyperphosphataemia
Hyperphosphataemia
Hyperphosphataemia is defined by a serum phosphate concentration higher than 1.5 mmol/L. Delayed
transport of samples to the laboratory can result in a spuriously elevated serum phosphate concentration.
Hyperphosphataemia is typically caused by:
impaired kidney phosphate excretion (eg kidney disease, tumoral calcinosis, hypoparathyroidism)
increased extracellular phosphate (eg rapid administration of phosphate, catabolic states, tissue or cell
lysis).
Chronic kidney disease is the most common cause; hyperphosphataemia caused by kidney disease is usually
chronic and asymptomatic. Clinical manifestations are usually related to associated hypocalcaemia and
tetany. Chronic hyperphosphataemia is primarily treated by managing the cause. It can also include restricting
phosphate intake, using phosphate binders and inducing diuresis (not recommended in patients with impaired
kidney function). Specialist management is required.
Acute severe hyperphosphataemia (with electrolyte disturbance and sudden death) has been reported after
taking preprocedural oral sodium phosphate laxatives (eg before a colonoscopy) (see Preparation for
colonoscopy: Lavage solutions for more information). The rapid onset of hyperphosphataemia (in contrast to
the chronic hyperphosphataemia seen with chronic kidney disease) causes cardiorespiratory collapse and
seizures. Emergency treatment with volume expansion, and urgent haemodialysis, may be required.
Key references
Hyperphosphataemia
Patel L, Bernard LM, Elder GJ. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in
CKD: A meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol 2016;11(2):232–44.
Hyperparathyroidism
Primary hyperparathyroidism
Parathyroid hormone should be measured in any patient with hypercalcaemia; for information about
management of severe acute hypercalcaemia secondary to primary hyperparathyroidism, see Hypercalcaemia.
In addition to symptoms of hypercalcaemia, patients with hyperparathyroidism can experience fatigue and
cognitive changes.
Primary hyperparathyroidism is most commonly caused by a single parathyroid adenoma. Definitive therapy
is surgery, which cures 95% of cases and has low morbidity. See Perioperative care for parathyroid surgery.
A ‘watch and wait’ approach can be considered instead of surgery in patients who are 50 years or older, and
have:
a total serum calcium concentration corrected for albumin lower than 2.90 mmol/L
normal kidney function
no nephrolithiasis or nephrocalcinosis
a bone mineral density (BMD) T-score higher than −2.5
no symptoms.
Monitor for onset of symptoms and measure total serum calcium concentration and kidney function every 6 to
12 months, and BMD every 2 years. Using this conservative approach, around 50% of these patients will not
require surgery during 10 years of follow-up. However, this can also result in decreased BMD.
Advise patients who elect not to have surgery to:
avoid a high calcium intake (ie from diet or calcium supplements)

limit vitamin D supplementation with colecalciferol (if required for deficiency) to 25 micrograms (1000
international units) daily
maintain a high water intake (approximately 2.5 litres daily), unless contraindicated.
Calcimimetic drugs (eg cinacalcet) can be used for hyperparathyroidism or parathyroid cancer if surgery is not
possible or is ineffective. These drugs are best used in specialist centres.
Patients younger than 40 years who present with hyperparathyroidism should be referred for genetic testing.
Patients with primary hyperparathyroidism can also have moderate hypophosphataemia; this usually resolves
with management of hyperparathyroidism, and no specific treatment is required.
Secondary and tertiary hyperparathyroidism

Secondary hyperparathyroidism typically occurs as a result of vitamin D deficiency—parathyroid hormone
release is increased as a secondary response to the low serum 25-hydroxyvitamin D concentration. Secondary
elevation of parathyroid hormone can also occur in patients with chronic kidney disease. Management
includes treatment of the underlying cause, and vitamin D supplementation if the patient is deficient.
Tertiary hyperparathyroidism is uncommon. The mechanism appears to be related to prolonged parathyroid

stimulation (secondary hyperparathyroidism) leading to an autonomous parathyroid response, which produces
hypercalcaemia. The most common causes are chronic kidney disease and kidney transplantation.
Management often requires partial removal of the parathyroid glands (see Perioperative care for parathyroid
surgery). Cinacalcet can be used with specialist advice to treat tertiary hyperparathyroidism in patients with
chronic kidney disease [Note 1].
Note 1: At the time of writing, cinacalcet is not available on the Pharmaceutical Benefits Scheme (PBS) for tertiary hyperparathyroidism. See
the PBS website for current information.
Perioperative care for parathyroid surgery

