SYMPOSIUM: NEONATOLOGY
streptococcus infections presenting within 7 days of life, also
Neonatal sepsis
Oliver Walker
Celyn B Kenny
Nitin Goel
Abstract
Neonatal sepsis is a cause of significant mortality and morbidity. It can
be early (less than 72 h) or late onset (more than 72 h age). Group B
Streptococcus (GBS) is the leading cause of early onset neonatal
sepsis (EONS). Risk factors include maternal sepsis, prolonged
rupture of membranes, chorioamnionitis and GBS colonization. Risk-
based predictive models are used to identify and screen infants.
Late onset neonatal sepsis (LONS) is largely caused by gram positive
organisms. Risks for LONS include prematurity, low birth weight and
common neonatal interventions and procedures. Signs and symptoms
of neonatal sepsis are often subtle leading to over and under treat-
ment. Standard investigations include blood cultures, full blood
count, C Reactive Protein and lumbar puncture. Procalcitonin is
being investigated as a sensitive and specific biomarker of bacterae-
mia in aiding diagnosis and management. Physiological monitoring
can be used to monitor the early signs of sepsis on the neonatal
unit and facilitate prompt intervention. EONS is treated with benzylpe-
nicillin and an aminoglycoside antibiotic, and most LONS can be
managed with narrow spectrum antibiotics, in addition to supportive
management as required. Antibiotic duration is best determined by
culture results, biomarkers and clinical response to treatment. This
article will discuss the evidence for treatment of neonatal sepsis and
offers practical advice and guidance for a clinician faced with this
important clinical dilemma.
Keywords early onset sepsis; group B streptococcus; late onset
sepsis; neonatal sepsis
Introduction
Neonatal sepsis is any form of infection that occurs within the
first 28 days of life. Sepsis is recognized as a leading cause of
mortality and morbidity in newborns and is responsible for one
third of neonatal deaths globally. Its incidence varies within
healthcare settings and between neonatal units across the globe.
We can broadly classify neonatal sepsis as:
 Early onset sepsis (EONS) e within 72 h of birth e acquired
before or soon after delivery and usually represent vertical
mother to infant transmission. Some clinicians class Group B
Oliver Walker BSc PhD MBBS MRCPCH, Neonatal Grid Trainee, Neonatal
Unit, University Hospital of Wales, Cardiff, UK. Conflicts of interest:
none declared.
Celyn B Kenny MBBCh, Paediatric Speciality Trainee, Neonatal Unit,
University Hospital of Wales, Cardiff, UK. Conflicts of interest: none
declared.
Nitin Goel MBBS MD MRCPCH FRCPCH, Consultant Neonatologist,
Neonatal Unit, University Hospital of Wales, Cardiff, UK. Conflicts of
interest: none declared.
PAEDIATRICS AND CHILD HEALTH 29:6
as EONS
 Late onset sepsis (LONS) e occurring more than 72 h after
birth e usually attributed to organisms acquired from hos-
pital or community environment
The perinatal period is a particularly risky time for the fetus
and newborn. Neonatal skin and mucous membranes are fragile
and immature neonates have an underdeveloped immune system
without the full complement of maternal antibodies.
The newborn’s journey from the uterus to the birth canal is
potentially a source of infection and these risks are extended if
the baby is transferred to the neonatal unit environment. The
newborn infant admitted to the neonatal unit is subjected to
multiple invasive clinical procedures and their bowel flora is
adversely affected by antibiotics use and feeding practices.
Early onset neonatal sepsis
Epidemiology and causative organisms
Culture-positive EONS has an incidence of around 0.5e0.9 per
1000 live births in infants 34 weeks gestation, representing
about 1% of neonatal unit admissions. Incidence and mortality is
higher in preterm and very low birth weight (VLBW) infants.
EONS presentation can vary, ranging from subtle early signs of
being unwell such as temperature instability and poor feeding to
pneumonia or a fulminating septic illness. Main routes of trans-
mission are from the mother via trans-placental or ascending
vaginal routes or via haematogenous spread in mothers with
bacteraemia or viraemia.
