SYMPOSIUM: INFECTION (AND IMMUNITY)
Neonatal bacterial
meningitis: an update
Paul T Heath
Ifeanyichukwu O Okike
Abstract
Meningitis is associated with significant mortality and morbidity in infants
in the first 3 months of life. The most recent national surveillance study
(1996e7) identified an overall mortality of 10% with 50% of cases having
some form of disability at 5 year follow-up (24% serious); a risk of serious
disability 16-fold higher than that of GP-matched controls. The mortality
has declined over the last two decades but there has been no change in
the long term morbidity. Despite this there have been no attempts to
assess the quality of current diagnostic and management strategies. It
seems likely that improved recognition, evaluation and treatment of
bacterial meningitis in infants could lead to a reduction in mortality and
morbidity. Similar analyses undertaken in the areas of paediatric menin-
gococcal disease and adult meningitis have revealed deficiencies in
healthcare delivery and suggested that these may play a part in adverse
outcomes.
This review will focus on the epidemiology, clinical features, diagnosis
and management of neonatal meningitis including choice of antibiotics
and the role of adjunctive therapies. We will also briefly review the mech-
anisms responsible for the brain injury that occurs so frequently.
Keywords bacteria; epidemiology; meningitis; neonates
Definition
Neonatal bacterial meningitis is a major disease that results in
death and significant morbidity worldwide. It is characterized by
an infection of the central nervous system (CNS) and caused by
a limited range of bacteria. Neonatal defines the period up to 28
days of age. However, when considering sepsis and meningitis,
the period of interest is conventionally considered to be the first
90 days of age. This is largely driven by the epidemiology of
Group B Streptococcus (GBS).
Epidemiology
Of all age groups it is the neonatal period that has the highest
incidence of meningitis. Worldwide the incidence is described as
Paul T Heath MBBS FRACP FRACPCH is a Reader in Paediatric Infectious
Diseases and Honorary Consultant in the Division of Child Health,
St Georges, University of London, Cranmer Terrace, London SW17 0RE,
United Kingdom. Conflicts of interest: none.
Ifeanyichukwu O Okike MD is a Clinical Research Fellow in the Division
of Child Health and Vaccine, Institute St Georges, University of London,
2nd Floor, Ingleby House, Blackshaw Road, London SW17 0QT, United
Kingdom. Conflicts of interest: none.
PAEDIATRICS AND CHILD HEALTH 20:11
between 0.22 and 2.66 per 1000 live births. The highest incidence
figures are in developing countries. See Table 1 for incidence
across the world. In the UK the latest estimated incidence (from
the mid 1990s) is 0.22 per 1000 live births which amounts to
approximately 250 cases/year.
It is very likely that these numbers are underestimated due to
limitations in testing and access to healthcare facilities. Indeed
any surveillance that relies on a positive bacterial culture will
only ever describe the minimum incidence.
In the UK prior to 1980 Gram negative bacteria (especially
Escherichia coli) were the leading cause of neonatal meningitis.
GBS however, emerged as a cause of neonatal sepsis in many
developed countries in the 1970s and 1980s, became the leading
cause of meningitis and has remained in that position ever since.
A limited range of bacteria may be associated with meningitis,
varying according to geographic location.
With rare exceptions such as spina bifida and other congenital
CNS defects, meningitis follows a bacteraemia and it is estimated
that approximately 25% of infants with bacteraemia will also
have meningitis. There are a range of risk factors (shown in
Table 2) associated with the development of neonatal bacter-
aemia and sepsis and these are therefore risk factors for menin-
gitis as well.
Microbiology
The age at presentation with neonatal sepsis and meningitis can
suggest both the probable organisms and their likely mode of
acquisition. Presentation in the first week of life (early onset) and
particularly in the first 2 days of life, reflects vertical transmission
(from the mother), while late onset infection suggests nosoco-
mial or community acquisition.
GBS (especially, capsular serotype III) is the leading causative
agent, implicated in up to 50% of cases. E. coli strains (especially
those possessing the K1 polysaccharide capsular antigen) are the
leading Gram negative agents, Gram negative enteric bacteria as
a group accounting for 30e40% of neonatal bacterial meningitis.
Other Gram negative bacteria implicated include Klebsiella,
Enterobacter, Citrobacter and Serratia species. The remaining
causes include Streptococcus pneumoniae (6%), Listeria mono-
cytogenes (5%), Staphylococci aureus and coagulase-negative
Staphylococci.
Causative pathogens may vary with time, geographic distri-
bution, predisposing factors, and mode of infection (see Table 3).
In the UK approximately 50% of neonates with meningitis in the
first 2 months of life present to hospital from home and the
Showing the incidence of neonatal bacterial meningitis
across the world
Incidence (cases/1000 live births)
Developed countries 0.3
Asia
Hong Kong 0.48
Kuwait 2.4
Africa and South Asia 0.81e6.1
Costa Rica 0.25e2.66
Table 1
526 2010 Published by Elsevier Ltd.
 SYMPOSIUM: INFECTION (AND IMMUNITY)
List of risk factors for sepsis/meningitis in neonates
List of risk factors:
C Prematurity
C Low birth weight i.e. less than 1500 g
C Maternal colonization with GBS
C Prolonged rupture of membranes (>18 h)
C Premature rupture of membranes
C Low socioeconomic status
C Male gender
C Invasive monitoring/need for resuscitation
Table 2
remaining 50% are already inpatients when the diagnosis is
made. This will influence the likely pathogens; hospitalized
patients will have been exposed to a wider range of more
unusual and potentially antibiotic resistant pathogens than those
who acquire their infections in the community.
Pathogenesis
The risk of sepsis and meningitis is greater in neonates than any
other age groups. The neonates immune system responds
differently to antigens compared to adults. Neonates could be
described as host with deficiencies in each of the major arms of
the immune system:

Deficiencies in cellular immunity.

Deficiencies in phagocytic function.

Deficiencies in humoral immunity e mucosal IgA is absent
and the majority of immunoglobulins (IgG) only cross the
placenta after 32 weeks gestation therefore are deficient in
babies born very prematurely.

Deficiencies in innate immunity (e.g. mucosal barriers, low
complement levels).
Microorganisms acquired at the time of birth colonize the skin
and mucosa of the naso- and oropharynx, conjunctivae and
umbilical cord of the infant. Invasion and septicaemia can occur
from any site, but it is more likely following procedures that
bypass skin or mucosal barrier defence mechanisms (endotra-
cheal suctioning, umbilical catheterization, venepuncture or
foetal scalp sampling) or following disruption of mucosal integ-
rity e.g. by viral infections. Bacteria may then pass via the
Causative organisms as shown in percentages from different studies
USA (1971e73) Holland (1976e82)
GBS 31 24
E. coli 38 47
Other GNR 9 11
Strep pneumo 2 6
Listeria 5 4
*Pseudomo spp.
CONS
Enterobacter spp.
E W England and Wales, GNR Gram negative rod, CONS coagulase-negative Staphylococcus
Table3
PAEDIATRICS AND CHILD HEALTH 20:11
mucosal epithelium into the subepithelial blood vessels from
where they can be transported to other parts of the body
including the CNS. The bloodebrain barrier (BBB) is character-
ized by a microvascular epithelium with tight junctions and it
separates the vascular and CNS compartments.
Meningitis is sequelae of bacteraemia and in animal models
the likelihood of meningitis correlates with the magnitude of the
bacteraemia.
Once in the CNS, the bacteria are free to replicate unchecked,
at least initially, as the CSF is relatively free of immune cells. As
this activity goes on, the cell wall products of bacteria act as
stimuli for pro-inflammatory and anti-inflammatory cytokines.
Although this host response is needed to eliminate the bacteria
and help the host to recover it is also undoubtedly a major cause
of brain injury. There is a pathogenehost interaction as shown in
Table 4 and brain injury is likely to occur as a result of the events
listed in Table 5.
Diagnosis
Examination of the cerebrospinal fluid through lumbar puncture
(LP) is the only way to confirm bacterial meningitis as clinical signs
are mainly nonspecific and unreliable and blood cultures may be
negative in 15e55% of cases of meningitis. Thus basing the need
for an LP on the presence of a positive blood culture will miss
a significant number of cases of meningitis. However, it is some-
times not possible to perform a lumbar puncture before antibiotics
are administered (and indeed not advisable in the presence of
shock or significant respiratory distress). Even so a delayed LP is
still likely to show the presence of CSF pleocytosis and thus
confirm the diagnosis of meningitis. This may mean that the
culture is however negative; better diagnostic tools such as real
time PCR, have an important (future) role to play in such cases.
There is controversy as to whether an LP should be performed
in all babies suspected of sepsis. In principle, it should be
considered in all neonates in whom sepsis is a possibility and
certainly performed in those where the blood culture is positive.
An LP done simply for maternal risk factors for sepsis (in a baby
who is clinically well) is likely to have a low yield.
It is also well known that a normal CSF study does not exclude
meningitis. In a large series of 9111 neonates that had an LP, 95
babies had meningitis and 13% of these babies initially had
normal CSF (i.e. no cells, normal protein and glucose).
Dallas (1969e89) EDW (1985e87) EDW (1996e97) Taiwan (1994e2001)
52 39 48 29
16 26 18 31
5 12 8 *
6
7 7 5
11
14
6
527 2010 Published by Elsevier Ltd.
 SYMPOSIUM: INFECTION (AND IMMUNITY)