All patients undergoing parathyroid surgery should avoid excessive calcium intake and maintain good
hydration before the operation.
Vitamin D deficiency can exacerbate primary hyperparathyroidism by causing concurrent secondary

hyperparathyroidism. If present, correct vitamin D deficiency before surgery with oral colecalciferol.
Overcorrection can increase the risk of kidney stones, so avoid a serum 25-hydroxyvitamin D concentration
above 100 nanomol/L. See here for more information about vitamin D supplementation.
Hungry bone syndrome is a state of acute onset severe hypocalcaemia (usually with hypophosphataemia) that
can occur after successful surgery for hyperparathyroidism (usually tertiary hyperparathyroidism). Patients at
particular risk are those with both:
moderate to severe hyperparathyroidism

evidence of parathyroid bone disease (eg elevated serum alkaline phosphatase concentration of bone
origin, radiological features of hyperparathyroidism, osteoporosis on bone densitometry).
Refer patients at risk of hungry bone syndrome for expert evaluation and care before parathyroid surgery. In
patients with tertiary hyperparathyroidism at risk of hungry bone syndrome, a course of preoperative calcitriol
is sometimes used by a specialist team to reduce the risk.
Key references
Hyperparathyroidism
Bilezikian JP, Bandeira L, Khan A, Cusano NE. Hyperparathyroidism. Lancet 2018;391(10116):168–78.
Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, et al. Guidelines for the management
of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin
Brandi ML, Bilezikian JP, Shoback D, Bouillon R, Clarke BL, Thakker RV, et al. Management of
hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 2016;101(6):2273–83.
Paget disease of bone
Introduction to Paget disease of bone
Paget disease of bone is a focal bone disorder characterised by excessive bone resorption by osteoclasts, and a
compensatory but disorganised increase in bone formation by osteoblasts. Paget disease can progress and deform
bones in one or more parts of the skeleton, causing bone pain, bony deformities, neurological syndromes,
osteoarthritis and arthropathies. The cause is unknown. Distinguishing between bone pain due to Paget disease and
joint pain due to associated osteoarthritis can be difficult. Paget-related pain typically occurs at rest, particularly at
night.
The prevalence of Paget disease increases with age. It has a mean age of onset of around 55 years, and affects
approximately 2 to 4% of people over 55 years. It most commonly affects Caucasian people of British origin. The
prevalence of Paget disease declined by 60% from 1974 to 1994, and appears to be continuing to decline.
Siblings and children of patients with Paget disease have a slightly higher risk of developing the disease. Consider
familial screening with measurement of serum alkaline phosphatase concentration after the age of 40 years.
Investigations used in Paget disease of bone

Bone-turnover markers can be used to diagnose Paget disease, and assess a patient’s response to treatment. These
include markers of:
bone formation (eg serum total and bone-specific alkaline phosphatase concentrations)
bone resorption (eg degradation products of type I collagen such as urinary deoxypyridinoline and N-
telopeptides).
Serum total alkaline phosphatase concentration is the main test used to confirm the diagnosis of Paget disease, as
well as to indicate disease activity and assess response to treatment; it is sensitive, cheap and convenient.
Reference ranges vary among laboratories, but a serum total alkaline phosphatase concentration above 125 units/L
in the absence of another cause (eg liver function abnormality, vitamin D deficiency, hyperparathyroidism)
suggests active Paget disease. A normal serum total alkaline phosphatase concentration does not exclude the
diagnosis; it can mean that a single bone is affected (mono-ostotic disease) or that the disease is relatively inactive.
In patients with impaired liver function, serum total alkaline phosphatase can be difficult to interpret; use bone-
specific alkaline phosphatase instead.
Because most patients with Paget disease are asymptomatic, a diagnosis is often made after an incidental finding
of:
raised serum total alkaline phosphatase concentration

