E

SECTION

INFECTIONS CAUSING
NEUROLOGIC MANISFESTATIONS

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 54 Acute Bacterial Meningitis
Rathi Guhadasan, Enitan D Carrol
Key features
l Bacterial meningitis is a medical emergency. Prompt
administration of parenteral antibiotics saves lives
l Symptoms of bacterial meningitis may be nonspecific,
especially in infants and young children
l Bacterial meningitis may be caused by hematogenous
seeding or spread from contiguous sites (otitis, sinusitis)
l The gold standard for the diagnosis of bacterial meningitis
is lumbar puncture with Gram stain and culture
l Common causative agents include Streptococcus
pneumoniae, Haemophilus influenzae and Neisseria
meningitidis. Causative agents in neonates includes Group B
streptococci and Gram-negative organisms. Listeria
monocytogenes can cause meningoencephalitis, usually in
immunocompromised, elderly and pregnant individuals
l In patients with HIV infection, acute bacterial meningitis
may present with similar clinical features to that of
cryptococcal meningitis and tuberculous meningitis, i.e. a
more indolent presentation
l Adjunctive dexamethasone appears to be of no benefit in
low-income countries
l Treatment of bacterial meningitis should target the (likely)
causative agent(s), but in resource-limited settings usually
involves the use of a third-generation cephalosporin such
as ceftriaxone or the use of oral chloramphenicol. In
non-resource-limited settings, ampicillin should also be
administered to individuals at risk of listeriosis, and
vancomycin should be added in areas with ceftriaxone-
resistant pneumococci. Neonates in non-resource-limited
settings are usually treated with ampicillin and gentamycin,
ceftriaxone or cefotaxime
l Many of the causative agents of bacterial meningitis are
preventable by currently available vaccines but use of these
vaccines is not universal in resource-limited settings
INTRODUCTION
Acute bacterial meningitis is defined as inflammation of the meninges
secondary to bacterial infection. Infection of the meninges arises sec-
ondary to colonization of the nasopharynx followed by mucosal
invasion, bacteremic spread and finally crossing the blood-brain
barrier into the subarachnoid space. The highest burden of disease
from bacterial meningitis exists in tropical and resource-limited
areas, where the infrequent use of vaccines targeting the common
502
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causative agents of acute bacterial meningitis, coupled with the HIV/
AIDS pandemic, has amplified the problem. Bacterial meningitis is
usually fatal without treatment. Therefore, prompt and accurate diag-
nosis, coupled with the timely administration of parenteral antibiot-
ics, is necessary in order to save lives [1]. The presenting clinical
features of bacterial meningitis may be similar to those of other
central nervous system (CNS) infections, such as tuberculous menin-
gitis, cryptococcal meningitis and viral meningitis. Historically, most
reports of bacterial meningitis in sub-Saharan Africa describe epidem-
ics of meningococcal meningitis caused by serogroup A, occurring
approximately every decade. More recently, other serogroups, such as
W-135, have been reported in Africa, although serogroup A continues
to predominate [2].
EPIDEMIOLOGY
The annual incidence of acute bacterial meningitis is 46 per 100,000
in high-income countries and 10-fold higher in developing countries.
There is a high case fatality rate in developing countries (1050%)
that is augmented by pre-existing comorbidities (e.g. malnutrition,
HIV infection and sickle cell disease), late presentation to health
services, emerging antibiotic resistance and lack of appropriate anti-
biotics, medical expertise and the use of conjugate vaccines against
the main three pathogens: Streptococcus pneumoniae, Haemophilus influ-
enzae, and Neisseria meningitidis.
Neisseria meningitidis-associated meningitis occurs across the globe,
but N. meningitidis can also cause large outbreaks, especially in
crowded conditions, and in the meningitis belt of Africa (Fig. 54.1),
where epidemics occur every 515 years in the Harmattan season (dry
and dusty with a strong wind between November and March) and
are associated with up to 10% mortality [3].
The peak incidence for S. pneumoniae and H. influenzae (Hib) men-
ingitis occurs in children. Hib meningitis is rare over the age of five
years, but pneumococcal and meningococcal meningitis can occur in
all age groups [3]. The predominant organism causing bacterial men-
ingitis in children in the tropics is S. pneumoniae (Fig. 54.2A). The
organisms that cause acute bacterial meningitis in adults in Africa are
shown in Figure 54.2 (B). In Southeast Asia, Streptococcus suis is a cause
of acute bacterial meningitis in adults.
NATURAL HISTORY, PATHOGENESIS,
AND PATHOLOGY
The most common bacteria causing acute bacterial meningitis (S.
pneumoniae, N. meningitidis, and H. influenzae) have neurotropic
potential, which allows them to invade the host mucosal epithelium,
multiply in the bloodstream and cross the blood brain barrier into
the cerebrospinal fluid (CSF). The bacteria colonize the nasopharyn-
geal epithelium by adhering to the epithelial lining of the respiratory
tractthe mechanisms of which vary depending on the organism.
Neisseria meningitidis and other Gram-negative bacteria adhere via pili;
S. pneumoniae binds by pneumococcal surface-associated proteins,
such as pneumococcal surface adhesion A (PsaA) or choline-binding
 Ac u te B a c te r i a l M eningitis 503