Pathogenetic sequence of bacterial neurotropism

Neurotropic stage Host defence Strategy of pathogen

Colonization or mucosal invasion Secretary IgA IgA protease secretion
Ciliary activity Ciliostasis
Mucosal epithelium Adhesive pili
Intravascular survival Complement Evasion of alternative pathway by polysaccharide capsule
Crossing of bloodebrain barrier Cerebral endothelium Adhesive pili
Survival within CSF Poor opsonic activity Bacterial replication

Table 4

Lumbar puncture and analysis of CSF aid clinicians in iden- There are no data on the timing of onset of clinical features.
tifying patients with meningitis. This however requires knowl- Classical clinical features often appear late and their appearance
edge of reference values for white blood cell (WBC) counts. may predict a worse outcome. This is area for which more data
These values are age dependent. A recent study by Kestenbaum are required.
et al in a large cohort of neonates without meningitis determined
age specific normal values as: 0e28 days old (median 3/ul, 95th Other investigations
centile 19/ul), 29e56 day old (median 2/ul, 95th centile 9/ul).
Cranial ultrasound scans should be performed in every case of
This supports a general perception of up to 20 cells/ul as being
neonatal bacterial meningitis to rule out complications such as
within normal limits in the neonate. However, as indicated above
brain abscesses, oedema, hydrocephalus and haemorrhage. As
only a negative CSF culture can reliably exclude bacterial
this is operator dependent, repeat scans should be considered if
meningitis. The role of LP in the management of neonatal
there is a high index of suspicion and to monitor progress.
bacterial meningitis is outlined in the Practice points.
Certain bacteria such as Citrobacter sp. for example, are partic-
ularly associated with cerebral abscesses.
History and physical examination
Early referral for audiological testing is important; the sooner
Nonspecific symptoms and signs are a feature of neonatal sepsis sensorineural deafness is diagnosed the sooner an intervention is
and meningitis: fever, hypothermia (or temperature instability), possible, and in the context of cochlear implants, for example,
poor feeding, abdominal distention, lethargy, irritability, seizures the better the outcome.
and coma.
Early-onset neonatal infection is described as a presentation Differential diagnosis
within the first few days of life (less than 7 days) and may have
As indicated the presentation is often nonspecific and a number
a fulminant course. It is often associated with maternal risk
of other conditions share similar clinical features. Alternative
factors for sepsis (e.g. prolonged rupture of membranes, pyrexia
diagnoses should be considered but an empiric antibiotic
and chorioamnionitis); meningitis is relatively less common as
regimen which is appropriate for meningitis should be started
compared with sepsis and pneumonia.
promptly awaiting definitive diagnosis.
Late onset presentations with infections are more often asso-
In addition to sepsis and other specific infections (urinary
ciated with meningitis. Neurological symptoms and signs include
tract infection, pneumonia, etc.), symptoms and signs may be
stupor and irritability (described in more than 75% of neonates
due to noninfectious conditions such as cardiac, pulmonary,
with meningitis); seizures, bulging anterior fontanel, extensor
gastrointestinal and metabolic disorders. Particular disorders that
posturing/opisthotonus, focal cerebral signs including gaze
may simulate the neurological features of meningitis include
deviation and hemiparesis, cranial nerve palsies are described in
haemorrhage, ischaemic stroke, hypoxic-ischaemic encephalop-
25e50%. Nuchal rigidity occurs in fewer than 25% of affected
athy, cerebral oedema and injuries due to non-accidental injury.
neonates (see Table 6).

Pathophysiology of brain injury in bacterial meningitis

Frequently seen signs/symptoms in neonatal bacterial
Pathophysiology of brain injury meningitis
Brain injury in meningitis is likely to occur as a result of the
following events: Sign/symptom % occurrence
C Alterations in cerebral blood flow including cerebral oedema, Fever/hypothermia/poor feeding, lethargy, >50
vasospasm and thrombosis vomiting, respiratory distress
C Soluble inflammatory mediators and infiltrating cells Convulsion 40
C Free radical scavengers Irritability 32
C Excitatory amino acids Full/bulging fontanel 28

Table 5 Table 6

PAEDIATRICS AND CHILD HEALTH 20:11 528 2010 Published by Elsevier Ltd.
 SYMPOSIUM: INFECTION (AND IMMUNITY)