pagetic lesions on X-rays or bone scans.
X-rays are useful in Paget disease for:
monitoring response to therapy (eg deformities in long bones, resolution of lytic lesions)
evaluating cases that are resistant to therapy (eg continuing symptoms, persistently elevated serum total
alkaline phosphatase concentration)
identifying lesions at critical sites (eg skull, vertebrae) in patients with neurological symptoms.
Nuclear bone scanning is a sensitive but nonspecific technique for detecting pagetic bone lesions. It is used to
determine the extent and distribution of disease, rather than for diagnosis. Bone biopsy is rarely required to
confirm the diagnosis of Paget disease, or to differentiate it from other lytic or sclerotic bone disorders.
Principles of managing Paget disease of bone

Bisphosphonates are the mainstay of treatment for Paget disease of bone. Analgesics and nonsteroidal anti-
inflammatory drugs (NSAIDs) can also be used to ease symptoms related to bone pain and secondary osteoarthritis
(see Pharmacological management of osteoarthritis).
Most patients with symptomatic Paget disease require a bisphosphonate to relieve symptoms and to prevent
complications. Asymptomatic Paget disease does not usually warrant treatment; there is no evidence that
bisphosphonates prevent bony deformities in asymptomatic patients. However, treatment should be considered for
any patient at increased risk of disease progression or complications, including patients who:
are young (eg less than 50 years)

have a lesion at a critical site (eg skull, vertebrae)
have active disease (as indicated by elevated serum total alkaline phosphatase) particularly in weight-bearing
bones, near major joints or in the skull or vertebrae
have neurological symptoms
have hypercalcaemia (which is aggravated by bed rest)
require orthopaedic surgery of or near a pagetic bone.
The primary aims of treatment of Paget disease are to relieve symptoms and prevent complications. Normalisation
of the serum total alkaline phosphatase concentration is a secondary goal, which usually occurs incidentally with
symptom relief. Pagetic lesions do not always normalise with treatment, but symptom relief and normalisation of
alkaline phosphatase indicate that the lesions have become inactive.
If the patient remains symptomatic despite normalisation of alkaline phosphatase, consider an alternative cause of
the symptoms.
Surgery is sometimes required to manage complications of Paget disease:
Secondary osteoarthritis can require joint replacement or another orthopaedic procedure.

Neurological syndromes associated with spinal Paget disease often respond to bisphosphonates, but surgical
decompression of the spinal cord or cauda equina may be required.
Cosmetic or dental deformities related to a pagetic lesion may require oral maxillofacial surgery.
Bisphosphonates for Paget disease of bone

Bisphosphonates inhibit bone resorption and reduce the abnormal bone remodelling caused by Paget disease to
normal or near-normal. For indications for bisphosphonate therapy and aims of treatment, see Principles of
managing Paget disease of bone.
A single dose of an intravenous bisphosphonate or a short course of an oral bisphosphonate can produce prolonged
clinical and biochemical remission that persists after withdrawal of therapy. A repeat course of therapy is
occasionally required if serum total alkaline phosphatase remains elevated after the initial treatment, but
continuous long-term treatment is not recommended—the long-term benefit of treating Paget disease with a
bisphosphonate beyond 2 to 3 years is unknown.
Intravenous zoledronic acid is the most effective bisphosphonate for Paget disease.
Intravenous zoledronic acid appears to be the most effective bisphosphonate for Paget disease; the vast majority of
patients achieve sustained remission following a single dose of zoledronic acid.
Use:
zoledronic acid 5 mg by intravenous infusion over at least 15 minutes.
Intravenous administration of zoledronic acid in primary care is safe provided that:

serum total calcium concentration corrected for albumin is in the normal range (2.10 to 2.60 mmol/L)
estimated glomerular filtration rate (eGFR) is greater than 35 mL/min/1.73 m2
the patient is well hydrated.
Markers of bone resorption are suppressed quickly following antipagetic treatment, while the serum total alkaline
phosphatase concentration can take more than 3 months to reach its nadir. Measure the serum total alkaline
phosphatase concentration 3 to 6 months after giving zoledronic acid. A single dose of zoledronic acid is usually
effective. Persistent elevation of serum total alkaline phosphatase concentration following zoledronic acid should
prompt consideration of an alternative cause (eg osteosarcoma, bony metastasis).
If zoledronic acid is not appropriate, use:
1 risedronate 30 mg orally, daily on an empty stomach, for 2 months
OR
pamidronate 60 mg by intravenous infusion over 4 hours.

2
Measure the serum total alkaline phosphatase concentration 3 months after completing the course of therapy, to
determine whether the patient has achieved biochemical remission. If the serum total alkaline phosphatase
concentration remains elevated or if the patient still has symptoms, consider a repeat course of treatment after 6 to
12 months. If a patient does not respond to repeat therapy, review the diagnosis of Paget disease.
In a patient with a progressive rise in serum total alkaline phosphatase concentration or atypical bone pain with
neuropathic complications, investigate the possibility of malignancy; osteogenic sarcoma is an exceedingly rare
complication of Paget disease.
In refractory Paget disease, consider trialling an alternative bisphosphonate (eg change from oral to intravenous
bisphosphonate). Resistance to pamidronate can occur, particularly following repeated infusions.
Monitoring following remission of Paget disease of bone