In the UK and US, the leading organism causing EONS is
Group B Streptococcus (GBS) (about 43%), followed by gram-
negative isolates mainly Escherichia Coli (E.coli) (25e29%) and
other gram positive organisms such as Streptococci and Staphy-
lococcus aureus (S. aureus). Less frequently Haemophilus influ-
enzae, Candida spp and Listeria monocytogenes can be isolated.
Listeria infection carries a significant mortality as meningitis and
has been associated with history of meconium stained liquor in
preterm births.
In the UK, GBS carriage rate in pregnant women is around 25
e33%. Of the infants born to GBS colonized women 1e2% will
develop invasive disease. Mortality rate of GBS sepsis can be
high up to 4e6%; with more than 10 times higher mortality in
preterm infants as compared to term infants.
Risk factors

Intrapartum fever (more than 38 C), prolonged rupture of
membranes (PROM) more than 18 h, maternal GBS colonisation/
bacteriuria and history of a previous infant with GBS are recog-
nized risk factors for EONS. Chorioamnionitis is the commonest
underlying reason for spontaneous preterm labour with maternal
UTI (most commonly E. Coli), being an important preceding risk
factor. Infection and mortality is inversely proportional to
gestation and birth weight.
Clinical presentation
The National Institute for Health and Clinical Excellence (NICE)
developed a guideline for management of EONS based on
maternal risk factors and infant clinical indicators. A baby with
one ‘red flag’ indicator or risk factor, or two or more ‘non-red
263 Crown Copyright Ó 2019 Published by Elsevier Ltd. All rights reserved.
 SYMPOSIUM: NEONATOLOGY
flag’ indicators should be assessed and screened for infection and
treated with antibiotics promptly without delay. The presence of
no red flags, but one ‘non-red flag’ qualifies for a period of close
observation for 12e24 h.
Clinical signs in the early stages of any infection may be subtle
and non-specific and include:
- Respiratory distress, tachypnoea or apnoea
-Lethargy or poor feeding
-Temperature instability less than 36 or more than 37.8
-Poor capillary refill time
-Tachycardia, or bradycardia in more serious cases
-Fulminant sepsis may present with respiratory failure, cyanosis
and shock.
Given the clinical picture the differential diagnoses include
pneumonia, generalized sepsis, meningitis, cardiac disease
and metabolic conditions. EONS may be clinically indistin-
guishable from hypoxic ischaemic encephalopathy at delivery.
Sepsis is increasingly recognized as a risk factor for neonatal
encephalopathy.
The Kaiser Permanente (KP) group in the US has developed a
different EONS screening and management algorithm to reduce
the unnecessary use of antibiotic in large number of healthy
newborns. This is available as a web-based application known as
Sepsis Risk Calculator. This algorithm adopts the Bayesian model.
It starts with the population risk of EONS and modifies this by
applying the maternal risk factors and then infant’s objective
clinical measures to specify an infant-specific final risk. Based on
this it then recommends the need for enhanced observations and/
or antibiotics. This is already used widely in the USA with re-
ported reductions of antibiotic use by as much as 50%.
With bacteria such as GBS and E. coli there can be rapid
progression from mild symptoms to death in less than 24 h;
possibly as a consequence of brisk systemic inflammatory
response through cytokine release. A high index of suspicion for
GBS infection is required in any term baby with respiratory
distress or in preterm infants who has more severe respiratory
distress than anticipated. Radiologically RDS and GBS lung
infection may be indistinct. In severe cases, persistent pulmonary
hypertension of the newborn, hypotension, metabolic acidosis,
tachycardia and poor peripheral perfusion may develop and are
poor prognostic features.
Evaluation and investigations in EONS
A neonate with signs and symptoms of sepsis requires prompt
assessment, identification of risk factors and initiation of anti-
biotic therapy. Negative tests should not preclude sepsis. How-
ever, if positive, they can be useful in supporting diagnosis and
as guidance in determining length of therapy.
