Kaye had a deep interest in medical history and was a College and to medical research and practice in

founding member of the Auckland Medical History Soci-
ety, which he chaired for many years. He was instru-
mental in establishing the Ernest and Marion Davis
Memorial Library and Lecture Halls on the Auckland
Hospital site, a great asset to the local medical commu-
nity. Kaye was a keen trout fisherman, beekeeper and
antiquarian. He made an immense contribution to the
New Zealand and Australia, and he will be greatly
missed by his many friends and colleagues.
Received 21 March 2018; accepted 6 April 2018.
Ian Holdaway and Ian Reid
Department of Endocrinology, Auckland Hospital and Greenlane
Clinical Centre, Auckland, New Zealand

doi:10.1111/imj.14102

CLINICAL PERSPECTIVES

Meningitis in adults: diagnosis and management

1 1,2
Nicholas Young and Mark Thomas
1
Department of Infectious Diseases, Auckland City Hospital, and 2Department of Molecular Medicine and Pathology, University of Auckland, Auckland,
New Zealand

Key words Abstract

meningitis, CT scan, lumbar puncture,
cerebrospinal fluid, Streptococcus pneumoniae,
Neisseria meningitidis.
Correspondence
Nicholas Young, Department of Infectious
Diseases, Level 6 Support Building, Auckland
City Hospital, Private Bag 92024, Grafton Road,
Grafton, Auckland 1030, New Zealand.
Email: nicholasy@adhb.govt.nz
Received 22 March 2018; accepted
5 August 2018.
Bacterial meningitis is a medical emergency. All clinicians who provide acute medical
care require a sound understanding of the priorities of managing a patient with sus-
pected meningitis during the first hour. These include obtaining blood cultures, per-
forming lumbar puncture and initiating appropriate therapy, while avoiding harmful
delays such as those that result from not administering treatment until neuroimaging
has been performed. Despite the increasing availability of newer diagnostic techniques,
the interpretation of cerebrospinal fluid parameters remains a vital skill for clinicians.
International and local guidelines differ with regard to initial empirical therapy of bacte-
rial meningitis in adults; the North American guideline recommends ceftriaxone and
vancomycin for all patients, while the Australian, UK and European guidelines recom-
mend that vancomycin only be added for patients who are more likely to have pneu-
mococcal meningitis or who have a higher likelihood of being infected with a strain of
Streptococcus pneumoniae with reduced susceptibility to ceftriaxone. Patients with risk fac-
tors for Listeria meningitis also require an anti-Listeria agent, such as benzylpenicillin, to
be added to this treatment regimen. Dexamethasone should be a routine component of
empirical therapy due to its proven role in reducing morbidity and mortality from
pneumococcal meningitis.

Introduction It is critical that clinicians recognise the need to prioritise

Bacterial meningitis is a potentially catastrophic infec-
tious disease associated with substantial mortality and a
risk of permanent disability in survivors.1 Despite ongo-
ing advances in diagnostic methods and treatment strate-
gies, mortality remains as high as 30% in pneumococcal
meningitis and 5–10% in meningococcal meningitis.2,3
However, outcomes are improved by prompt therapy.4–6
Funding: None.
Conflict of interest: None.
initial investigations while not delaying life-saving treat-
ment with dexamethasone and antibiotics, which should
be administered as soon as possible within the first hour
following presumptive diagnosis. This article will focus
on diagnostic and management issues that a clinician
will face when dealing with a suspected case of
community-acquired bacterial meningitis in an adult.
While we do not address non-infectious causes of men-
ingitis, such as those caused by malignancy, medications
or autoimmune conditions, these should also be consid-
ered in the differential diagnosis of meningitis.