Following remission, retest serum total alkaline phosphatase concentration every 2 years to detect relapse; also
monitor for recurrence of symptoms or progression of pagetic lesions. More frequent assessment is appropriate for
patients who had severe disease at baseline (eg serum total alkaline phosphatase concentration above 600 units/L)
or patients with neurological symptoms. Relapse is more common and occurs earlier (most commonly within 1 to
2 years) following treatment with risedronate than zoledronic acid.
Key references
Introduction to Paget disease of bone
Britton C, Walsh J. Paget disease of bone - an update. Aust Fam Physician 2012;41(3):100–3.
Cooper C, Harvey NC, Dennison EM, van Staa TP. Update on the epidemiology of Paget's disease of bone. J Bone
Miner Res 2006;21 Suppl 2:P3–8.
Cundy T. Is the prevalence of Paget's disease of bone decreasing? J Bone Miner Res 2006;21 Suppl 2:P9–13.
Poor G, Donath J, Fornet B, Cooper C. Epidemiology of Paget's disease in Europe: the prevalence is decreasing. J
Bone Miner Res 2006;21(10):1545–9.
Ralston SH, Corral-Gudino L, Cooper C, Francis RM, Fraser WD, Gennari L, et al. Diagnosis and management of
Paget's disease of bone in adults: a clinical guideline. J Bone Miner Res 2019:e3657.
Shaker JL. Paget's disease of bone: a review of epidemiology, pathophysiology and management. Ther Adv
Musculoskelet Dis 2009;1(2):107–25.
Investigations used in Paget disease of bone
Principles of managing Paget disease of bone
Ralston SH, Corral-Gudino L, Cooper C, Francis RM, Fraser WD, Gennari L, et al. Diagnosis and management of
Paget's disease of bone in adults: a clinical guideline. J Bone Miner Res 2019:e3657.
Reid IR, Lyles K, Su G, Brown JP, Walsh JP, del Pino-Montes J, et al. A single infusion of zoledronic acid produces
sustained remissions in Paget disease: data to 6.5 years. J Bone Miner Res 2011;26(9):2261–70.
Reid IR, Miller P, Lyles K, Fraser W, Brown JP, Saidi Y, et al. Comparison of a single infusion of zoledronic acid with
risedronate for Paget's disease. N Engl J Med 2005;353(9):898–908.
Singer FR, Bone HG, 3rd, Hosking DJ, Lyles KW, Murad MH, Reid IR, et al. Paget's disease of bone: an Endocrine
Society clinical practice guideline. J Clin Endocrinol Metab 2014;99(12):4408–22.
Tan A, Goodman K, Walker A, Hudson J, MacLennan GS, Selby PL, et al. Long-term randomized trial of intensive
versus symptomatic management in Paget's disease of bone: The PRISM-EZ study. J Bone Miner Res
2017;32(6):1165–73.
Bisphosphonates for Paget disease of bone
Gutteridge DH, Retallack RW, Ward LC, Stuckey BG, Stewart GO, Prince RL, et al. Clinical, biochemical, hematologic,
and radiographic responses in Paget's disease following intravenous pamidronate disodium: a 2-year study. Bone
1996;19(4):387–94.
Reid IR, Lyles K, Su G, Brown JP, Walsh JP, del Pino-Montes J, et al. A single infusion of zoledronic acid produces
sustained remissions in Paget disease: data to 6.5 years. J Bone Miner Res 2011;26(9):2261–70.
Reid IR, Miller P, Lyles K, Fraser W, Brown JP, Saidi Y, et al. Comparison of a single infusion of zoledronic acid with
risedronate for Paget's disease. N Engl J Med 2005;353(9):898–908.
Singer FR, Bone HG, 3rd, Hosking DJ, Lyles KW, Murad MH, Reid IR, et al. Paget's disease of bone: an Endocrine
Society clinical practice guideline. J Clin Endocrinol Metab 2014;99(12):4408–22.
Osteomalacia and rickets
Osteomalacia
Osteomalacia is a disorder of incomplete bone mineralisation that causes loss of bone mineral density (BMD)
and increased bone fragility in adults. The symptoms are often minor and nonspecific (eg bone pain, muscle
weakness), and can be absent altogether.
In developed countries, vitamin D deficiency accounts for most cases of osteomalacia in patients with normal