Blood gas: this is clinically very relevant as it may reveal a mixed
respiratory or metabolic acidosis.
White cell counts: white blood cell (WBC) counts, differential,
absolute neutrophil counts, and the ratio of immature to total
neutrophils (I/T ratio) in the blood are widely used as screening
tests for neonatal sepsis. Unfortunately, none of these tests have
good positive predictive value. The values of WBC are age-
dependent, and should be used in clinical context along with
the natural rise and fall in the first few hours and days of life.
PAEDIATRICS AND CHILD HEALTH 29:6
Acute phase reactants: CRP is the most commonly available
acute phase reactant. Its levels rise in response to IL-6 secretion
by macrophages and T-cells. Babies can have a negligible CRP
result at birth even with positive blood cultures, but 12e24 h
later the CRP may rise. Serial CRP measurements are used to
facilitate decision making regarding lumbar punctures (LP),
monitoring the progress of infection and determining duration of
antibiotic therapy.
CRP has limited sensitivity and a poor positive predictive
value, in the detection of EONS. An increase is seen non-
specifically with any inflammation, asphyxia, meconium aspi-
ration and prolonged rupture of membranes.
Procalcitonin, a precursor for calcitonin and composed of 116
amino acids, has been proposed as a more reliable biomarker for
neonatal sepsis. Levels of procalcitonin are undetectable in healthy
individuals thus demonstrating its high negative predictive value.
In the face of bacterial sepsis, levels have been seen to rise
dramatically and may be more sensitive and specific in the differ-
entiation between neonatal infection and inflammation compared
with CRP. A cut-off value of 2.4 ng/ml has high specificity and
sensitivity. A natural rise is seen in the first 24e36 h following
birth, so a higher cut off point is needed for this age group. There
are reports in the USA, that the use of procalcitonin as a guide can
reduce the duration of antibiotics used in EONS by up to 50%.
Blood culture: blood cultures are the gold standard in diagnosing
bacteraemia. Previous reports suggested positive yields of 15
e20%; however with modern culture bottles and inoculating
adequate volume of blood (minimum 1 ml) in a single paediatric
culture bottle, the yields can be much higher. Utmost aseptic
precautions should be taken while obtaining the blood sample
for culture, to avoid contaminant organisms. Cultures can be
negative even in the face of signs and symptoms of infection.
Time to positivity (TTP) for most blood cultures is 36e48 h.
Lumbar puncture: early onset meningitis is extremely uncom-
mon (0.01e0.02/1000 live births). In EONS, LP should not be a
routine investigation; however a high CRP, clinical symptoms
suggesting meningitis or a positive blood culture, can be in-
dications to consider LP. There is debate over the usefulness of a
specific CRP cut off value in undertaking a lumbar puncture in
EONS. CSF values indicative of neonatal meningitis are also not
well established, especially as obtaining a non-bloodstained tap
can be technically challenging in a neonate and results are
affected by delays in analysis. In most studies, the normal CSF
white cell count in healthy, uninfected preterm or term neonates
is less than 10 cells/mm3, with more than 95% having counts of
fewer than 20 cells/mm3. However, the levels are age and
gestation dependent, with the higher cell counts recorded during
the first week. In a blood stained tap there has been no proven
diagnostic benefit in comparing the ratio of CSF WBC count and
red blood cells with that of peripheral blood sample. CSF protein
levels are usually, but not always, elevated in neonates with
meningitis. CSF glucose level (normally 70e80% of serum level)
usually drops significantly with bacterial meningitis but, may
remain normal as well.
Urine: obtaining uncontaminated urine specimens in babies is
challenging but important. A suprapubic aspiration of urine
264 Crown Copyright Ó 2019 Published by Elsevier Ltd. All rights reserved.
 SYMPOSIUM: NEONATOLOGY
(SPA) or fresh catheter specimen urine or a clean catch sample
following thorough skin cleansing is required. Urine cultures are
of greater importance in LONS.