Management
Early diagnosis and aggressive management are vital. In Recommended antibiotics dosages
a community setting any baby with suspected bacterial menin-
Antibiotic Dose Frequency
gitis should be transferred to a secondary care as an emergency.
(mg/kg/dose)
Although the introduction of new antibiotic regimens (particu-
Penicillin G 60 12 hourly 7 days old
larly with 3rd generation cephalosporins) as well as better
8 hourly 1e3 weeks old
neonatal intensive care have probably contributed to a significant
6 hourly >4 weeks old
decline in mortality over the last three decades the overall
morbidity remains unchanged. The experience with meningo- Ampicillin 100 As for penicillin
coccal disease in the UK, where improved outcome has coincided Amoxicillin 100 As for penicillin
with the introduction of more aggressive fluid management and Cefotaxime 50 12 hourly <7 days old
supportive care suggest that the same may be possible for 8 hourly 1e3 weeks
neonatal sepsis and meningitis. 6 hourly >3 weeks
Certainly early use of appropriate antibiotics (covering
Ceftazidime 50 As for cefotaxime
the likely pathogens and excellent CSF penetration) is
Gentamicin 5 36 hourly <32 weeks gestation
important, in Gram negative meningitis for example, it is
24 hourly >32 weeks gestation and over
known that time to sterilization of the CSF has an impact on
outcome.
Table 8
This implies using the correct antibiotics from the outset i.e.
appropriate empiric antibiotics. The range of possible pathogens The addition of an aminoglycoside to a penicillin for the
is known and a combination of cefotaxime and amoxicillin is treatment of GBS infection is based on in vitro studies and animal
therefore likely to provide excellent cover for community models. There is no difference in mortality between ceftriaxone
acquired neonatal meningitis. and penicillin but ceftriaxone has better CSF penetration and
For babies already in hospital or discharged recently from a higher rate of CSF clearance. Cochrane reviews of intrathecal or
hospital the antibiotic therapy should take into account the intraventricular antibiotics indicate no benefit for either of these
resistance pattern of pathogens circulating within the neonatal interventions.
unit. All neonatal units should undertake local surveillance and
the advice of the local microbiologist will be valuable in choosing Adjunctive therapies
appropriate empiric regimens. A combination of cefotaxime and
amoxicillin together with an aminoglycoside is one recommen- Corticosteroids have been shown to decrease neurological
dation which accounts for the possibility of cephalosporin morbidity especially hearing loss in children with Hib and
resistant Gram negative bacteria. Vancomycin may also be pneumococcal meningitis. All of the paediatric meningitis and
considered although true coagulase-negative staphylococcal steroid studies excluded babies in the first 1 month of life
meningitis is rare. however, so there are few data for this age group. One study from
There is little evidence basis to guide the duration of anti- Jordan addressed this question in neonates in a randomized
biotics for neonatal meningitis. By convention at least 2 weeks clinical trial and found no difference in mortality and morbidity.
are recommended for GBS and at least 3 weeks for Gram negative This study may not be applicable to other settings however, as
meningitis. These figures should be considered as minimum. there were very few babies with GBS meningitis.
Details of recommended antibiotics, dosages and duration are Several agents that modify mediators of the inflammatory
shown in Tables 7 and 8. cascade (e.g. reactive oxygen species, nitric oxide, and excitatory
amino acids) have been shown in animal models to reduce
neurological damage. These may be candidates for future clinical
trials in humans.

Summary of antibiotics and duration of therapy

Bacteria Antibiotics or combination

Duration List of long term complications seen in neonatal
Group B Streptococcus Penicillin or cephalosporin
14 days bacterial meningitis
or more
Gram negative enteric Cefotaxime  aminoglycoside 21 days C Mental retardation
bacteria or more C Seizures, focal or generalized
Pseudomonas Ceftazidime  aminoglycoside 21 days C Cerebral palsy
or more C Hydrocephalus
Streptococcus Cefotaxime 14 days C Sensorineural hearing loss
pneumonia or more C Behavioural problems
Listeria monocytogenes Ampicillin aminoglycoside 21 days C Speech and language disorders
or more C Impaired vision

Table 7 Table 9

PAEDIATRICS AND CHILD HEALTH 20:11 529 2010 Published by Elsevier Ltd.
 SYMPOSIUM: INFECTION (AND IMMUNITY)
Summary of current recommendations regarding adjunctive
therapy:

Do not use corticosteroid in children younger than 3 months
with suspected bacterial meningitis.