Senegal

Mauritania Eritrea
Mali
Niger
Gambia Chad
Sudan

Guinea-Bissau

Ethiopia
Guinea

Burkina Faso
Cote d'Ivoire Northern Kenya
Democratic
Ghana Nigeria
Republic
Southern of Congo
Togo Nigeria
Benin Cameroon Uganda
Meningitis belt
Central African
Republic

FIGURE 54.1 Map of African meningitis belt.

13%

5%

40% Pneumococcus
Hib
11% Meningococcus
Salmonella spp.
Negative cultures

28%

22%

S. pneumoniae
N. meningitidis
Other Gram negatives
2% S. aureus
2%
FIGURE 54.2 The proportion of acute bacterial meningitis Alph-Haemolytic strep.
attributed to each pathogen in children and adults in Malawi 4% Cryptococcus
Reproduced with permission from Lin AL, Safdieh JE. The evaluation 1% TB
1% 59%
and management of bacterial meningitis: Current practice and Not meningitis
emerging developments. Neurologist 2010;16:14351. (A) Cause of 5%
Probable bacterial meningitis
childhood bacterial meningitis 2002. (B) Causes of meningitis 4%
in adults in Malawi, 2007.

protein A (CbpA) [4]. Young children mount inadequate immune
responses to bacterial capsular polysaccharides, rendering them par-
ticularly vulnerable to these infections [5]. Bacteria invade the mucosal
epithelium via a number of processes that include transcytosis,
through phagocytes in a Trojan horse manner, or directly following
damage to the integrity of the mucosa, such as occurs with a viral
infection. Survival within the bloodstream depends on the bacteria
avoiding host defence mechanisms, particularly complement-
dependent killing. Neisseria meningitidis and S. pneumoniae both
recruit complement factor H, the main regulator of the alternative
complement pathway that controls early activation of the comple-
ment cascade. Neisseria meningitidis produces Factor H binding protein
and the S. pneumoniae proteins CbpA and pneumococcal surface
protein C (PspC) bind complement factor H.