Other sites: surface cultures are of limited value. Colonization in
the absence of suspicious clinical signs does not warrant anti-
biotic treatment. However this can be useful if disseminated
Herpes is suspected.
Radiology: chest radiograph (CXR) should be considered in a
baby undergoing EONS screening as pneumonia may be present
with limited clinical signs.
Treatment of EONS
Supportive care: prompt treatment of suspected sepsis is
important as delay in recognizing and treating can result in
serious morbidity or death. Supportive management may include
non-invasive respiratory support with nasal cannula oxygen,
nasal CPAP or heated humidified high-flow nasal cannula
(HFNC) oxygen therapy. Mechanical ventilation may be required
in non-responding cases or with severe respiratory acidosis.
IV fluids and feeding via nasogastric tube may be required in
babies with significant respiratory distress. Blood glucose should
be monitored and abnormalities corrected promptly. Severe
cases with shock and hypotension should be promptly managed
through volume support with crystalloids and inotropic support.
Antibiotic treatment: if the decision to treat has been made,
antibiotics should be administered within the first hour. Ben-
zylpenicillin with an aminoglycoside such as gentamicin is
standard first line treatment in the UK. This provides narrow
spectrum coverage for typical EONS pathogens. Cephalospo-
rins do not provide better efficacy in terms of common patho-
gens and may have an adverse effect on the infant’s
microbiome. If S. aureus is suspected, flucloxacillin should
replace benzylpenicillin. If Listeria is suspected or identified,
amoxicillin should substitute benzylpenicillin. Once culture
results are available antibiotic regimen should be rationalized
and targeted appropriately.
Antibiotic therapy should be commenced promptly in sus-
pected infection and they should be stopped as soon as sepsis is
excluded. In general the following all apply:
 With suspected infection but asymptomatic baby, CRP not
rising and cultures negative at 36e48 h e antibiotics should
discontinued.
 Antibiotics started on high clinical suspicion of infection, yet
negative cultures and an elevated CRP e a longer course
(usually 5 days) may be warranted.
 If pneumonia is evident on CXR, but negative blood cultures
e a 5-day course may be appropriate.
 If blood cultures positive and CSF cultures negative e treat
for a minimum of 10 days in gram positive and 14 days in
gram negative organisms.
 With positive CSF cultures, and/or a clinical diagnosis of
meningitis e treatment may be required for at least 21 days,
depending on the organism isolated.
Potential hazards of antibiotics: gentamicin has a narrow
therapeutic window and persistent high serum levels may result
PAEDIATRICS AND CHILD HEALTH 29:6
in ototoxicity and sensorineural hearing loss. There are two
different mechanisms associated with gentamicin toxicity e a
high trough gentamicin concentration damaging the sensory cells
and genetically determined ototoxicity. 1:500 individuals carry a
mitochondrial DNA mutation linked with permanent profound
hearing loss from aminoglycosides even when drug levels are
within the therapeutic range.
Antibiotics, particularly those with broad-spectrum activity,
alter the natural microflora of the infant, in particular gut flora.
This can result in a rise of antibiotic resistance among the normal
commensals and the emergence of other resistant pathogens.
Over the past three decades in the developed world, there have
been reports of substantial increases in the incidence of allergic
and autoimmune diseases in young children. These have shown
association with altered microbiome secondary to peripartum
antibiotic exposure.
Prevention of EONS
The maternal to fetal transmission can be decreased by identi-
fying GBS carriage in late pregnancy along with early recognition
and adequate treatment of chorioamnionitis. Vertical trans-
mission can be prevented through the administration of intra-
partum antibiotic prophylaxis using penicillin or cefazolin/
clindamycin. Treatment is more effective if commenced at least 4
hours prior to delivery. At-risk women can be identified by e
universal bacteriological screening (at 35e37 wks) or using a
risk-based approach. Despite concerns over emerging resistance,
GBS in most countries remains susceptible to penicillin. In the
UK routine screening is not currently recommended.