or near-normal kidney function. It typically only occurs if the serum 25-hydroxyvitamin D concentration is
lower than 20 nanomol/L. Specialist referral is recommended if osteomalacia is suspected.
Osteomalacia can also be caused by severe kidney disease (chronic kidney disease–mineral and bone disorder
[CKD-MBD]) and hypophosphataemia (eg tumour-induced osteomalacia). More complex treatment regimens
and specialist management are required for these patients.
Transiliac bone biopsy with double tetracycline is the gold-standard test for diagnosis of osteomalacia, but this
test is invasive. A diagnosis of osteomalacia caused by vitamin D deficiency can be made based on the
combination of:
typical symptoms (bone and muscle pain)

characteristic biochemical changes, including:
reduced serum 25-hydroxyvitamin D concentration
reduced serum calcium concentration
reduced serum phosphate concentration
increased serum parathyroid hormone concentration
increased serum alkaline phosphatase concentration
reduced BMD.
A history of limited exposure to sunlight supports the diagnosis.
The aim of treating osteomalacia is to:
relieve symptoms
prevent complications and recurrence
reverse the underlying causes (if possible)
correct vitamin D deficiency, hypocalcaemia, hypophosphataemia and secondary hyperparathyroidism,
and normalise serum alkaline phosphatase.
For osteomalacia caused by vitamin D deficiency, supplementation with colecalciferol reduces bone pain and
increases muscle strength within weeks. For an adult with normal kidney function, use:
colecalciferol 100 to 175 micrograms (4000 to 7000 international units) orally, daily
for 4 to 8 weeks, then reduce to 25 to 50 micrograms (1000 to 2000 international units)
daily.
Continue treatment for at least 6 to 12 months, with biochemical testing (serum 25-hydroxyvitamin D,
calcium, phosphate, parathyroid hormone and alkaline phosphatase concentrations) every 3 months, until all
biochemical abnormalities are corrected. If the risk for vitamin D deficiency is ongoing, continue treatment
indefinitely.
Higher oral colecalciferol doses are usually required in patients with gastrectomy or fat malabsorption, obese
patients, and patients taking a drug (eg rifampicin, an antiepileptic) that alters metabolism and storage of 25-
hydroxyvitamin D in the liver. Patients with intestinal malabsorption may need parenteral administration of
vitamin D for maintenance of normal serum calcium concentration. Higher colecalciferol doses taken less
frequently can be considered to improve adherence—these regimens may increase the risk of dosing errors, so
are not routinely recommended first line.
Ensure all patients with osteomalacia maintain a total daily calcium intake of 1300 mg, since the combination
of calcium and vitamin D prevents fractures (see Calcium for advice on achieving adequate calcium intake).
Rickets
Overview of Rickets
Rickets is a condition that occurs in children, in which inadequate mineralisation of the skeleton causes
bowing and distortion of bones, limb pain and fractures.
In developed countries, vitamin D deficiency accounts for most cases of rickets in children with normal or
near-normal kidney function. Vitamin D supplementation with colecalciferol is the mainstay of treatment for
these patients.
Rickets can also be caused by severe kidney disease, hypophosphataemia (eg X-linked hypophosphataemic
rickets) and vitamin D–dependent rickets (types 1 or 2 [Note 1]).
Note 1: Vitamin D–dependent rickets type 1 is a deficiency of the enzyme that catalyses the conversion of 25-hydroxyvitamin D to 1,25-
dihydroxyvitamin D. Vitamin D–dependent rickets type 2 is a mutation of the vitamin D receptor gene, leading to resistance to 1,25-
dihydroxyvitamin D.
Rickets caused by vitamin D deficiency