1294 Internal Medicine Journal 48 (2018) 1294–1307

© 2018 Royal Australasian College of Physicians

Diagnosis
Clinical features and clues to the responsible
pathogen
A patient who presents with recent onset of headache,
fever, neck stiffness or altered mental state would
prompt most clinicians to consider the possibility of men-
ingitis. At least two of these four features will be present
in 95% of patients with bacterial meningitis and should
lead to urgent diagnostic work-up for this condition.7
The classic triad of bacterial meningitis consists of fever,
neck stiffness and altered mental state; however, reliance
on all three of these signs being present will result in
more than 50% of cases of bacterial meningitis being
missed.7
Some clinical features and patient characteristics may
provide clues to the responsible pathogen. Meningitis
due to Neisseria meningitidis may begin with an influenza-
like illness, with symptoms such as fever, muscle aches
and vomiting, before meningitis becomes clinically
apparent. Rapid onset and progression of symptoms over
hours is typical and can be helpful to distinguish this
condition from self-limiting viral infections. A patient
with meningitis and a non-blanching petechial or purpu-
ric rash strongly suggests meningococcal disease,
although the rash may also be blanching, maculopapular
or absent. The level of suspicion must be particularly
high for patients presenting in the context of an estab-
lished meningococcal epidemic.8 Meningitis due to Strep-
tococcus pneumoniae should be suspected in patients with
predisposing conditions, such as otitis media, sinusitis,
mastoiditis, cerebrospinal fluid (CSF) leak, cochlear
implants, asplenia, human immunodeficiency virus
(HIV) infection or other immunosuppressive conditions
or medications.9 Patients at risk of Listeria monocytogenes
meningitis include those aged ≥50, those taking long-
term glucocorticoids or other immunosuppressive drugs
and those with diabetes, alcoholism, cirrhosis, end-stage
renal failure, malignancy, HIV infection or organ
transplantation.10
Neuroimaging: computed tomography before
lumbar puncture is not usually required
In many patients with meningitis, performing a lumbar
puncture (LP) and starting empirical treatment are
unnecessarily delayed while waiting for computed
tomography (CT) of the head.11 CT prior to LP should
not be performed for most patients for several reasons.
First, and most importantly, if a patient is not pretreated
with antibiotics, the sequence of CT followed by LP fol-
lowed by antibiotics causes an unacceptable delay in
Internal Medicine Journal 48 (2018) 1294–1307
© 2018 Royal Australasian College of Physicians
Meningitis in adults
starting treatment and increases the likelihood of an
unfavourable outcome.6 Second, the yield of CT is low in
patients who do not have clinical features of raised intra-
cranial pressure (ICP), with 97% having a normal
result.12 Third, if a patient is pretreated with antibiotics
prior to CT and LP, the yield of CSF culture will be signif-
icantly decreased, although a diagnosis can often still be
obtained through polymerase chain reaction (PCR)
testing.11
CT prior to LP is recommended for patients who have
one or more clinical features that increase the probability
of having raised ICP, to attempt to identify those most at
risk of brain herniation following LP. However, guide-
lines differ as to which clinical features constitute an
indication to perform CT prior to LP (Table 1). The lack
of consensus about which patients should undergo a CT
prior to LP reflects uncertainties about the reliability of
CT scans to detect raised ICP16 and about whether CT
evidence of raised ICP is associated with an increased
risk of brain herniation following LP.4 Scepticism of the
value of neuroimaging is reflected in the Swedish
guideline,15 which recommends CT prior to LP only for
patients who have signs of imminent brain herniation,
focal neurological deficits (not including cranial nerve
palsies) or who have had cerebral symptoms for more
than 4 days (which increases the likelihood of cerebral
pathology other than acute meningitis). A recent study
suggested that use of the Swedish guideline in place of
the Infectious Diseases Society of America guideline
might result in a shorter time to initiation of therapy, an
approximately 33% reduction in mortality and an
approximately 24% increase in favourable outcome in
patients with bacterial meningitis.17 This suggests that
more stringent selection of patients who undergo CT
before LP has the potential to significantly improve out-
comes in patients with bacterial meningitis. If CT before
LP is deemed to be necessary, it is vital that blood cul-
tures are taken, and dexamethasone and antibiotics are
started without delay.
CSF analysis
CSF analysis is of vital importance in suspected meningitis
as clinical characteristics alone are unable to distinguish
meningitis from other diagnoses, and bacterial from non-
bacterial aetiologies.18 For the majority of patients who do
not require CT prior to LP and do not have another clini-
cal contraindication to LP, CSF analysis should be per-
formed within 1 h of the presumptive diagnosis
of meningitis without awaiting further investigations,
such as platelet count or coagulation studies. Clinical con-
traindications to LP include anticoagulation, clinical evi-
dence of disseminated intravascular coagulation and local
1295
Young & Thomas
Table 1 Indications for CT head prior to LP
IDSA guideline13
Immunosuppression HIV infection, immunosuppressive therapy,
post-transplantation
Background of CNS Mass lesion, stroke or focal CNS infection
disease
Seizures Seizures within a week prior to presentation
Level of GCS < 15
consciousness
Focal neurological Focal deficit including cranial nerve palsies
deficit
Papilloedema Indication for CT
Duration of No recommendation
symptoms
BP, blood pressure; CNS, central nervous system; CT, computed tomography; ESCMID, European Society of Clinical Microbiology and Infectious Dis-
eases; GCS, Glasgow Coma Scale; HIV, human immunodeficiency virus; IDSA, Infectious Diseases Society of America; LP, lumbar puncture.
infection or loss of skin integrity at the puncture site.19 LP
is safe in patients taking aspirin, but safety is less well
established for those taking other anti-platelet agents,
such as clopidogrel or ticagrelor, or for those on dual anti-
platelet therapy; deferring LP is recommended in these
circumstances.19
Appearance and opening pressure
Appearance of the CSF should be noted; cloudy or turbid
fluid suggests a significant concentration of leukocytes in
the sample (although xanthochromia, elevated protein
concentration or a high number of bacterial colony-
forming units may also cause this appearance).13 A
manometer should be used to measure opening pressure
in the lateral decubitus position; in bacterial meningitis,
opening pressure is typically >20 cm H2O, although
other factors, such as patient anxiety and positioning,
may artifactually elevate this.13
Gram stain
Once CSF is delivered to the laboratory, a Gram stain
should be rapidly performed. If bacteria are seen, this
provides a presumptive microbiological diagnosis upon
which directed therapy can be based.13 The presence of
Gram-positive cocci suggests S. pneumoniae, Gram-
negative diplococci N. meningitidis and Gram-positive
bacilli L. monocytogenes (which are the first, second and
third most common causes of community-acquired bac-
terial meningitis in adults, respectively).10 Gram-
negative bacillary meningitis is rare in immune-
competent adults unless indwelling neurosurgical
1296
ESCMID guideline14 Swedish guideline15
Severely immunocompromised Not an indication for CT
state
No recommendation Not an indication for CT
New onset seizures Not an indication for CT
GCS < 10 ‘Imminent herniation’: unconscious plus one
or more of rigid dilated pupils, increased
BP and bradycardia, abnormal respirations,
opisthotonus, loss of all reactions
Focal deficit excluding cranial Focal deficit excluding cranial nerve palsies
nerve palsies
No recommendation Avoid LP if present but fundoscopy not
mandatory
No recommendation >4 days of cerebral symptoms
devices are present.1 The likelihood of a positive Gram
stain ranges from 25% to 97% and is highly correlated
with the concentration of bacterial colony-forming units
in the CSF; a negative stain therefore cannot exclude this
diagnosis.13 A positive Gram stain is more likely in pneu-
mococcal meningitis compared with meningococcal or
Listeria meningitis and is less likely if antibiotics have
been given prior to LP.20
Cell counts and chemistry
If the Gram stain is negative, the CSF leukocyte count is
often helpful in distinguishing bacterial from non-
bacterial meningitis (Table 2). Meningitis is confirmed
when the leukocyte count in the CSF exceeds 5 cells/μL.
A leukocyte count of ≥1000 cells/μL with a neutrophilic
predominance is highly suggestive of bacterial
meningitis,1 whereas <1000 cells/μL with a lymphocytic
predominance is more consistent with viral meningitis,
tuberculous meningitis (TBM) or cryptococcal meningi-
tis.20 Bacterial meningitis due to L. monocytogenes is an
important exception, with approximately 60% of cases
having a leukocyte count of <1000 cells/μL, which may
be lymphocytic.10 If a traumatic tap occurs, the leukocyte
count should be corrected by deducting one leukocyte
for every 500–1000 red cells in the CSF.23
It is critical that these leukocyte ranges are not viewed
as absolute cut-off values. Bacterial meningitis can pre-
sent with counts significantly lower than 1000 cells/μL,
and rare cases with normal counts on initial CSF analysis
have been described.24 In addition, 10% of cases have a
lymphocytic predominance.13 In very early presentations
Internal Medicine Journal 48 (2018) 1294–1307
© 2018 Royal Australasian College of Physicians

