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ESPID Reports and Reviews

CONTENTS
Prevention and Treatment of Bacterial Meningitis

EDITORIAL BOARD

Co-Editors: Delane Shingadiaand Irja Lutsar


David Burgner (Melbourne, Australia)
Luisa Galli (Rome, Italy)
Christiana Nascimento-Carvalho
(Bahia, Brazil)
Ville Peltola (Turku, Finland)

Board Members

Nicole Ritz (Basel, Switzerland)


Ira Shah (Mumbai, India)
Matthew Snape (Oxford, UK)
George Syrogiannopoulos
(Larissa, Greece)

Tobias Tenenbaum (Mannhein, Germany)


Marc Terbruegge (Southampton, UK)
Marceline van Furth (Amsterdam,
The Netherlands)
Anne Vergison (Brussels, Belgium)

Prevention and Treatment of Bacterial Meningitis in Resource


Poor Settings
Elizabeth Molyneux, FRCPCH and Jenala Njirammadzi, MBBS

he etiology and incidence of bacterial


meningitis (BM) in resource poor settings is changing. Antibiotic resistance patterns have altered and empirical antibiotic
treatment options need review. Recent studies have assessed adjuvant therapies and supportive care.

THE EFFECT OF VACCINES ON THE


INCIDENCE AND ETIOLOGY OF
BACTERIAL MENINGITIS
In the past decade, there have been
remarkable reductions in child mortality
driven largely by public health efforts. In HIV
endemic countries, the role out of prophylactic
cotrimoxazole and the increased availability
of antiretroviral therapy has coincided with a
reduction in the incidence of Streptococcus
pneumoniae infections. The role out of these
programs and increasing access to conjugate
vaccines for Haemophilus influenzae b (Hib),
pneumococci and Group A meningoccoci
(MenAfriVac) are changing the epidemiology
and incidence of meningitis. Hib vaccine is
Accepted for publication January 23, 2015.
From the Department of Paediatrics, College of Medicine, Queen Elizabeth Central Hospital, Blantyre,
Malawi.
The authors have no conflicts of interest to disclose.
Address for correspondence: Elizabeth M. Molyneux,
FRCPCH, Department of Paediatrics, College of
Medicine, Queen Elizabeth Central Hospital, Blantyre, Malawi. E-mail: emmolyneux@gmail.com.
Copyright 2015 by Wolters Kluwer Health, Inc. All
rights reserved.
ISSN: 0891-3668/15/3404-0441
DOI: 10.1097/INF.0000000000000665

part of the extended program for immunization


in 72 countries leading to a rapid reduction of
invasive Hib infections.1
Meningococcal meningitis is the most
common bacterial meningitis worldwide and
Group A was the most common epidemiccausing meningococcus. In 2010, a conjugated vaccine, MenAfriVac became available
that is highly efficacious even in young children and also increases herd immunity. By
2016, 26 African meningitis belt countries
will have immunized their most vulnerable
age groups. But there is more to be done:
serogroup A disease has decreased but serogroups W135 and X have caused recent outbreaks.2,3 In the United States, the Advisory
Committee on Immunisation Practices states
that immunogenicity of meningococcal conjugate vaccines decreases with time, and recommends a booster dose after 5 years.4
The 13-valent pneumococcal vaccine, licensed in 2010, has been added
to the extended program for immunization schedule in many countries, with
the expectation of being introduced in
50 countries by 2015. This will reduce
pneumococcal invasive disease by about
4070%depending on prevalent serotypes and incidence of HIV infection.5 In
holoendemic malarial areas, BM caused by
nontyphoidal salmonellae species waxed
and then waned over the past decade. In
some areas, this followed the mass introduction of bed nets, indoor spraying and
the change from a failing first line antimalarial treatment regimen to effective artemesinin-based combination therapy.5

DIAGNOSIS
Examination of cerebrospinal fluid
(CSF) is the gold standard diagnostic test in
BM. In many resource poor settings, despite
lack of laboratory support, clinicians should
have a low threshold for doing a lumbar puncture. The appearance and Gram stain of CSF
assist diagnosis. If there is no laboratory, a
multistix urine dipstick test will identify low
glucose, high protein and white cells (a positive leucocyte esterase patch) in CSF.

GENERAL MANAGEMENT
Children with BM are often managed
with limited resources against a background of
other diseases or ill health that compromise the
outcome even when optimal care is provided.