Vitamin D deficiency is increasing in the general community, and nutritional rickets is re-emerging as a
significant health concern for children. See Who should have their vitamin D measured for information about
risk factors for vitamin D deficiency. A consensus statement on preventing and treating nutritional rickets was
published in 2016 [Note 2]. Rickets caused by vitamin D deficiency should be managed with specialist advice.
Vitamin D supplementation reduces bone pain and increases muscle strength within weeks. To treat vitamin D
deficiency causing rickets, use:
colecalciferol
neonate: 25 micrograms (1000 international units) orally, daily for 3 months
child 1 to 12 months: 75 micrograms (3000 international units) orally, daily for 3
months
child more than 12 months: 125 micrograms (5000 international units) orally, daily for
3 months.
Megadose therapy can be considered to improve adherence. For megadose therapy in a child older than
12 months, use:
colecalciferol 3750 micrograms (150 000 international units) orally, as a single dose.
Dose can be repeated every 4 to 6 weeks if required.
Use a smaller dose for children between 3 and 12 months—seek expert advice. Megadose therapy is not
recommended in children less than 3 months of age.
Long-term supplementation is usually needed unless risk factors change substantially. A suitable long-term
maintenance dose is:
colecalciferol 10 micrograms (400 international units) orally, daily.
Some patients require a higher maintenance dose. Consider supplemental calcium in patients treated for
vitamin D deficiency if dietary calcium intake is inadequate.
Note 2: Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, et al. Global consensus recommendations on prevention and
management of nutritional rickets. J Clin Endocrinol Metab 2016;101(2):394-415. [URL]
Hypophosphataemic rickets
Hypophosphataemic rickets is a hereditary form of rickets (most commonly X-linked dominant). It is often
recognised from family history. It can also be recognised in infants aged 6 to 12 months old who develop
bowing of the legs in the absence of vitamin D deficiency. The diagnosis is confirmed by:
low serum phosphate concentration
serum calcium concentration at the lower end of the normal range
elevated serum alkaline phosphatase
reduced fractional kidney phosphate reabsorption
radiological evidence of rickets.
Specialist management is required. Early and consistent therapy with high-dose oral phosphate and calcitriol
allows bone mineralisation with straighter limbs and facilitates optimal growth, while minimising secondary
hyperparathyroidism. See also Hypophosphataemia.
The aim of therapy is to maximise growth rather than to normalise the serum phosphate concentration. With
adequate therapy, rickets should resolve and the serum alkaline phosphatase should return to a normal or near-
normal concentration.
Treatment may need to be continued into adulthood—adults with X-linked hypophosphataemic rickets often
have osteomalacia and skeletal symptoms.
Key references
Rickets
Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician's guide to X-linked hypophosphatemia.
J Bone Miner Res 2011;26(7):1381–8.
Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, et al. Global consensus recommendations on
prevention and management of nutritional rickets. J Clin Endocrinol Metab 2016;101(2):394–415.
Osteogenesis imperfecta
Osteogenesis imperfecta is a connective tissue disorder characterised by bone fragility, leading to increased
risk of fracture. It has several clinical and genetic subtypes of varying severity and can be diagnosed at any
age, from in utero to adulthood. Blue sclerae, wormian bones of the skull, joint hypermobility and opalescent
dentition can be present. Specialist management is required.
Intravenous bisphosphonate therapy (pamidronate or zoledronic acid) is recommended for children and young
adults with moderate to severe disease. Its use is associated with increased bone mass, enhanced mobility and
growth, reduced pain and fracture rate, and vertebral modelling. The Australian Paediatric Working Group
provides more detailed information about the use of bisphosphonates in young people [Note 1].
Note 1: Simm PJ, Biggin A, Zacharin MR, Rodda CP, Tham E, Siafarikas A, et al. Consensus guidelines on the use of bisphosphonate therapy in
children and adolescents. J Paediatr Child Health 2018;54(3):223-33. [URL]
Key references
Simm PJ, Biggin A, Zacharin MR, Rodda CP, Tham E, Siafarikas A, et al. Consensus guidelines on the use of
bisphosphonate therapy in children and adolescents. J Paediatr Child Health 2018;54(3):223–33.
Short stature in children
Short stature in children is rarely pathological; it is typically related to constitutional delay of growth and
maturation (particularly in boys), or familial short stature. Pathological endocrine causes of short stature (eg
growth hormone deficiency, hypothyroidism, Cushing syndrome) only account for about 10 to 15% of cases.
Interpreting a child’s height in the context of parental height is central to the differentiation of normal height
variants from potentially pathological variants. The mid-parental height can give an indication of the child’s
final adult height; to calculate mid-parental height, use the formula shown in Box 19.5.
Formula for mid-parental height (Box 19.5) [NB1] [NB2]
NB1: All heights measured in centimetres.
NB2: Mid-parental height may be less accurate if parents are at opposite extremes of height.
Blood tests are not required unless the child is significantly short for their family or is growing slowly.
Random growth hormone measurements are not useful given the pulsatile nature of growth hormone
secretion. Plasma insulin-like growth factor 1 (IGF-1) concentration or stimulated growth hormone
measurements are required if growth hormone deficiency is suspected.
Specialist referral can be considered if:
the child’s height is below the 1st percentile for age and sex according to a relevant growth chart [Note
1]
the child is significantly shorter than expected in the context of the parental heights
growth velocity is abnormally low [Note 2] (eg below the 25th percentile for sex, with consideration of
maturation level) [Note 3].
Short stature rarely requires treatment.
Short stature rarely requires treatment. Growth hormone can only be prescribed by a paediatrician or
endocrinologist. For information about its availability on the Pharmaceutical Benefits Scheme (PBS), see
Growth hormone therapy in children.
Note 1: See the Australasian Paediatric Endocrine Group website for growth charts.
Note 2: Growth velocity is assessed with at least three serial height measurements, at least 3 months apart, over 12 months.
Note 3: See The Royal Children’s Hospital website for growth velocity charts.
Growth hormone therapy in children