Table 2 Typical CSF findings in healthy adults and adult patients with meningitis1,13,20–22
Opening pressure CSF leukocytes
(cm H2O) (cells/μL)
Normal CSF ≤20 0–5
Bacterial meningitis† >20 ≥1000
Viral meningitis‡ ≤20 <1000
neutrophilic within first 48 h)
Tuberculous Normal or elevated 100–500
meningitis
Eosinophilic meningitis Normal or elevated <1000
Cryptococcal >20 <200
meningitis
†Excluding Listeria meningitis, where CSF leukocytes are often <1000 cells/μL and CSF may be lymphocytic. ‡Excluding HSV and VZV meningitis,
where protein may be ≥1.0 g/L. CSF, cerebrospinal fluid; HSV, herpes simplex virus; VZV, varicella zoster virus.
of viral meningitis, there may be a neutrophilic predomi-
nance, which typically becomes lymphocytic within
48 h.25
CSF protein is usually elevated in meningitis of both
bacterial and viral aetiology due to increased perme-
ability of the blood–brain barrier as a consequence of
inflammation.1 This elevation is typically greater in
bacterial and TBM (≥1 g/L) than in viral meningitis
(<1 g/L), with the exception of meningitis due to the
herpes simplex virus (HSV) or varicella zoster virus
(VZV), where protein may be ≥1 g/L.20,26 As with the
leukocyte count, CSF protein should be corrected for a
traumatic tap by deducting 0.01 g/L for every 1000 red
cells.23
Hypoglycorrhachia (low CSF glucose) is another help-
ful pointer towards bacterial meningitis, although it is
also seen in TBM and cryptococcal meningitis.21,27 CSF
glucose varies proportionally to blood glucose, with a
normal CSF-to-blood glucose ratio being 0.6.28 A normal
ratio is usually found in viral meningitis.20 A ratio of
≤0.5 has 100% sensitivity for bacterial meningitis but
specificity of only 57%.22 When a ratio of ≤0.23 is used,
specificity improves to 99% but at the cost of sensitiv-
ity.29 These values are minimally affected by pretreat-
ment with antibiotics. The CSF-to-blood glucose ratio
may be less helpful in hyperglycaemic patients as CSF
glucose levels begin to plateau once blood glucose
exceeds 5.5 mmol/L (100 mg/dL).28
Given that no single CSF parameter can reliably dis-
tinguish bacterial from non-bacterial causes of meningi-
tis, clinicians must exercise caution when interpreting
these parameters. Consideration of clinical features and
CSF parameters together often cannot confidently
exclude the possibility that a patient has bacterial men-
ingitis. In these cases, most experienced clinicians
would err on the side of caution and treat for bacterial
meningitis while awaiting further microbiological
results.30
Internal Medicine Journal 48 (2018) 1294–1307
© 2018 Royal Australasian College of Physicians
Meningitis in adults
Predominant cell type CSF CSF-to-blood glucose
protein (g/L) ratio
Lymphocytes 0.15–0.45 0.6
Neutrophils ≥1.0 ≤0.5
Lymphocytes (may be <1.0 0.6
Lymphocytes ≥1.0 ≤0.5
≥10% eosinophils <1.0 0.6
Lymphocytes >0.45 ≤0.5
Culture
The sensitivity of culture is 60–90% for CSF collected
before antibiotic treatment has been started, with posi-
tive results generally available within 24–48 h.13 The
yield of culture decreases significantly in the pretreated
patient, in whom other tests, such as PCR or bacterial
antigen testing (BAT), may be necessary to identify the
pathogen. In addition to CSF cultures, blood cultures
should be taken in all cases of suspected bacterial men-
ingitis as a pathogen may be isolated through this route
despite negative Gram stain and culture of CSF.14
Bacterial antigen testing
Many laboratories offer BAT on CSF samples, most often
for the detection of S. pneumoniae. The pneumococcal
BAT has been reported to have a specificity in excess of
95% for pneumococcal meningitis and a sensitivity rang-
ing between 67% and 100%.13 This test can be per-
formed within minutes of the sample arriving in the
laboratory and can provide more rapid confirmation of
pneumococcal meningitis than either PCR or culture.
However, given the variable sensitivity of this test, a neg-
ative pneumococcal BAT should not justify the early dis-
continuation of S. pneumoniae-specific therapy, such as
dexamethasone or vancomycin, if this has been com-
menced. In Australia, a positive pneumococcal BAT is
considered an indication for adding vancomycin to the
empirical antibiotic regimen.31
Polymerase chain reaction
Multiplex PCR assays can detect the presence of many
important bacterial and viral pathogens in CSF, including
N. meningitidis, S. pneumoniae, enteroviruses, HSV, VZV
and mumps virus, with sensitivity and specificity
≥90%.13 Misleading positive viral results have occasion-
ally been described in cases of confirmed bacterial men-
ingitis.32 PCR has been used successfully for the
1297
Young & Thomas
diagnosis of Listeria meningitis, but assays are not yet
widely available.33 In Australia and New Zealand, the
accessibility of multiplex PCR varies based on location; a
result can be available within hours if the assay is avail-
able in-house but may take days if the sample needs to
be delivered to a reference laboratory. When compared
with bacterial culture, PCR is much less affected by pre-
treatment with antibiotics, with one study showing sen-
sitivity of 89% in samples collected on days 1–3 of
antibiotic treatment, 70% on days 4–6 and 33% on days
7–10. In comparison, no CSF cultures were positive in
samples collected more than 1 day after initiation of
antibiotics.34
Lactate, procalcitonin and C-reactive protein
CSF lactate, serum procalcitonin (PCT) and serum C-
reactive protein (CRP) may be helpful in distinguishing
bacterial from non-bacterial meningitis. A meta-analysis
reported that a CSF lactate of ≥35 mg/dL (3.9 mmol/L)
had 93% sensitivity and 99% specificity for bacterial
meningitis.35 CSF lactate is not proportional to serum
lactate, but it may be elevated in central nervous system
(CNS) conditions other than bacterial meningitis, such as
viral encephalitis or seizures.14 Another meta-analysis
showed that elevated serum PCT had 90% sensitivity
and 98% specificity for bacterial meningitis and was
more sensitive and specific than CRP; the definition of
elevated PCT varied between the individual studies, with
cut-off values from ≥0.25 to ≥2.13 ng/mL (normal <0.1
ng/mL).36 PCT is particularly helpful in the diagnosis of
early bacterial meningitis as it becomes detectable within
3–4 h of onset of symptoms, compared with the 12–24 h
that CRP takes to rise.37 When PCT measurement is not
readily available, CRP may provide some useful informa-
tion; one study showed that patients with bacterial men-
ingitis had a median CRP of 162 mg/L (95% confidence
interval 39–275) compared with a median of 13 mg/L
(95% confidence interval 9–17) in non-bacterial menin-
gitis.38 Pretreatment with antibiotics decreases the sensi-
tivity of all three of these tests.35,36,38
Aseptic meningitis: not synonymous with
viral meningitis
Viral meningitis is most commonly caused by the entero-
viruses and is self-limiting, although HSV or VZV menin-
gitis may warrant antiviral therapy in some
circumstances.39,40 HIV is an important yet overlooked
cause of viral meningitis. The yield of testing for HIV was
shown in one report from North Carolina where stored
CSF samples from 57 patients who had presented with
non-bacterial meningitis were retrospectively tested for
1298
HIV RNA. This was detected in three patients, two of
whom had acute HIV infection as the likely cause for
their presentation. None had been prospectively
diagnosed.41
Not all patients with aseptic meningitis have viral
meningitis, and it is important to consider other causes if
a viral aetiology is not confirmed by PCR.42 Suspicion for
a non-viral aetiology should be heightened in those with
a subacute presentation, in immunosuppressed patients,
in people from tuberculosis-endemic countries, in those
with risk factors for sexually transmitted infection and in
those with exposure to farm animals, faecally contami-
nated water or who have recently travelled to countries
in Southeast Asia or the Pacific region.
Cryptococcal meningitis should be considered in
patients with a subacute presentation. While this disease
is commonly associated with acquired immunodefi-
ciency syndrome (AIDS) or other forms of immunosup-
pression, it can also occur in seemingly
immunocompetent people; amongst HIV negative
patients with cryptococcal meningitis, 30% have no
identifiable risk factors for this disease.21 Typical CSF
parameters are shown in Table 2, although cryptococcal
meningitis can be present despite normal CSF parame-
ters in patients with HIV infection.43 A high opening
pressure is characteristic of this condition, and the diag-
nosis can be confirmed through CSF analysis for crypto-
coccal antigen, India ink staining and fungal cultures,
which are positive in 97%, 51% and 89% of HIV-
negative cases respectively.21
TBM can present as either an acute or subacute illness
and should be considered in people who have lived in a
low- or middle-income country. If TBM is suspected, a
large volume of CSF (10–20 mL) should be sent to the
lab for acid-fast stain, PCR (such as with the GeneXpert
MTB/RIF system) and mycobacterial cultures (which
require incubation for up to 6 weeks).27 The yield of
these investigations is improved by testing large volumes
of CSF, but all tests suffer from imperfect sensitivity,
which is approximately 30% for acid-fast stain and
approximately 60% for PCR or culture.44,45
Listeria meningitis may present with symptoms and
CSF parameters that mimic viral meningitis. Intracere-
bral abscess may also present in a similar manner, with
or without focal neurological signs.46 Leptospirosis can
cause acute meningitis; this diagnosis should be consid-
ered in those who work with animals or who have had
exposure to faecally contaminated water.47 Meningitis
can be a manifestation of secondary syphilis.1 In a
patient with CSF eosinophilia of ≥10% or peripheral
blood eosinophilia, and with recent travel to Southeast
Asia or the Pacific region, eosinophilic meningitis (most
commonly caused by Angiostrongylus cantonensis) should
Internal Medicine Journal 48 (2018) 1294–1307
© 2018 Royal Australasian College of Physicians