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504 HUNTERS TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
1 2
Mucosa
3
Bloodstream
4 5
Blood
brain
barrier
7 6
CSF
Autolysis
IL-1b
TNF-
8 9
IL-6
Bacterial
products
FIGURE 54.3 Pathogenesis of bacterial meningitis. 1. Adherence and
colonization of mucosa; 2. Invasion of blood stream; 3. Multiplication in
bloodstream; 4. Increased permeability of blood brain barrier and bacteria
cross blood-brain barrier; 5. Infiltration of CSF by white cells; 6. Release of
pro- inflammatory cytokines; 7. Uncontrolled replication of bacteria in
sanctuary site, CSF; 8. Bacterial products stimulate inflammatory cascade;
9. Activated leukocytes lead to production of matrix metalloproteinase
(MMP) and oxidants.
Bacterial translocation of the blood brain barrier is a result of specific
bacteria-host interactions involving cell signal transduction pathways
with effects on actin cytoskeleton rearrangements [6]. Bacteria cross
the blood brain barrier by a number of processes that include: (i)
disruption of the tight junctions; (ii) transcellular migration by tran-
scytosis; and, (iii) surviving within phagocytes using a Trojan horse
mechanism.
Once within the CSF, bacteria enter a sanctuary site with relatively low
concentrations of complement and antibody. Bacteria and bacterial
products (resulting from autolysis) stimulate an inflammatory
response of pro-and anti-inflammatory cytokines. In turn, the pro-
inflammatory cells stimulate the release of chemokines. Neuronal cell
death occurs mainly in the hippocampus, through apoptosis, and in
the cortex, through necrosis. White matter injury also occurs, second-
ary to small-vessel vasculitis, focal ischemia or venous thrombosis.
The process is summarized in Figure 54.3.
CLINICAL FEATURES
In infants and young children, clinical features are very non-specific
and include fever, lethargy, irritability, poor feeding, seizures, respira-
tory distress, vomiting and diarrhea, and a bulging fontanelle [7, 8],
while older children and adults have headache (8095%), photopho-
bia (3050%), neck stiffness (5090%), lethargy, confusion, and
positive Kernigs sign (resistance to knee extension upon passive hip
flexion; 5%) and Brudzinskis sign (hip flexion upon passive neck
flexion; 5%) [1, 8]. Adults with acute bacterial meningitis usually
present with features of fever, neck stiffness and altered mental status.
However, it has recently been proposed that this triad should now
become a quartet to include fever, neck stiffness, headache and altered
mental status, which are present in 95% of adults with acute bacterial
meningitis [9]. More advanced disease may include opisthotonus,
focal neurologic deficit (2030%), seizures (1530%) and a reduced
level of consciousness (Fig. 54.4).
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FIGURE 54.4 Opisthotonus in a Malawian child with bacterial meningitis.
MMP
NO
A rash may be present in 1015% of cases of acute bacterial
meningitismost commonly this is the purpuric rash of meningo-
coccal meningitis with septicemia, but a purpuric rash may also be
caused by other pathogens. Shock and disseminated intravascular
coagulation occur in meningococcemia. Cushings triad of systemic
hypertension, bradycardia and respiratory depression occurs late and
indicates raised intracranial pressure and shift of brain compartments
[8]. HIV-positive children with acute bacterial meningitis are more
likely to present in extremis and have pneumococcal meningitis, sei-
zures or a focus of infection, such as otitis media. They take longer to
defervesce and are more likely to die or experience recurrence.
Patients should be monitored closely for dehydration, shock, seizures,
altered conscious level or rising intracranial pressure. Cerebrovascular
events, such as infarction and/or edema, obstructive or communicat-
ing hydrocephalus, epidural abscess and subdural empyema are
uncommon complications. Immune complex-mediated arthritis
occurs late in Hib or meningococcal illness. Neurologic sequelae, such
as deafness, cognitive impairment and developmental delay, occur in
540% of survivors [8].
PATIENT EVALUATION, DIAGNOSIS,
AND DIFFERENTIAL DIAGNOSIS
PATIENT EVALUATION
Initial evaluation should include a thorough history to elicit informa-
tion on duration of illness, history of seizures, anti-retroviral or anti-
tuberculous treatment, HIV status and previous antibiotics or
anti-malarials. Examination should include assessment of nutritional
status, presence of a rash, examination of the fontanelle and eliciting
neck stiffness. In the tropics, features of acute bacterial meningitis
often overlap with those of severe malaria or cerebral malaria, leading
to difficulties in the early recognition of acute bacterial meningitis in
children. Several predictor algorithms to assist in establishing the
diagnosis of acute bacterial meningitis have been derived, most of
which include laboratory data. Only two of these have been evaluated
in resource-poor settings. In children, Berkley etal. reported that the
presence of one or more of the following is an indication for lumbar
puncture [10]: bulging fontanelle, neck stiffness, cyanosis, impaired
consciousness, partial seizures and seizures outside the febrile convul-
sions age range. Thwaites etal. described a weighted diagnostic score
to distinguish acute bacterial meningitis from tuberculous meningitis
in adults, which included age, white blood cell count, duration of
history of illness, CSF white cell count and CSF percentage neu-
trophils [11]. In areas with a high incidence of HIV infection, S.
pneumoniae is the commonest cause of acute bacterial meningitis;
however, tuberculous meningitis and cryptococcal meningitis are also
 Ac u te B a c te r i a l M eningitis 505