If, for clinical reasons, bacteriological swabs need to be taken
this should include a combined low vaginal and rectal swab.
Detection of GBS on high vaginal swab and non-selective media is
associated with increased risk of transmission to the neonate.
Women with GBS bacteriuria or with history of a previous baby
with neonatal GBS disease should be considered for prophylactic
antibiotics. Antibiotics are not recommended for babies born to
mothers with GBS carriage who undergo elective section without
preceding labour or rupture of membranes. A Bayesian approach to
directed therapy (like KP sepsis risk calculator) is helpful. Women
with risk factors such as intrapartum pyrexia, prematurity, PROM,
should have lower threshold for consideration of antibiotics.
Late onset neonatal sepsis
Epidemiology and causative organisms
Incidence of LONS is approximately 8/1000 live births, and af-
fects about 7% of neonatal unit admissions. It is usually the
result of nosocomially acquired organisms. Mortality is higher
with fungal and gram negative infections and in more preterm,
lower birthweight infants. The majority of LONS occurs in pre-
mature and VLBW babies with incidence ranging between 16 and
30% and approaching 50% in extremely low birth weight
(ELBW) babies. Of all LONS, gram positive organisms comprise
70%, gram negative 25% and fungi about 5%.
Coagulase negative Staphylococci (CoNS) accounts for
approximately half of all LONS. Presence of central lines is
an important risk factor for CoNS. Other major isolates are
S. aureus, E. coli, Enterococcus, Klebsiella and Enterobacteriaceae.
Meningitis is more frequently a feature of LONS than EONS.
S. aureus sepsis or meningitis has a high mortality (up to 25%).
265 Crown Copyright Ó 2019 Published by Elsevier Ltd. All rights reserved.
 SYMPOSIUM: NEONATOLOGY
Candida spp (most commonly C albicans and C parapsilosis)
account for almost all fungal infections e they are relatively
infrequent in the UK even in ELBW infants. Invasive Candidiasis
is associated with high mortality and increased risk of adverse
neurodevelopmental outcome in survivors. Use of prophylactic
Fluconazole in first 6 weeks of life significantly reduces the risk
of invasive fungal infection in VLBW and ELBW infants.
Risk factors for LONS
Factors predisposing to nosocomial infection and LONS include
being premature, VLBW/ELBW, intensive care, lack of enteral
feeding, not receiving maternal breast milk, breakage of natural
barriers, invasive procedures, having an indwelling catheter,
receiving parenteral nutrition (PN) via central lines, prolonged
mechanical ventilation, H2 receptor antagonists (e.g. ranitidine),
and exposure to antenatal antibiotics. Babies who had gut sur-
gery or gut related problems are at significant risk. Prolonged use
of antibiotics is associated with increased antibiotic resistance
and increased rates of necrotising enterocolitis (NEC) and death
in ELBW infants. Broad spectrum antibiotics (especially third
generation cephalosporins) are an important risk factor for
fungal infections.
Clinical presentation
Clinical signs in the early stages of any infection may be subtle
and non-specific. These include:
-Worsening respiratory distress, increasing desaturations and
oxygen requirements, and apnoea
-Lethargy, quiet state
-Feed intolerance
-Temperature instability
-Prolonged capillary refill time
-Hyperglycaemia
-Lactic acidosis
-Cyanosis and shock
Progression from mild symptoms to death can occur in less
than 24 h with gram negative bacteria such as E. coli and Kleb-
siella. Bowel sounds may be relatively silent as functional ileus
due to generalized sepsis. A high pitched cry, abnormal move-
ments, back-arching, and tense fontanelle, are late features of
neonatal meningitis. In evaluation for LONS, the limbs and joints
should be examined for signs of osteomyelitis and septic arthritis.
Evaluation and investigations in LONS
A neonate with suspected LONS requires prompt evaluation and
if required, initiation of antibiotic therapy. Progression can be
rapid. If tests are positive, they can be useful in guiding treatment
and determining the length of therapy. Careful evaluation as well
as a complete examination, including skin and catheter insertion
sites, should be performed.