EMPIRICAL FIRST LINE


TREATMENT AND ANTIBIOTIC
RESISTANCE
The World Health Organization
(WHO) recommends ceftriaxone or cefotaxime as first line, empirical, antibiotic therapy
for children with suspected BM. Cefotaxime
is more expensive and requires 8 hourly injections (ceftriaxone is 12 hourly or once daily).
If cephalosporins are not available, WHO recommends penicillin or ampicillin and chloramphenicol in older children, and pencillin
or ampicillin and gentamicin in infants.6
S. pneumoniae susceptibility to penicillin varies worldwide; in Malawi, resistance has been stable at 1618%.5 Falade et al7
reported no penicillin-resistant S. pneumoniae

The ESPID Reports and Reviews of Pediatric Infectious Diseases series topics, authors and contents are chosen and approved
independently by the Editorial Board of ESPID.
The Pediatric Infectious Disease Journal Volume 34, Number 4, April 2015

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The Pediatric Infectious Disease Journal Volume 34, Number 4, April 2015

Molyneux and Njirammadzi

TABLE 1. Empirical Antibiotic Treatment for Bacterial Meningitis in Resource Poor Settings
Age
<7 days

>7 days,
<2 months

Main Causes

Ceftriaxone 50mg/kg/bd

Streptococcus pyogenes

Cefotaxime 50mg/kg tds or


Ampicillin 50mg/kg bd
IV/IM for 1421 days
21 Days for Gram negative
Ampicillin 50mg/kg bd
IV/IM 1421 days
Ceftriaxone 100mg/kg /day

Enterobacteriae
Listeria
monocytogenes*
S. agalactiae
S. pyogenes
Enterobacteriae
Nontyphoidal
salmonellae spp
Staphylococcus aureus
L. monocytogenes

223 months

25 years

First Line Treatment

Streptococcus agalactiae

Streptococcus
pneumoniae
Haemophilus influenzae
Neisseria meningitidis
Nontyphoidal
salmonellae spp
Enterobacteriae
S. pneumoniae
H. influenzae

>514 years

N. meningitidis
S. pneumoniae

>14 years

N. meningitidis
S. pneumoniae
N. meningitidis

Alternative Treatment
Benzylpenicillin
50,000 iu/kg bd
+ Gentamicin 7.5mg/kg od
(smaller doses for prems)
IV/IM 1421 days
21 Days for Gram negative
Benzylpenicillin
50100,000 iu/kg qds
+ Gentamicin 7.5mg/kg od

Cefotaxime 50mg/kg qds or


Ampicillin 50mg/kg qds
IV/IM 1421 days

IV/IM 1421 days


21 days if Gram negative

Add cloxacillin 50mg/kg tds


(bd if <7 days old)
Ampicillin 50mg/kg tds
IV/IM 1421 days
Ceftriaxone 100mg/kg/day or

Benzylpenicillin
100.000 iu/kg qds
+ Chloramphenicol 25 mg/kg qds
IV/IM 1014 days
IV/IM 710 days

Cefotaxime 50mg/kg qds


IV/IM 1014 days
IV/IM 710 days
IV/IM 21 days
IV/IM 21 days
Ceftriaxone 100mg/kg/day or
Cefotaxime 50mg/kg qds
IV/IM 1014 days
IV/IM 710 days
Ceftriaxone 100mg/kg/day or
Cefotaxime 50mg/kg qds
IV/IM 1014 days
IV/IM 710 days
Ceftriaxone 2g/day or
Cefotaxime 50mg/kg qds
IV/IM 1014 days
IV/IM 710 days

Benzylpenicillin 100.000 iu/kg qds


+ Chloramphenicol 25 mg/kg qds
IV/IM 1014 days
IV/IM 710 days
Benzylpenicillin 100.000 iu/kg qds
+ Chloramphenicol 25mg/kg qds
IV/IM 1014 days
IV/IM 710 days
Benzylpenicillin 100,000 iu/kg qds or
+ chloramphenicol 25mg/kg qds
IV/IM 1014 days
IV/IM 710 days

Based on the WHO Pocket Book of Hospital Care for Children.6 Known local susceptibilities must guide first choice of antimicrobial therapy. If the bacterial agent is unidentified use
the longer course of antibiotics. If complications such as a cerebral abscess are suspected or the child is HIV positive a longer course of antibiotics may be needed. A repeat lumbar puncture
may be done after 23 days to assess bacterial erasure and should be repeated if there is clinical deterioration.
*Listeria monocytogenes is uncommon where unpasteurized dairy products and processed meats are unavailable to pregnant women.
Enterobacteriae may be best treated with daily ceftriaxone doses divided and given 12 hourly.
Salmonella meningitis requires prolonged treatment of 46 weeks of antibiotics usually ceftriaxone and ciprofloxacin. A repeat lumbar puncture at the end of treatment is necessary if
there is any doubt about complete infection eradication.
Tds indicates 8 hourly; qds, 6 hourly; bd, twice daily; od, once daily.

isolates in 2009 in Nigeria, and a Ugandan


report showed no full resistance, but 83%
intermediate penicillin resistance.8 Hib is
resistant to chloramphenicol and to ampicillin
in most countries. Nontyphoidal salmonellae
species have become resistant to chloramphenicol, cotrimoxazole and ampicillin, leaving the options of ciprofloxacin and/or ceftriaxone. Table1 shows the common causes of
bacterial meningitis in different age groups
and recommended treatment schedules.
In the non-neonatal group, S. pneumoniae is the most common etiological agent,
and if penicillin susceptibility is unknown
a third generation cephalosporin should be
given. Empirical treatment can start with a
cephalosporin and change to an appropriate narrow-spectrum antibiotic if and when
the cause is identified. In Malawi, more
neonatal cases were effectively treated by

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ceftriaxone than by penicillin + gentamicin


(99.1% vs. 91.8%; P = 0.006), especially for
Gram-negative isolates (95.1% vs. 86.0%;
P = 0.012).9 Amikacin or parentral ciprofloxacin are effective for many Gram-negative
bacterial infections (including ESBL), and
can be added for Gram-negative bacteria
when a third generation cephalosporin fails.