Do not use activated protein C or recombinant bacterial
permeability-increasing protein.
Prognosis
Prognosis is affected by a range of factors including gestational
age at infection (the more premature the baby the worse the
prognosis), the pathogen (certain Gram negative infections such
as citrobacter are associated with a worse prognosis), the clin-
ical features at presentation and the presence of and ability to
control seizures. A list of long term complications is shown in
Table 9.
A retrospective study of 101 cases of neonatal (greater than 34
weeks gestation) bacterial meningitis identified early predictors
of adverse outcome at 1 year of age (death or moderate/severe
disability). Twelve hours after admission the important predic-
tors of adverse outcome were presence of seizures, presence of
coma, use of inotropes, and leucopenia less than 5000  10\9
(sensitivity 68%, specificity 99%). Ninety-six hours after
admission, predictors of adverse outcome were seizure duration
of greater than 72 h, coma, use of inotropes, and leucopenia
(sensitivity 88%, specificity 99%).
Follow-up
Frequent follow-up immediately after the illness can help reas-
sure parents but also identify potential problems. The intervals
can be spaced out as the baby grows and remains well. A close
monitoring of development and performance should be main-
tained. Substantial follow-up until at least school age is necessary
for full evaluation of the long term sequelae.
Prevention
Ultimately, the best means for improving the outcome of
neonatal meningitis is to prevent it altogether. Possible strategies
include intrapartum antibiotic prophylaxis for the prevention of
early-onset GBS disease, vaccination against GBS, and the
prevention of nosocomial or community spread of pathogens
through better infection control measures (and optimizing
coverage with established vaccines e.g. pneumococcal conju-
gates). Although the use of intrapartum antibiotics will reduce
the burden of early-onset GBS infections, the majority of GBS
meningitis occurs after the first week of life. Therefore only
routine use of an effective GBS vaccine is likely to have any
impact on the incidence of GBS meningitis. Although suitable
vaccine candidates exist, there remain issues regarding optimal
vaccination strategies (e.g. pregnancy vaccination vs. adolescent
vaccination) as well as how to demonstrate efficacy.
PAEDIATRICS AND CHILD HEALTH 20:11
The major focus for improving the outcome for the near future
lies in identifying strategies for earlier diagnosis, earlier treat-
ment and better management of cases of neonatal meningitis.A
FURTHER READING
Draft NICE guideline for management of bacterial meningitis in children
younger than 16 years of age.
Garges HP, Moody MA, Cotton CM, et al. Neonatal meningitis: what is the
correlation among cerebrospinal fluid cultures, blood cultures and
cerebrospinal fluid parameters? Pediatrics 2006; 117: 1094e100.
Harvey D, Holt DE, Bedford H. Bacterial meningitis in the newborn:
a prospective study of mortality and morbidity. Semin Perinatol June
1999; 23: 218e25.
Heath PT, Nik Yusoff NK, Baker CJ. Neonatal meningitis. Arch Dis Child
Fetal Neonatal Ed May 2003; 88: F173e8.
Holt DE, Halket S, de Louvois J, et al. Neonatal meningitis in England and
Wales: 10 years on. Arch Dis Child Fetal Neonatal Ed 2001; 84: F85e9.
Isaacs D. The management of neonatal meningitis. Curr Pediatr 2000; 10:
96e103.
Kestenbaum L, Ebberson J, Zorc JJ, et al. Defining cerebrospinal fluid white
blood cell count reference values in neonates and young infants.
Pediatrics 2010; 125: 257e64.
Klinger G, Chin CN, Beyene J, et al. Predicting the outcome of neonatal
bacterial meningitis. Pediatrics 2000; 106: 477e82.
Polin RA, Harris MC. Neonatal bacterial meningitis. Semin Neonatal 2001;
6: 157e72.
Ray B, Mangalore J, Harikumar C, et al. Is lumbar puncture necessary for
evaluation of early neonatal sepsis? Arch Dis Child 2006; 91: 1033e5
(E-medicine).
Practice points
Role of LP when evaluating neonates with sepsis:
C In strongly suspected cases LP should be included in the
examination of sepsis.
C LP can safely be omitted in asymptomatic babies with only
perinatal risk factors who are being evaluated for early sepsis.
Role of repeat lumbar puncture in neonatal bacterial meningitis
during or after treatment:
C Do not perform a repeat LP in neonates who are receiving
antibiotic treatment that the causative organism is susceptible
to and are making good clinical recovery.
C Do not perform a repeat LP before stopping antibiotic treat-
ment in neonates who are clinically well.
C Perform a repeat lumbar puncture in neonates who have
persistent or re-emergent pyrexia, clinical deterioration, new
clinical findings (especially neurological findings), or persis-
tently abnormal inflammatory markers.
530 2010 Published by Elsevier Ltd.