be considered, particularly if the patient gives a history
of consumption of fresh vegetables or raw snails. Eosino-
phils can be misidentified as neutrophils if CSF analysis
is automated, and thus the laboratory should be alerted
if this diagnosis is suspected.48
Management
Immediate priorities, before and on arrival to
hospital
In bacterial meningitis, prompt treatment is life-saving.
For patients who present to primary care with suspected
meningococcal disease, pre-hospital treatment with par-
enteral benzylpenicillin or ceftriaxone has been advo-
cated.19,31 Intuitively, the benefits of early antibiotic
administration seem clear. However, evidence that this
practice improves outcomes is lacking; observational
studies have reported that pretreated patients have
worse outcomes, although this may be because those
who were pretreated had more severe disease than those
who were not.49 An alternative hypothesis for this find-
ing is that rapid bacteriolysis following antibiotic admin-
istration may precipitate shock due to the release of
meningococcal endotoxins; this could be deleterious if it
occurs in the community, rather than in the hospital
where there is greater access to fluid resuscitation and
inotropic support. This theory is also unproven.49 Given
this lack of evidence, the role of pre-hospital antibiotics
remains unclear; they should be given to patients who
present to rural or remote practices and face a prolonged
transport time to a secondary care facility.31
On arrival at hospital, the patient should be placed in
droplet precautions to prevent potential nosocomial
transmission of meningococcal infection and resuscitated
as required.8 Blood and, ideally, CSF cultures should be
quickly obtained, following which dexamethasone and
antibiotics should be given, aiming for administration
within 1 h of admission.4 The importance of timely ther-
apy has been demonstrated in multiple studies, with one
study showing an increase in mortality of 13%4 and
another showing an increase in mortality and disability
of 30%50 for every hour that treatment is delayed. In
most cases, CSF should be obtained prior to the com-
mencement of antimicrobials, although in certain situa-
tions, this introduces an unacceptable delay to
treatment; these situations include the need to obtain a
CT prior to LP, a clinical contraindication to LP, multiple
failed attempts at this procedure or in patients with sep-
tic shock.19 In these cases, dexamethasone and antibi-
otics should be given once blood cultures have been
drawn, and CSF should be obtained at the earliest possi-
ble opportunity.
Internal Medicine Journal 48 (2018) 1294–1307
© 2018 Royal Australasian College of Physicians
Meningitis in adults
Early consultation with an infectious diseases physi-
cian may improve patient outcomes. In one study,
patients with bacterial meningitis who were managed by
infectious diseases physicians were significantly more
likely to commence antibiotics within 1 h of presentation
and to receive dexamethasone, and were less likely to
experience treatment delays while awaiting
neuroimaging.5
Empirical therapy
Most guidelines recommend dexamethasone plus ceftri-
axone in the initial empirical treatment of community-
acquired bacterial meningitis in adults. While the North
American guideline13 recommends the addition of van-
comycin for all patients, guidelines from Australia,31 the
UK19 and Europe14 recommend the addition of vanco-
mycin only for patients who are more likely to have
pneumococcal meningitis or who have personal or epi-
demiological risk factors for being infected with a
S. pneumoniae strain with reduced susceptibility to ceftri-
axone. In Australia, the inclusion of vancomycin in the
initial empirical regimen is recommended for patients
with known or suspected otitis media or sinusitis, for
those who have been treated with beta-lactam antibi-
otics recently and for those with Gram-positive cocci in
the CSF or with a positive pneumococcal BAT.31 An
anti-Listeria agent should also be added for patients with
risk factors for Listeria meningitis (age ≥ 50, long-term
use of glucocorticoids or other immunosuppressive
drugs, diabetes, alcoholism, cirrhosis, end-stage renal
failure, malignancy, HIV infection and organ transplan-
tation).10 Benzylpenicillin and trimethoprim/sulfameth-
oxazole are active against L. monocytogenes, but
ceftriaxone and vancomycin are not. An approach to ini-
tial investigation and management is summarised in
Figure 1, and an approach to empirical therapy is sum-
marised in Table 3.
Dexamethasone
Dexamethasone reduces cerebral inflammation, oedema
and ICP in experimental models of bacterial meningitis.51
In a meta-analysis of clinical trials, early treatment with
dexamethasone reduced mortality rates in patients with
pneumococcal meningitis from 36% to 30%, as well as
significantly reducing hearing loss and other neurological
sequelae.2 These beneficial effects were not seen in a sub-
group analysis of patients with meningococcal meningitis,
although dexamethasone treatment is unlikely to be
harmful in this group if given.14 Guidelines recommend
the empirical use of 10 mg dexamethasone intravenously
(IV) every 6 h in patients with bacterial
1299
Young & Thomas

Use droplet precautions

Urgently address airway or

circulatory compromise

Draw bloods including blood

cultures

Is there an indication for CT Yes 10mg dexamethasone IV q6h and

head prior to LP? (Table 1) antibiotics (Table 3)

No
Obtain CT head

Is there a clinical Yes 10mg dexamethasone IV q6h and

†
contraindication to LP? antibiotics (Table 3)

No

Perform LP Perform LP as soon as safely possible

10mg dexamethasone IV q6h Tailor to directed therapy once

and antibiotics (Table 3) pathogen identified

Figure 1 Initial investigation and management of adults with suspected bacterial meningitis. †Anti-coagulation, anti-platelet therapy other than aspi-
rin, dual anti-platelet therapy, clinical evidence of disseminated intravascular coagulation, local infection or loss of skin integrity at puncture site, raised
intracranial pressure on computed tomography (CT) head if performed. IV, intravenous; LP, lumbar puncture.

meningitis,13,14,19,31 although it would be reasonable to
omit this if the clinical presentation strongly suggests
meningococcal meningitis. Other corticosteroids should
not be used due to their inferior CNS penetration.13 Dexa-
methasone should be started before or at the same time
as the first antibiotic dose in order to attenuate cerebral
inflammation caused by antibiotic-mediated bacterioly-
sis.2 It is unclear if dexamethasone has any benefit when
started after the first antibiotic dose, although some
experts recommend that it can be started up to 4 h after
this.14 There have been theoretical concerns that dexa-
methasone may decrease antibiotic penetration into the
CNS by reducing meningeal inflammation; however, one
study demonstrated adequate CSF vancomycin concen-
trations despite treatment with dexamethasone.52 For
unclear reasons, the beneficial effects of dexamethasone

1300 Internal Medicine Journal 48 (2018) 1294–1307

© 2018 Royal Australasian College of Physicians
 Meningitis in adults

Table 3 Empirical therapy for adults with suspected bacterial meningitis in Australia

First-line therapy Therapy for patients with Therapy for patients with severe T
immediate cell-mediated reaction to penicillins†
penicillin hypersensitivity

Dexamethasone‡ PLUS Dexamethasone‡ Dexamethasone‡

ceftriaxone§ PLUS ceftriaxone§ PLUS moxifloxacin¶
If higher likelihood of pneumococcal Add vancomycin‡‡ Add vancomycin‡‡ Add vancomycin‡‡
meningitis††, or recent β-lactam use
If risk factors for Listeria meningitis Add benzylpenicillin§§ Add trimethoprim/ Add trimethoprim/sulfamethoxazole¶¶
sulfamethoxazole¶¶

†For example, toxic epidermal necrolysis or Stevens–Johnson syndrome. ‡Dexamethasone dosed at 10 mg IV q6hr. §Ceftriaxone dosed at 2 g IV
q12hr. ¶Moxifloxacin dosed at 400 mg IV q24hr. ††Known or suspected otitis media or sinusitis, Gram-positive cocci in the CSF, positive pneumococcal
BAT. ‡‡Vancomycin IV dosed to achieve a trough concentration of 15–20 mg/L. §§Benzylpenicillin dosed at 2.4 g IV q4h. ¶¶Trimethoprim/sulfamethox-
azole dosed at 160/800 mg IV q6hr. BAT, bacterial antigen testing; CSF, cerebrospinal fluid; IV, intravenous.