DURATION OF ANTIBIOTIC
THERAPY
A large multicountry study (n = 1004)
in resource poor settings compared the outcome of 5 versus 10 days of ceftriaxone for
BM caused by one of the 3 most common
etiological agents, S. pneumoniae, Neisseria meningitidis and Hib.10 Randomization
was on day 5 and only in stable patients with
no complications. Children receiving 5 days

of antibiotic therapy had a similar outcome


to those who received 10 days of treatment
(60.4% vs. 60.8% survival without sequelae,
26% vs. 27.2% with sequelae).

ADJUVANT TREATMENT
Dexamethasone
Corticosteroids as adjuvant treatment
in BM remain controversial. In a large study,
in African children dexamethasone conferred
no benefit.11 A Cochrane review of adjuvant
steroid therapy found no benefit to outcome
in poorly resourced centers.12

Glycerol
Glycerol has been used to reduce
intracranial pressure. A multicountry South
American study reported encouraging
results; when severe neurological sequelae

2015 Wolters Kluwer Health, Inc. All rights reserved.

The Pediatric Infectious Disease Journal Volume 34, Number 4, April 2015

and death were combined, glycerol was beneficial compared with placebo (OR: 0.44; 95%
CI: 0.250.76; P = 0.003).13 In a Malawian
study in which paracetamol and glycerol
were the active adjuvant therapies, there was
no benefit or harm by adding glycerol or paracetamol to standard antibiotic therapy.14

SUPPORTIVE CARE
Supportive care is critical and the
importance of good nursing care and monitoring cannot be over-emphasized. Fluids should
be monitored, seizures controlled, adequate
calorie intake ensured and serum glucose and
electrolytes kept within normal limits.
A Cochrane review found no evidence
for fluid restriction and some evidence to
support maintenance intravenous fluids in the
first 48 hours in settings with high mortality
rates and late presentations.15 Where children
present early and mortality is lower, evidence
is insufficient to guide practice.
Seizures must be controlled promptly.
WHO recommends rectal diazepam and/or
paraldehyde followed by phenobarbitone if
convulsions continue. Intractable seizures are
difficult to manage without mechanical ventilator support and loading doses of anticonvulsant drugs such as phenobarbitone have
to be repeated despite the risk of respiratory
failure. Neonatal seizures are usually managed with phenobarbitone.

ANAEMIA AND MALNUTRITION


Anemia and malnutrition are common
comorbidities. Roine et al16 found that correcting anemia (less than 8g/dL) with a blood
transfusion reduced mortality in BM to 23%
from 39% without transfusion (P = 0.003).
Also, the odds for death increased by 1.98
in mild, 2.55 in moderate and 5.85 in severe
malnutrition.

PROGNOSIS
Case fatality rate is as high as 37%
depending on the cause, age and other cofactors.13 The prognosis is worse in infants, in
children with low CSF white cell counts or
low glucose, low blood pressure, anemia,
persistent convulsions and those who arrive

Prevention and Treatment of Bacterial Meningitis

late or in coma. To these are added malnutrition and immunosuppression.

COMPLICATIONS
Acute complications other than those
mentioned already include subdural empyema
or intracranial abscess. If fever does not settle
an ultrasound scan of the head should be done
in children with an open fontanelle. Large subdural collections and intracranial abscesses can
be drained trans-fontanelle by experienced personnel. Antibiotic therapy should be prolonged.
Fever may also be caused by infected injection
or cannula sites, joints or chest infections.
Long-term neurological sequelae are
frequent and often devastating. Some hearing
loss occurs in up to 30% of survivors, especially following pneumococcal or Salmonella
spp. meningitis. Hydrocephalus may present
after weeks or months. Therefore, all survivors should have their hearing tested and
head size monitored after discharge. Followup should include physical, neurological and
developmental assessments.

FUTURE RESEARCH

Monitoring of incidence and antibiotic


sensitivity must continue to be able to
inform empirical treatment.
Rapid diagnostic tests to identify the
causative agent would reduce the overuse
of broad-spectrum antibiotics.
Research is needed into adjuvant therapy
and seizure control.
Improved neonatal care to reduce infection rates.
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2015 Wolters Kluwer Health, Inc. All rights reserved.


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