Growth hormone therapy for children is accessible through the Pharmaceutical Benefits Scheme via the
Australian growth hormone program [Note 4]. It must be prescribed and managed by a specialist
endocrinologist or paediatrician. The program allows for the use of growth hormone therapy in the following
circumstances:
growth hormone deficiency

growth retardation secondary to an intracranial lesion or cranial irradiation
Turner syndrome
growth failure associated with chronic kidney disease
short stature due to short stature homeobox (SHOX) gene disorders
short stature (height below the 1st percentile for age and sex according to a relevant growth chart [Note
5]) and slow growth (below the 25th percentile for sex, with consideration of maturation level [Note 6]),
with no aetiology found
neonates and infants at risk of hypoglycaemia secondary to growth hormone deficiency
Prader-Willi syndrome
hypothalamic–pituitary disease secondary to a structural lesion, with hypothalamic obesity–driven
growth.
Note 4: See information about the growth hormone program on the Department of Health website.
Note 5: See the Australasian Paediatric Endocrine Group website for growth charts.
Note 6: See The Royal Children’s Hospital website for growth velocity charts.
Key references
Taylor-Miller T, Simm P. Growth disorders in adolescents. Australian Family Physician 2017;46:913–7.

http://www.racgp.org.au/afp/2017/december/growth-disorders-in-adolescents/
Growth hormone therapy in children
Department of Health. Pharmaceutical Benefits Scheme (PBS) growth hormone program. Canberra: Australian
Government Department of Health; Last updated 2015.
http://www.health.gov.au/internet/main/publishing.nsf/Content/health-pbs-general-supply-hghapplication

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Clinical assessment of pain

Introduction to assessing pain

Factors influencing the perception of pain (Figure 1.1)

Classification of pain (Table 1.1)

subcutaneous superficial lymph solid or hollow organs

spinal cord injury or

pain in a numb area

For assessment of pain in children, see Pain assessment in children.

Consider the following points in your assessment:

history of event or circumstances surrounding the onset of pain (eg trauma)

Pain assessment: history

Pain severity is usually measured using unidimensional scales. These include:

Be clear when asking the patient a question. Is it:

the average pain over the last 24 hours

Aggravating and relieving factors

Patient’s understanding of the pain

Pain assessment: examination

Mental state examination

Pain assessment: investigations

Pain assessment: acute pain

Pain assessment: recurrent or chronic pain

reassess the original diagnosis or pathology

Ask the patient specific questions about:

screening—especially in patients with cancer, as pain is a common consequence of advanced disease

Pain assessment: people with communication difficulties

People with impaired cognition

When uncertainty remains

The responses to acute pain include immediate reflex responses that:

are behavioural (eg withdrawal, exclamation, checking, protection and rest)

inadequate initial pain relief

acute chest pain

Stepwise approach to acute pain management

IN = intranasal; IV = intravenous; NSAID = nonsteroidal anti-inflammatory drug; SC = subcutaneous

Step 1. Mild acute pain

paracetamol 1 g orally, 4- to 6-hourly, up to a maximum of 4 g daily. For dosing of

The paracetamol content of all medications must be considered.

Step 2. Moderate acute pain

Nonsteroidal anti-inflammatory drugs

OR (depending on patient comorbidities)

2 diclofenac 25 to 50 mg orally, 2 or 3 times daily. For dosing of diclofenac in children, see

Major adverse effects of nonsteroidal anti-inflammatory drugs (Table 1.2) [NB1]

System Adverse effects Comments

risk factors include perioperative use in older and

1 codeine 30 to 60 mg orally, 6-hourly as necessary [Note 1]

1 tramadol immediate-release 50 to 100 mg orally, up to 4 times daily as necessary

Adverse effects with short-term use of opioids (Table 1.3) [NB1]

System Adverse effects—short term

Step 3. Severe acute pain

morphine 2.5 to 10 mg SC, as a single dose.

Opioid doses in older people must be carefully titrated to effect.

Stepwise approach to acute pain management

Analgesia: mild-to-moderate pain. Clinical Knowledge Summaries, UK; 2010. [URL]

Acute pain in older people

Reassessment is necessary for continuous or recurrent pain following acute trauma.

Acute pain: minor trauma

Wounds and lacerations

Sprains and strains

Dislocations and fractures

oxycodone immediate-release 2.5 to 15 mg orally, 4-hourly as necessary. Use the lower

Minor chest injuries

An oral opioid such as oxycodone is frequently necessary. Use:

oxycodone immediate-release 2.5 to 15 mg orally, 4-hourly as necessary. Use the lower

Acute pain: major trauma

Major chest injuries