seem confined to high-income countries, which is unfor-
tunate given that bacterial meningitis is many times more
prevalent in the developing world.2
If pneumococcal meningitis is diagnosed, treatment
with dexamethasone should be continued for 4 days.
Dexamethasone can be stopped if meningococcal menin-
gitis is diagnosed.14 Dexamethasone should also be
stopped if Listeria meningitis is diagnosed as there is evi-
dence that patients who receive this treatment have a
higher mortality rate than those who do not.53
Antibiotics
Because almost all strains of N. meningitidis and many
strains of S. pneumoniae are sensitive to ceftriaxone, most
guidelines recommend 2 g ceftriaxone IV every
12 h.13,14,19,31 It is important to note that ceftriaxone pro-
vides no cover for L. monocytogenes.13 In those with IgE-
mediated allergies to penicillins (including anaphylaxis),
ceftriaxone is likely to be safe due to negligible rates of
cross-reactivity between penicillins and third-generation
cephalosporins.54 However, in those with severe T cell-
mediated reactions to penicillins, such as toxic epidermal
necrolysis or Stevens–Johnson syndrome, the safety of
Table 4 European Committee on Antimicrobial Susceptibility Testing
MIC breakpoints of benzylpenicillin and ceftriaxone for treatment of
S. pneumoniae infections56
MIC breakpoint (mg/L)
Susceptible
Benzylpenicillin
Meningitis ≤0.06
Non-meningitis ≤0.06
Ceftriaxone
Meningitis and non-meningitis ≤0.5
MIC, minimum inhibitory concentration.
ceftriaxone is not well established. For these patients,
moxifloxacin can be used as an alternative empirical
therapy, or ciprofloxacin plus vancomycin if moxifloxa-
cin is not available.
S. pneumoniae isolates were uniformly susceptible to
penicillin and ceftriaxone prior to the 1970s. However,
since then, the proportion of strains with a modestly
increased minimum inhibitory concentration (MIC) to
these antibiotics has steadily risen. Fortunately, this has
not had major effects on the treatment of pneumococcal
infections outside of the CNS as concentrations exceed-
ing these modestly elevated MIC are readily achieved in
serum and tissues by high-dose IV administration. In
contrast, the concentration of either penicillin or ceftri-
axone that is achieved in the CSF is many times lower
than that in the serum and may be too low to be active
against the infecting strain of S. pneumoniae.55 MIC
breakpoints of penicillin are defined differently for men-
ingitis and non-meningitis infections caused by
S. pneumoniae (Table 4).
Figure 2A shows the distribution of penicillin MIC for
37 742 isolates of S. pneumoniae,57 and 2B the concentra-
tions of penicillin in serum and in CSF during 4 h after
the IV administration of 1.2 g benzylpenicillin.58 In all
patients at 1 h after treatment, and in most patients at 2 h
after treatment, the concentration of penicillin in serum
exceeded the MIC of all pneumococcal isolates. In con-
trast, no patient had a CSF penicillin concentration that
exceeded the MIC of all pneumococcal isolates at any
point during the 4 h after administration. However, in all
patients throughout the 4-h period, the concentrations of
Resistant penicillin in CSF were >0.06 mg/L. Studies of animals
with pneumococcal meningitis treated with beta-lactam
>0.06 antibiotics, such as penicillin or ceftriaxone, show that
>2 maximal bacterial killing is achieved when the CSF con-
centrations of the beta-lactam antibiotic exceed the mini-
>2
mum bactericidal concentration (MBC) of the antibiotic
for >90% of the treatment interval.62 Because the MIC

Internal Medicine Journal 48 (2018) 1294–1307 1301

© 2018 Royal Australasian College of Physicians
Young & Thomas

Figure 2 (A) Distribution of penicillin minimum inhibitory concentrations (MIC) for 37 742 S. pneumoniae isolates; black bars represent strains suscep-
tible to penicillin using meningitis criteria (MIC < 0.06 mg/L), and white bars represent strains resistant to penicillin (MIC > 0.06 mg/L).57 (B) Penicillin
concentrations in serum (solid circles and bars) and in cerebrospinal fluid (CSF) (open circles and dashed bars) in eight patients following a 1.2 g intra-
venous (IV) bolus of benzylpenicillin.58 (C) Distribution of ceftriaxone MIC for 3238 S. pneumoniae isolates; black bars represent strains susceptible to
ceftriaxone (MIC ≤ 0.5 mg/L), and grey bars represent strains with decreased susceptibility to ceftriaxone (MIC > 0.5 mg/L).57 (D) Ceftriaxone concen-
trations in serum (solid circles and bars)59 and in CSF (open circles and dashed bars)60,61 in adult patients following a 2 g IV bolus of ceftriaxone.

closely approximates the MBC for most beta-lactam anti-
biotics, the presence of antibiotic concentrations greater
than the MIC throughout each treatment interval is likely
to provide maximal bacterial killing. Treatment with ben-
zylpenicillin (2.4 g IV every 4 h) is therefore very likely to
be effective for patients with pneumococcal meningitis
caused by strains with MIC ≤ 0.06 mg/L but less likely to
be effective for patients with meningitis caused by strains
with penicillin MIC > 0.06 mg/L.
Figure 2C shows the distribution of ceftriaxone MIC
for 3238 isolates of S. pneumoniae,57 and Figure 2D shows
the concentrations of ceftriaxone in serum59 and in
CSF60,61 during 24 h after the IV administration of 2 g
ceftriaxone. Throughout the 24-h period, the concentra-
tions of ceftriaxone in serum were consistently higher
than the MIC of all strains of S. pneumoniae, and the con-
centrations of ceftriaxone in CSF were consistently ≥1
mg/L. Treatment with ceftriaxone (2 g IV every 12 h) is
therefore very likely to be effective for the majority of
patients with pneumococcal meningitis but may be
ineffective in patients with meningitis caused by
S. pneumoniae strains with ceftriaxone MIC >2 mg/L.
Because CSF concentrations of ceftriaxone may not be
sufficient to treat S. pneumoniae strains with reduced sus-
ceptibility to ceftriaxone, the supplementation of initial
therapy with vancomycin should be considered. In
Australia, the addition of vancomycin is recommended
for patients who are most likely to have pneumococcal
meningitis, such as those with known or suspected otitis
media or sinusitis and those who have Gram-positive
cocci seen in the CSF analysis or a positive pneumococ-
cal BAT.31 Vancomycin should also be added for patients
with risk factors for infection with a S. pneumoniae strain
with reduced susceptibility to ceftriaxone, such as those
treated with beta-lactam antibiotics in the last 3 months;
recent hospitalisation and residence in a long-term care
facility have also been identified as risk factors for a resis-
tant strain.63 If pneumococcal meningitis is confirmed,
vancomycin should be continued until the ceftriaxone
MIC is available.64 In Australia, in 2012, 10% of
S. pneumoniae isolates from sterile sites demonstrated
decreased susceptibility to penicillin (MIC > 0.06 mg/L),
but only 2% demonstrated decreased susceptibility to
ceftriaxone (MIC > 0.5 mg/L).65 At Auckland City Hospi-
tal in New Zealand during 2017, 35% of S. pneumoniae
isolates from blood or CSF demonstrated decreased sus-
ceptibility to penicillin, while 11% demonstrated
decreased susceptibility to ceftriaxone, suggesting that
the addition of vancomycin should be routine when
empirically treating patients with meningitis in Auck-
land.66 Resistance to vancomycin has not yet been
reported for S. pneumoniae.