Investigations are similar to those in EONS with some further
considerations:
Lumbar puncture: a lumbar puncture (LP) should be performed
as part of the sepsis screen in LONS. Infants with overt localized
infection can be exempted, e.g. pneumonia, NEC, and babies who
are critically ill and would not be able to tolerate the procedure.
Thrombocytopenia is a relative contraindication to LP; if essential
a platelet transfusion should be given to cover the procedure.
PAEDIATRICS AND CHILD HEALTH 29:6
Other sites: routine swabbing of sites such as the umbilicus,
groin, ear, nose, throat, pharynx and rectum are informative
about colonization. Tracheal aspirates are of value if taken
immediately after placement of ETT; in several day old ET tubes,
the evaluation of sepsis is difficult and represents more of
colonization.
Radiology: chest radiograph (CXR) should be considered in a
baby with clinical signs of respiratory distress. An abdominal
radiograph (AXR) may be helpful in the differentiation between
septic ileus and NEC.
Haematological investigations:
Neutrophil count e contrary to older children and adults,
white cell count does not accurately predict neonatal sepsis.
Serial values may be more useful. Infection may result in neu-
tropenia or neutrophilia (<5  109/l or >20  109/l respec-
tively). Mortality rates are high in neonates who fail to mount a
neutrophil response to infection or whose neutrophil supply
becomes exhausted by severe infection. I/T ratio may be useful
in diagnosing and monitoring infection. The maximum normal
value is 0.16 during the first 24 h of age, 0.14 by 48 h, 0.13 by 60
h till 5 days of age and 0.12 until the end of the first month. I/T
ratio of more than 0.2 is a useful marker of infection. Another
feature suggesting infection is the presence of toxic granulation
in the neutrophils.
Platelet count e thrombocytopenia is a common feature of
generalized infection and NEC.
CRP e serial measurements of CRP are recommended to
facilitate decisions regarding LP, duration of antibiotic therapy
and in monitoring the progress of infection. Persistently elevated
CRP during antibiotic therapy suggests ongoing infection or
inflammation.
Polymerase chain reaction (PCR) e PCR has very high
sensitivity and specificity and can provide more rapid diagnosis
of bacteraemia and viraemia. Currently it is used for targeted
diagnosis for e.g. in suspected Herpes infection.
Physiological monitoring: recent studies show that monitoring
of physiological data is a promising non-invasive method to
predict sepsis before clinical/biochemical signs appear. The
greatest advancement is in the monitoring of Heart Rate Char-
acteristics index (HRCi or HeRO). It has been introduced into
neonatal practice following a large randomized controlled trial in
the US in VLBW infants.
In the healthy state there is beat-to-beat variability and
numerous small accelerations (sympathetic) and decelerations
(parasympathetic). Reduced variability and transient de-
celerations in heart rate, mediated by the autonomic nervous
system, can occur hours to days before clinical suspicion of
sepsis is evident. HRCi or HeRO monitoring records heart rate
intervals in data sets of 20e25 min duration. Results are pre-
sented as the “fold increased risk” a baby will deteriorate from
sepsis in the next 6e24 h (Figure 1). For example, a score of 1 is
low risk, more than 2 is a 2-fold higher chance and more than 3 is
3-fold and so on. The values are updated hourly and presented as
a graphical trend over 5 days.
HRC or HeRO monitoring cannot determine the exact time of
sepsis onset and other conditions including severe IVH, chronic
266 Crown Copyright Ó 2019 Published by Elsevier Ltd. All rights reserved.
 SYMPOSIUM: NEONATOLOGY
Figure 1 HeRO/HRC monitoring showing risk score (top) and heart rate trace at any given point (bottom) over time. The current risk score is clearly
displayed (orange).
lung disease, surgery, acute respiratory decompensation and
medications (steroids, muscle relaxants and anticholinergics) can
elevate HeRO. However in these cases a relative change in an
infant’s usual baseline can be used to detect sepsis.