commonly associated with HIV-infectionthe presenting clinical fea-

tures of all three diseases are very similar [1]. A clinical algorithm for
the management of CNS infections in adults has been described for
use in resource-poor settings with a high prevalence of HIV; it dem-
onstrated reduced time to diagnosis and treatment of cryptococcal
meningitis.
DIAGNOSIS
The gold standard for the diagnosis of acute bacterial meningitis
involves a lumbar puncture with Gram staining and culturing of CSF.
Characteristic laboratory findings suggestive of acute bacterial menin-
gitis include a CSF white cell count of >1000 cells/mm3 with a neu-
trophil predominance, an elevated protein of >50mg/dl and a CSF
to blood glucose ratio of <0.6. Lower CSF cell counts are seen in
children and immunocompromised patients [1]. If there has been
partial pretreatment with antibiotics, there may be lymphocyte pre-
dominance in the CSF. A large study of predominantly HIV-infected
adults with acute bacterial meningitis found that CSF analysis was
normal in 4% of cases. CSF Gram staining is inexpensive but requires
experienced staff to accurately interpret findings. The sensitivity of
Gram staining is reported to be between 5090% with a high specifi-
city [1]. In the absence of prior antibiotic treatment, culturing of CSF
is 8085% sensitive in adults and children.
Latex agglutination tests are simple and rapid to perform, but their
cost is still prohibitive for resource-limited settings and refrigeration
is required for the kits. Studies have shown that they do not add much
to the microbiologic diagnosis of acute bacterial meningitis in areas
with microbiologic capability. In contrast, the sensitivity and specifi-
city of cryptococcal latex agglutination tests are high and this may
help to rapidly differentiate between bacterial and cryptococcal etiol-
ogy in areas of high HIV incidence. A recently developed duplex rapid
diagnostic test for N. meningitidis has been evaluated on CSF samples
from Niger and reported very good sensitivities and specificities for
serogroup A and serogroup W135 [12].
Nucleic acid amplification using PCR targeting bacterial DNA is sensi-
tive but the major drawback in the tropics include the cost and
requirement for specialized equipment and technical expertise.
TREATMENT
ANTIBIOTICS
In addition to airway and hemodynamic stabilization and supportive
management, antibiotics are the cornerstone of acute bacterial men-
ingitis treatment. Untreated, acute bacterial meningitis is almost
always fatal; early treatment improves clinical outcome [8]. When
acute bacterial meningitis is suspected, high-dose empirical intrave-
nous antibiotic treatment based on the likely organisms for the
patients age and susceptibility patterns of that region should be com-
menced without delay (Table 54-1) [1, 8].
Ceftriaxone is recommended by the World Health Organization
(WHO) as first-line therapy [1]. Intravenous and intramuscular
administration routes are equally effective, as is once-daily dosing [1].
However, chloramphenicol (in oily suspension) remains the first
choice for treatment in many low-income settings as it is cheap and
readily available. It is contraindicated in infants aged below two
months [8]. The WHO recommends a single intramuscular injection
of ceftriaxone or oily chloramphenicol to treat epidemic meningococ-
cal meningitis [3, 13], although longer courses are advised if the child
has fever, seizures or coma after the first 24 hours of treatment [1, 3,
13]. Single dosing is reasonably safe during epidemics as 95% of cases
are expected to be caused by meningococcus, which responds well to
this treatment; however, single dose is absolutely contraindicated in
non-epidemic situations or for babies under 2 months of age, where
the risk of partial treatment of pneumococcal, Hib or Group B strep-
tococcal meningitis is high [3]. In all categories, the WHO recom-
mends regular clinical reassessment and referral if there is no
improvement after 48 hours, or coma or repeated seizures [3]. A
randomized, controlled trial compared 4- and 7-day ceftriaxone treat-
ment courses in Chilean children and showed rapid initial recovery
in both groups (the most common pathogens in this study were Hib
and meningococcus) [14]. A large multicountry, double-blind, pla-
cebo-controlled, randomized equivalence study of 5 versus 10 days of
treatment with ceftriaxone in 1004 children, concluded that in chil-
dren beyond the neonatal age-group with purulent meningitis caused
by S. pneumoniae, H. influenzae type b, or N. meningitidis who are
stable by day 5 of ceftriaxone treatment, there was no difference in
relapse or bacteriological failure rates between the two groups [15].