1302 Internal Medicine Journal 48 (2018) 1294–1307

© 2018 Royal Australasian College of Physicians

Other considerations
Many patients with bacterial meningitis are critically
unwell and will require support in the intensive care
unit. This may include airway support with mechanical
ventilation, circulatory support with inotropes, medical
or surgical reduction of raised ICP and medical manage-
ment of coagulopathy, hyponatraemia and seizures.
Later in the course of meningococcal disease, those with
purpura fulminans may require debridement or amputa-
tion of necrotic tissues and reconstruction with skin
grafts or flaps.67 For adults with pneumococcal meningi-
tis, predisposing conditions, such as otitis media, sinusitis
or mastoiditis, should be sought and managed in con-
junction with otorhinolaryngology if required.9
Directed therapy
Once a presumptive microbiological diagnosis has been pro-
vided by Gram stain or confirmed by culture or PCR, fur-
ther therapy can be directed at the identified pathogen.13
Streptococcus pneumoniae
For pneumococcal meningitis, a 10–14-day course of IV
therapy should be completed, with dexamethasone given
during the first 4 days.13 In patients infected with
ceftriaxone-susceptible strains, vancomycin can be discon-
tinued and treatment continued with 2 g ceftriaxone IV
every 12 h. If the isolate is penicillin-susceptible, clinicians
may consider changing to 2.4 g benzylpenicillin IV every
4 h to avoid continuing with an unnecessarily broad-
spectrum agent.56 If the isolate is ceftriaxone-intermediate
or -resistant, options include continuing ceftriaxone and
vancomycin if the patient has responded well to initial
therapy (with consideration of the addition of rifampicin)
or changing to 400 mg moxifloxacin IV every 24 h.31,68
Survivors have a 5% risk of recurrence of pneumococcal
meningitis, and thus pneumococcal vaccination is recom-
mended; this is particularly important for those with a
predisposing immunodeficiency or CSF leak.14
Neisseria meningitidis
A dose of 1.8 g benzylpenicillin IV every 4 h should be
used for the treatment of meningococcal meningitis in
Australia and New Zealand.31 Ceftriaxone can be used for
patients with immediate penicillin hypersensitivity54 and
moxifloxacin or ciprofloxacin used for patients with
severe T cell-mediated reactions to penicillins.13,31 While
strains with intermediate susceptibility to penicillin are
increasingly detected, high doses of penicillin are clinically
effective.69 Although frank resistance to penicillin remains
rare, vigilance is required given the emergence of a
penicillin-resistant clade of N. meningitidis serogroup W in
Internal Medicine Journal 48 (2018) 1294–1307
© 2018 Royal Australasian College of Physicians
Meningitis in adults
2016 and the identification of a penicillin-resistant ser-
ogroup B isolate in 2010, both from Western
Australia.69,70 While most guidelines recommend between
5 and 7 days of antibiotic therapy for meningococcal
meningitis,13,31,64 experience with 88 patients during a
very large meningococcal epidemic in New Zealand found
that 3 days of benzylpenicillin was effective treatment,
strongly suggesting that longer courses are unnecessary.71
Dexamethasone can be stopped in patients with con-
firmed meningococcal meningitis.14
Patients with meningococcal disease should be placed
in droplet precautions until 24 h of antibiotic therapy
has been given.8 In cases of suspected or confirmed
meningococcal disease, public health authorities should
be notified and clearance antibiotics administered to
close contacts. Options for non-pregnant persons include
ciprofloxacin (a single 500 mg oral dose) or rifampicin
(600 mg orally twice/day for 2 days); rifampicin should
be avoided in women taking the oral contraceptive pill
or in patients for whom there are other important drug
interactions. Ceftriaxone (a single intramuscular dose of
250 mg) is the preferred option for pregnant women.
Penicillin does not adequately eradicate nasopharyngeal
carriage of meningococci; thus, clearance antibiotics are
also required for the index case unless at least one dose
of ceftriaxone has been given during treatment. Clear-
ance antibiotics should be initiated as soon as possible,
ideally on the day of diagnosis, but should still be given
up to 14 days following exposure. Vaccination for close
contacts is also recommended if the infecting organism is
in a vaccine-preventable serogroup. However, serotyping
usually requires referral of the specimen to a reference
laboratory, and results may not be available within the
appropriate timeframe to implement vaccination.8,72
Listeria monocytogenes
A dose of 2.4 g benzylpenicillin IV every 4 h (or 2 g amoxi-
cillin IV every 4 h) is the treatment of choice for meningitis
caused by L. monocytogenes. Trimethoprim/sulfamethoxa-
zole can be used for patients with penicillin allergy.13
The addition of gentamicin appears to reduce mortality,
although this has not been proven in randomised tri-
als.53,64 Optimal treatment duration is unknown, but IV
antibiotics are generally continued for at least 21 days.13
Dexamethasone should be discontinued immediately if
L. monocytogenes has been identified, because of the worse
outcome in patients who receive dexamethasone.53
Viral meningitis
Dexamethasone and antibiotics can be discontinued if
CSF parameters are consistent with viral meningitis, pro-
vided the clinical suspicion for bacterial meningitis is
low. Enteroviral meningitis is self-limiting and requires
1303
Young & Thomas
only supportive care. HSV meningitis is also self-limiting
in immunocompetent patients; symptomatic treatment
alone is reasonable, although 7–10 days of antiviral
treatment (with acyclovir, valacyclovir or famciclovir)
has been shown to improve neurological outcomes in
immunocompromised hosts.39 It is vital to recognise that
HSV encephalitis (usually caused by HSV-1) is a distinct
entity from HSV meningitis (usually caused by HSV-2);
in HSV encephalitis, treatment with IV acyclovir is criti-
cal in reducing mortality and disability.40 The optimal
treatment of VZV meningitis is unknown, although most
clinicians would give antivirals unless the patient was
already improving without therapy.40 Meningitis caused
by acute HIV infection requires ongoing follow up and
management from an experienced specialist.
Deteriorating patients
Neuroimaging is indicated in patients who fail to
improve or in whom neurological abnormalities or sei-
zures develop, to evaluate for hydrocephalus, venous
sinus thrombosis, subdural empyema or intracerebral
abscess. These complications occur most commonly in
patients with pneumococcal meningitis.67 Repeat LP
should be considered in those who fail to improve after
48 h of treatment and who have unremarkable neuro-
imaging; this is particularly important for patients with
meningitis caused by a strain of S. pneumoniae with
reduced susceptibility to ceftriaxone.13
Primary prevention
Childhood vaccination against Haemophilus influenzae sero-
type b has led to the near-complete elimination of menin-
gitis caused by this pathogen in countries with adequate
vaccination coverage.72 Pneumococcal vaccination is
incorporated into the immunisation schedules of both
Australia and New Zealand; vaccination has reduced the
rates of pneumococcal meningitis in children and adults,
albeit with a rise in the proportion of cases caused by
serotypes not included in vaccines.72 No effective vaccines
have been developed against L. monocytogenes.
In Australia, most cases of meningococcal disease are
caused by serogroups W, B and Y, which were responsible
for 43%, 36% and 16% of cases in 2016 respectively.73
Serogroup C disease has become very rare since the conju-
gate meningococcal C vaccine was introduced to the
Australian immunisation schedule in 2003, with the excep-
tion of an outbreak of serogroup C disease in 2017 among
men who have sex with men in Melbourne.74,75 In 2018,
the serogroup C vaccine was replaced in the Australian
immunisation schedule by a quadrivalent conjugate vac-
cine against serogroups A, C, W and Y, which is
1304
administered at 12 months of age.74 In New Zealand,
meningococcal serogroups B and C are of the most impor-
tance, but no meningococcal vaccines are included in the
New Zealand immunisation schedule.72 Vaccination against
serogroups A, C, W and Y is recommended for people at
high risk of meningococcal disease, including patients with
terminal complement deficiencies or asplenia, those with
HIV infection, military recruits and some travellers, such as
those whose destination is the ‘meningitis belt’ in sub-
Saharan Africa. For pilgrims to the Hajj in Saudi Arabia,
quadrivalent meningococcal vaccination is a requirement
of entry.72 Producing effective vaccines against meningo-
coccal serogroup B has proven difficult due to its poorly
immunogenic capsule. In New Zealand, between 2004 and
2008, the MeNZB vaccine was offered to children and ado-
lescents and had a modest effect on the nationwide menin-
gococcal epidemic; however, this vaccine was targeted
against the epidemic strain alone and produced only a rela-
tively weak and short-lived immune response.72 Advances
have occurred in serogroup B vaccine development, and a
vaccine (Bexsero, GlaxoSmithKline) that is immunogenic
against an estimated 76% of group B meningococcal strains
is now available in Australia for private purchase. The
duration of protection remains unknown.74
Conclusion
The likelihood of confirming the responsible pathogen
in cases of community-acquired bacterial meningitis
has been improved by newer techniques, such as mul-
tiplex PCR. However, a thorough understanding of the
interpretation of basic CSF parameters, as well as the
caveats of relying on CSF parameters alone to exclude
bacterial meningitis, is required to accurately diagnose
this often terrifying condition. Clinicians should collect
blood cultures and CSF and initiate treatment within
1 h of making a presumptive clinical diagnosis of bacte-
rial meningitis. They should be aware of the worse out-
comes that occur when neuroimaging unnecessarily
delays LP and the initiation of treatment. Prompt ther-
apy with dexamethasone plus ceftriaxone, with the
addition of vancomycin and/or benzylpenicillin when
indicated, improves the chance of a positive outcome
for patients affected by this devastating and disabling
disease.
Acknowledgements
Dr Stephen Ritchie (Department of Infectious Diseases,
Auckland City Hospital and Department of Molecular
Medicine and Pathology, University of Auckland) kindly
reviewed the manuscript and gave helpful advice.
Internal Medicine Journal 48 (2018) 1294–1307
© 2018 Royal Australasian College of Physicians