Treatment of LONS
There is no consensus on the best antibiotic regimens for neo-
nates. Each antibiotic has its own benefits and side effects. In
general, narrow spectrum antibiotics should be used wherever
possible, and only used when significant infection is likely.
Supportive treatment should include central line removal if
high suspicion of line sepsis, escalation in respiratory support as
required and monitoring and stabilisation of blood glucose.
Enteral feeds may be withheld, if there are concerns about
abdominal sepsis. Intravenous fluids with fluid boluses or iono-
tropic support are used in shock and hypotension.
Antibiotic treatment: the majority of the leading causes of
LONS, other than CoNS, can be treated by antibiotic regimen
such as flucloxacillin and gentamicin. Vancomycin and teico-
planin are the antibiotics of choice for CoNS infections in pres-
ence of central lines, but their excessive use has been associated
with the development of vancomycin resistant enterococcal in-
fections and resistant gram-negative infections. Flucloxacillin is
the best antibiotic to treat Methicillin Sensitive S. aureus (MSSA).
Gentamicin will treat most gram-negative bacteria, some of
which e.g. Pseudomonas sp., give rise to significant mortality.
A cephalosporin given either alone or in combination with
amoxicillin may not adequately cover a number of Enterobac-
teriaceae. If there is inadequate clinical improvement or dete-
rioration, repeat cultures should be taken and antibiotic
therapy changed according to the local guidelines and in dis-
cussion with microbiologists. Vancomycin with gentamicin
provides good gram-negative and gram-positive cover but
potentially has additive renal toxicity. For b-lactamase
eproducing organisms (Serratia, Citrobacter, and Entero-
bacter), or other difficult to treat organisms, the use of a car-
bapenem (e.g. meropenem), which is inherently resistant to
beta-lactamases may be considered.
PAEDIATRICS AND CHILD HEALTH 29:6
Amphotericin (a polyene), fluconazole (a triazole) and mica-
fungin (an echinocandin only active against Aspergillus and
Candida spp) are used to treat neonatal invasive fungal infection.
Monitoring response to therapy: if the baby remains unwell,
there are persisting abnormal laboratory markers or ongoing pos-
itive blood cultures, further investigations should be undertaken.
Consideration should also be given to optimizing antibiotic doses,
changing antibiotic regimens or removing indwelling catheters.
Length of treatment: while antibiotic therapy should be
commenced promptly for suspected infection, they should be
stopped as soon as sepsis has been excluded. In general the
following apply:
 If suspected infection, the baby is asymptomatic, and nega-
tive cultures at 36e48 h e antibiotics should be stopped.
 Antibiotics started on high clinical suspicion of infection, yet
negative cultures and an elevated CRP e a longer course
(usually 5 days) may be warranted.
 If blood cultures positive and CSF cultures negative e treat
for a minimum of 10 days in gram positive and longer for
gram negative organisms.
 If S. aureus is isolated, treatment should be for at least 14
days, as it can seed other tissues.
 With positive CSF cultures, and/or a clinical diagnosis of
meningitis e treatment may be required for at least 21 days,
depending on the organism isolated.
 Osteomyelitis, endocarditis and deep abscesses which are
not surgically drained, may require several weeks of anti-
biotic therapy.
The length of treatment course may require extension in those
with slow clinical and microbiological resolution, and requires
specialist input.
Potential hazards of antibiotics: all antibiotics, particularly
broad-spectrum antibiotics, alter the natural microflora of the
patient, particularly in the gut. This may result in an increase in
antibiotic resistance among normal commensals or the emer-
gence of other pathogens.
267 Crown Copyright Ó 2019 Published by Elsevier Ltd. All rights reserved.
 SYMPOSIUM: NEONATOLOGY

Prevention of infection Cailes B, Kortsalioudaki C, Buttery J, et al. Epidemiology of UK

neonatal infections: the neonIN infection surveillance network. Arch
Infection control strategies include hand hygiene and washing
Dis Child Fetal Neonatal Ed 2018 Nov; 103: F547e53.
techniques, barrier precautions, minimal handling and the
Dong Y, Speer CP. Late-onset neonatal sepsis: recent developments.
implementation of care bundles for processes such as line
Arch Dis Child Fetal Neonatal Ed 2015; 100: F257e63.
insertion.
Fairchild KD, Schelonka RL, Kaufman DA, et al. Septicemia mortality
Antibiotic stewardship programs have been shown to reduce
reduction in neonates in a heart rate characteristics monitoring trial.
infection rates and inappropriate antibiotic use. Reports of
Pediatr Res 2013 Nov; 74: 570e5.
vancomycin-resistant enterococcus, beta lactamaseeproducing
Kuzniewicz MW, Puopolo KM, Fischer A, et al. A quantitative, risk-
organisms (E coli, Klebsiella, Enterobacter), and highly resistant
based approach to the management of neonatal early-onset
Acinetobacter, Burkholderia, and Serratia are increasing in the
sepsis. JAMA Pediatr 2017 Apr 1; 171: 365e71.
neonatal population. A reminder that antibiotics must always be
Mukhopadhyay S, Puopolo KM. Risk assessment in neonatal early
used judiciously.
onset sepsis. Semin Perinatol 2012 Dec; 36: 408e15.
The earlier enteral feeds are commenced the lower the risk of
Puopolo KM, Draper D, Wi S, et al. Estimating the probability of
nosocomial infections. Breast milk has been shown to protect
neonatal early-onset infection on the basis of maternal risk factors.
babies from late onset infection. Introducing 0.5 ml/kg of “tro-
Pediatrics 2011 Nov; 128: e1155e63.
phic” breast milk in the first hours of life, in VLBW, will facilitate
Santos RP, Tristram D. A practical guide to the diagnosis, treatment,
gut colonisation with normal bacteria (lactobacilli and bifido-
and prevention of neonatal infections. Pediatr Clin North Am 2015
bacteria). Breast milk also contains secretory antibodies, immune
Apr; 62: 491e508.
cells, lactoferrin and prebiotics which can stimulate beneficial
Shane AL, Sanchez PJ, Stoll BJ. Neonatal sepsis. Lancet, 2017 oct 14;
gut flora. Such bacteria are critical for the development of the
390.
immune system, of mucosal barrier function, gut motility and
digestive functions.

Long term risks of neonatal sepsis Practice points

Survivors of neonatal sepsis are more likely to have poor growth,
develop cerebral palsy, to have lower scores on neuro-
developmental scales and to have visual impairment. Multiple
episodes, invasive candidiasis and NEC are all associated with
increased risk of neurodevelopmental impairment. A C
FURTHER READING
Bedford Russell AR, Kumar R. Early onset neonatal sepsis: diagnostic
dilemmas and practical management. Arch Dis Child Fetal Neonatal
Ed 2015 Jul; 100: F350e4.
Bion J, Richardson A, Hibbert P, et al. ‘Matching Michigan’: a 2-year
stepped interventional programme to minimise central venous
catheter-blood stream infections in intensive care units in England.
BMJ Qual Saf 2013; 22: 110e23.
C Early onset neonatal sepsis occurs within the first 72 h of
life whereas late onset neonatal sepsis occurs after this
time; with different causative organisms and approach to
management.
Accurate identification of risk factors and clinical signs are
key to successful management.
C Algorithms using background risk, maternal risk factors in
combination with the infant’s clinical picture, have the po-
tential to decrease antibiotic usage.
C CRP and white cell counts have poor predictive value.
Procalcitonin and physiological monitoring tools have the
potential for early detection of neonatal sepsis.
C Survivors of neonatal sepsis are at risk of poor growth and
a poor neurodevelopmental outcome.

PAEDIATRICS AND CHILD HEALTH 29:6 268 Crown Copyright Ó 2019 Published by Elsevier Ltd. All rights reserved.