References
1 Tunkel AR, van de Beek D, Scheld W.
Acute meningitis. In: Bennett J, Dolin R
and Blaser M, eds. Principles and Practice
of Infectious Diseases, 8th edn.
Philadelphia: Elsevier/Saunders; 2015;
1097–137.
2 Brouwer MC, McIntyre P, Prasad K, van
de Beek D. Corticosteroids for acute
bacterial meningitis. Cochrane Database
Syst Rev 2015: CD004405.
3 Strelow VL, Vidal JE.
Invasive meningococcal disease.
Arq Neuropsiquiatr 2013; 71: 653–8.
4 Glimaker M, Johansson B, Grindborg O,
Bottai M, Lindquist L, Sjolin J. Adult
bacterial meningitis: earlier treatment
and improved outcome following
guideline revision promoting prompt
lumbar puncture. Clin Infect Dis 2015;
60: 1162–9.
5 Grindborg O, Naucler P, Sjolin J,
Glimaker M. Adult bacterial
meningitis-a quality registry
study: earlier treatment and
favourable outcome if initial
management by infectious diseases
physicians. Clin Microbiol Infect 2015;
21: 560–6.
6 Proulx N, Frechette D, Toye B, Chan J,
Kravcik S. Delays in the administration
of antibiotics are associated with
mortality from adult acute bacterial
meningitis. QJM 2005; 98: 291–8.
7 van de Beek D, de Gans J, Spanjaard L,
Weisfelt M, Reitsma JB, Vermeulen M.
Clinical features and prognostic factors
in adults with bacterial meningitis. N
Engl J Med 2004; 351: 1849–59.
8 Australian Government Department of
Health. Invasive Meningococcal Disease.
Canberra, Australia: Communicable
Diseases Network Australia; 2017.
9 Mook-Kanamori BB, Geldhoff M, van
der Poll T, van de Beek D. Pathogenesis
and pathophysiology of pneumococcal
meningitis. Clin Microbiol Rev 2011; 24:
557–91.
10 Brouwer M, van de Beek D,
Heckenberg S, Spanjaard L, de Gans J.
Community-acquired Listeria
monocytogenes meningitis in adults. Clin
Infect Dis 2006; 43: 1233–8.
11 Michael B, Menezes BF, Cunniffe J,
Miller A, Kneen R, Francis G et al.
Effect of delayed lumbar punctures on
the diagnosis of acute bacterial
meningitis in adults. Emerg Med J 2010;
27: 433–8.
Internal Medicine Journal 48 (2018) 1294–1307
© 2018 Royal Australasian College of Physicians
12 Hasbun R, Abrahams J, Jekel J,
Quagliarello V. Computed tomography
of the head before lumbar puncture in
adults with suspected meningitis. N Engl
J Med 2001; 345: 1727–33.
13 Tunkel AR, Hartman BJ, Kaplan SL,
Kaufman BA, Roos KL, Scheld WM
et al. Practice guidelines for the
management of bacterial meningitis.
Clin Infect Dis 2004; 39: 1267–84.
14 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: S37–62.
15 Glimaker M, Johansson B, Bell M,
Ericsson M, Blackberg J, Brink M et al.
Early lumbar puncture in adult bacterial
meningitis--rationale for revised
guidelines. Scand J Infect Dis 2013; 45:
657–63.
16 Larsen L, Poulsen FR, Nielsen TH,
Nordstrom CH, Schulz MK,
Andersen AB. Use of intracranial
pressure monitoring in bacterial
meningitis: a 10-year follow up on
outcome and intracranial pressure
versus head CT scans. Infect Dis (Lond)
2017; 49: 356–64.
17 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: 321–8.
18 Attia J, Hatala R, Cook D, Wong J.
Does this adult patient have acute
meningitis? JAMA 1999; 282:
175–81.
19 McGill F, Heyderman RS, Michael BD,
Defres S, Beeching NJ, Borrow R et al.
The UKjoint specialist societies
guideline on the diagnosis and
management of acute meningitis and
meningococcal sepsis in
immunocompetent adults. J Infect 2016;
72: 405–38.
20 Gray L, Fedorko D. Laboratory
diagnosis of bacterial meningitis. Clin
Microbiol Rev 1992; 5: 130–45.
21 Pappas PG, Perfect JR, Cloud GA,
Larsen RA, Pankey GA, Lancaster DJ
et al. Cryptococcosis in human
immunodeficiency virus-negative
patients in the era of effective azole
therapy. Clin Infect Dis 2001; 33: 690–9.
22 Tamune H, Takeya H, Suzuki W,
Tagashira Y, Kuki T, Honda H et al.
Cerebrospinal fluid/blood glucose ratio
Meningitis in adults
as an indicator for bacterial meningitis.
Am J Emerg Med 2014; 32: 263–6.
23 Seehusen D, Reeves M, Fomin D.
Cerebrospinal fluid analysis. Am Fam
Physician 2003; 68: 1103–8.
24 Hase R, Hosokawa N, Yaegashi M,
Muranaka K. Bacterial meningitis in the
absence of cerebrospinal fluid
pleocytosis: a case report and review of
the literature. Can J Infect Dis Med
Microbiol 2014; 25: 249–51.
25 Feigin RD, Shackelford PG. Value of
repeat lumbar puncture in the
differential diagnosis of meningitis. N
Engl J Med 1973; 289: 571–4.
26 Kaewpoowat Q, Salazar L, Aguilera E,
Wootton SH, Hasbun R. Herpes simplex
and varicella zoster CNS infections:
clinical presentations, treatments
and outcomes. Infection 2016; 44:
337–45.
27 Philip N, William T, John D. Diagnosis
of tuberculous meningitis: challenges
and promises. Malays J Pathol 2015;
37: 1–9.
28 Hegen H, Auer M, Deisenhammer F.
Serum glucose adjusted cut-off values
for normal cerebrospinal fluid/serum
glucose ratio: implications for clinical
practice. Clin Chem Lab Med 2014; 52:
1335–40.
29 Spanos A, Harrell FE Jr, Durack DT.
Differential diagnosis of acute
meningitis. An analysis of the predictive
value of initial observations. JAMA
1989; 262: 2700–7.
30 Fitch MT, van de Beek D. Emergency
diagnosis and treatment of adult
meningitis. Lancet Infect Dis 2007; 7:
191–200.
31 Antibiotic Expert Groups. Therapeutic
Guidelines: Antibiotic. Version 15.
Melbourne, Australia: Therapeutic
Guidelines Limited; 2014.
32 McBride S, Fulke J, Giles H, Hobbs M,
Suh J, Sathyendran V et al.
Epidemiology and diagnostic testing for
meningitis in adults as the
meningococcal epidemic declined at
Middlemore Hospital. N Z Med J 2015;
128: 17–24.
33 Le Monnier A, Abachin E, Beretti JL,
Berche P, Kayal S. Diagnosis of Listeria
monocytogenes meningoencephalitis by
real-time PCR for the hly gene. J Clin
Microbiol 2011; 49: 3917–23.
34 Brink M, Welinder-Olsson C,
Hagberg L. Time window for positive
cerebrospinal fluid broad-range
bacterial PCR and Streptococcus
1305
Young & Thomas
pneumoniae immunochromatographic
test in acute bacterial meningitis. Infect
Dis (Lond) 2015; 47: 869–77.
35 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:
255–62.
36 Vikse J, Henry BM, Roy J,
Ramakrishnan PK, Tomaszewski KA,
Walocha JA. The role of serum
procalcitonin in the diagnosis of
bacterial meningitis in adults: a
systematic review and meta-analysis. Int
J Infect Dis 2015; 38: 68–76.
37 Markanday A. Acute phase reactants in
infections: evidence-based review and a
guide for clinicians. Open Forum Infect
Dis 2015; 2: ofv098.
38 Ray P, Badarou-Acossi G, Viallon A,
Boutoille D, Arthaud M, Trystram D
et al. Accuracy of the cerebrospinal fluid
results to differentiate bacterial from
non bacterial meningitis, in case of
negative Gram-stained smear.
Am J Emerg Med 2007; 25: 179–84.
39 Noska A, Kyrillos R, Hansen G,
Hirigoyen D, Williams DN. The role of
antiviral therapy in
immunocompromised patients with
herpes simplex virus meningitis. Clin
Infect Dis 2015; 60: 237–42.
40 Logan SA, MacMahon E. Viral
meningitis. BMJ 2008; 336: 36–40.
41 Hanson K, Reckleff J, Hicks L,
Castellano C, Hicks C. Unsuspected HIV
infection in patients presenting with
acute meningitis. Clin Infect Dis 2008;
47: 433–4.
42 Thomas M, Sasadeusz J. Neurological
infections. In: Yung A, Spelman D,
Street A, McCormack J, Sorrell T and
Johnson P, eds. Infectious Diseases: A
Clinical Approach, 3rd edn. Melbourne,
Australia: IP Communications; 2010;
246–60.
43 Darras-Joly C, Chevret S, Wolff M,
Matheron S, Longuet P, Casalino E et al.
Cryptococcus neoformans infection in
France: epidemiologic features of and
early prognostic parameters for
76 patients who were infected with
human immunodeficiency virus. Clin
Infect Dis 1996; 23: 369–76.
44 Erdem H, Ozturk-Engin D, Elaldi N,
Gulsun S, Sengoz G, Crisan A et al. The
microbiological diagnosis of tuberculous
meningitis: results of Haydarpasa-1
1306
study. Clin Microbiol Infect 2014; 20:
O600–8.
45 Nhu NT, Heemskerk D, Thu do DA,
Chau TT, Mai NT, Nghia HD et al.
Evaluation of GeneXpert MTB/RIF for
diagnosis of tuberculous meningitis. J
Clin Microbiol 2014; 52: 226–33.
46 Prasad K, Kumar A, Gupta PK,
Singhal T. Third generation
cephalosporins versus conventional
antibiotics for treating acute bacterial
meningitis. Cochrane Database Syst Rev
2007: CD001832.
47 Wang N, Han YH, Sung JY, Lee WS,
Ou TY. Atypical leptospirosis: an
overlooked cause of aseptic meningitis.
BMC Res Notes 2016; 9: 154.
48 Ramirez-Avila L, Slome S, Schuster FL,
Gavali S, Schantz PM, Sejvar J et al.
Eosinophilic meningitis due to
Angiostrongylus and Gnathostoma
species. Clin Infect Dis 2009; 48: 322–7.
49 Harnden A, Ninis N, Thompson M,
Perera R, Levin M, Mant D et al.
Parenteral penicillin for children with
meningococcal disease before hospital
admission: case-control study. BMJ
2006; 332: 1295–8.
50 Koster-Rasmussen R, Korshin A,
Meyer CN. Antibiotic treatment delay
and outcome in acute bacterial
meningitis. J Infect 2008; 57: 449–54.
51 Borchorst S, Moller K. The role of
dexamethasone in the treatment of
bacterial meningitis – a systematic
review. Acta Anaesthesiol Scand 2012; 56:
1210–21.
52 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: 250–5.
53 Charlier C, Perrodeau É, Leclercq A,
Cazenave B, Pilmis B, Henry B et al.
Clinical features and prognostic factors
of listeriosis: the MONALISA national
prospective cohort study. Lancet Infect
Dis 2017; 17: 510–9.
54 Campagna JD, Bond MC,
Schabelman E, Hayes BD. The use of
cephalosporins in penicillin-allergic
patients: a literature review. J Emerg
Med 2012; 42: 612–20.
55 Weinstein MP, Klugman KP, Jones RN.
Rationale for revised penicillin
susceptibility breakpoints versus
Streptococcus pneumoniae: coping with
antimicrobial susceptibility in an era of
resistance. Clin Infect Dis 2009; 48:
1596–600.
56 European Committee on Antimicrobial
Susceptibility Testing (homepage on the
Internet). Breakpoint tables for
interpretation of MICs and zone
diameters. Version 8.0. 2018. [cited
20 Mar 2018]. Available from URL:
http://www.eucast.org/clinical_
breakpoints/
57 European Committee on Antimicrobial
Susceptibility Testing. Antimicrobial
wild type distributions of
microorganisms. 2018. [cited 2018 Feb
2]. Available from URL: https://mic.
eucast.org/Eucast2/
58 Schoth PE, Wolters EC. Penicillin
concentrations in serum and CSF
during high-dose intravenous treatment
for neurosyphilis. Neurology 1987; 37:
1214–6.
59 Patel IH, Chen S, Parsonnet M,
Hackman MR, Brooks MA, Konikoff J
et al. Pharmacokinetics of ceftriaxone in
humans. Antimicrob Agents Chemother
1981; 20: 634–41.
60 Chandrasekar PH, Rolston KV,
Smith BR, LeFrock JL. Diffusion of
ceftriaxone into the cerebrospinal fluid
of adults. J Antimicrob Chemother 1984;
14: 427–30.
61 Cabellos C, Viladrich PF, Verdaguer R,
Pallares R, Liñares J, Gudiol F. A single
daily dose of ceftriaxone for bacterial
meningitis in adults: experience with
84 patients and review of the
literature. Clin Infect Dis 1995; 20:
1164–8.
62 Lutsar I, McCracken GH Jr,
Friedland IR. Antibiotic
pharmacodynamics in cerebrospinal
fluid. Clin Infect Dis 1998; 27: 1117–29.
63 Vanderkooi OG, Low DE, Green K,
Powis JE, McGeer A. Predicting
antimicrobial resistance in invasive
pneumococcal infections. Clin Infect Dis
2005; 40: 1288–97.
64 van de Beek D, Brouwer MC,
Thwaites GE, Tunkel AR. Advances in
treatment of bacterial meningitis. The
Lancet 2012; 380: 1693–702.
65 Toms C, de Kluyver R. Invasive
pneumococcal disease in Australia 2011
and 2012. Commun Dis Intell Q Rep 2016;
40: E267–84.
66 LabPLUS. Antimicrobial susceptibility
test results for Gram-positive isolates
recovered from clinical specimens.
Auckland, New Zealand: LabPLUS,
Internal Medicine Journal 48 (2018) 1294–1307
© 2018 Royal Australasian College of Physicians

2018 [cited 2018 Jun 25]. Available
from URL: http://www.labplus.co.nz/
assets/Uploads/2017-Gram-Positive-
Antimicrobial-Report.pdf
67 van de Beek D, de Gans J, Tunkel AR,
Wijdicks EF. Community-acquired
bacterial meningitis in adults. N Engl J
Med 2006; 354: 44–53.
68 Weisfelt M, de Gans J, van de Beek D.
Bacterial meningitis: a review of
effective pharmacotherapy. Expert Opin
Pharmacother 2007; 8: 1493–504.
69 Abeysuriya SD, Speers DJ, Gardiner J,
Murray RJ. Penicillin-resistant Neisseria
meningitidis bacteraemia, Kimberley
region, March 2010. Commun Dis Intell Q
Rep 2010; 34: 342–4.
Internal Medicine Journal 48 (2018) 1294–1307
© 2018 Royal Australasian College of Physicians
70 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: 1364–7.
71 Briggs S, Ellis-Pegler R, Roberts S,
Thomas M, Woodhouse A. Short course
intravenous benzylpenicillin treatment
of adults with meningococcal disease.
Intern Med J 2004; 34: 383–7.
72 Ministry of Health. Immunisation
Handbook 2017. Wellington,
New Zealand: Ministry of Health; 2017.
73 Australian Government Department of
Health. Invasive meningococcal disease
public dataset. 2017 [cited 2018 Jun 26].
Meningitis in adults
Available from URL: http://www9.health.
gov.au/cda/source/pub_menin.cfm
74 National Centre for Immunisation
Research and Surveillance.
Meningococcal vaccines for Australians.
2018 [cited 2018 Feb 4]. Available from
URL: http://www.ncirs.edu.au/assets/
provider_resources/fact-sheets/
meningococcal-Vaccine-fact-sheet.pdf
75 Department of Health and Human
Services. Outbreak of invasive
meningococcal C disease in men who
have sex with men (MSM). 2017 [cited
2018 Jun 26]. Available from URL:
https://www2.health.vic.gov.au/about/
news-and-events/healthalerts/alert-
meningococcal-c-december-2017
1307