TABLE 54-1 WHO Recommended Empirical Antibiotic Treatment in Non-epidemic Situations in Resource-poor Settings
without Laboratory Support

Age group Likely pathogens Treatment Duration of treatment

02 months Streptococcus agalactiae Ceftriaxone 100 mg/kg/day o.d 7 days
Streptococcus pyogenes 21 days for Gram-negative bacilli (Escherichia coli,
Enterobacteria non-typhoidal Salmonella)
223 months Streptococcus pneumoniae Ceftriaxone 100mg/kg/day o.d 5 days
Haemophilus influenzae b 21 days
Neisseria meningitidis
Enterobacteria
25 years S. pneumoniae Ceftriaxone 100mg/kg/day o.d 5 days
H. influenzae b
N. meningitidis
514 years S. pneumoniae Ceftriaxone 100mg/kg/day o.d (max. 2 g) 5 days
N. meningitidis

>14 years S. pneumoniae Ceftriaxone 2 g/day o.d 5 days

N. meningitidis
Elderly S. pneumoniae Ceftriaxone 2 g/day 5 days
N. meningitidis
o.d., once daily.

Source from World Health Organization. Standardised treatment of bacterial meningitis in Africa in epidemic and non-epidemic situations; 2007. Available at: http://www.who.
int/csr/resources/publications/meningitis/WHO_CDS_EPR_2007_3/en/index.html.

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506 HUNTERS TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
High rates of Hib and pneumococcal chloramphenicol resistance
occur in Africa (1013%) and Southeast Asia [3, 16]. Pneumococcal
resistance to cephalosporins is a growing global concern; as many as
41% of isolates worldwide (5% in Africa) demonstrate cephalosporin
and penicillin resistance [1, 3, 17], necessitating the addition of van-
comycin or rifampin [16].
In non-resource-limited settings, ampicillin should also be adminis-
tered to individuals at risk of listeriosis; neonates in non-resource-
limited settings are usually treated with ampicillin and gentamycin,
cetriaxone or cefotaxime.
Epidemics are usually caused by meningococci; empiric treatment
usually involves ceftriaxone in any age group and irrelevant of pre-
gancy status, or oily chloramphenical in children over 2 years of age
and non-pregnant adults [3].
ADJUVANT THERAPIES
If administered prior to the initiation of antibiotics, studies in resource-
rich developed countries suggest that dexamethasone can decrease
long term sequelae and mortality from Hib and pneumococcal men-
ingitis [3, 7, 18, 19]. However, there are major differences between the
cohorts of patients evaluated in these studies and patients in resource-
limited settings, including late presentation for clinical care, pre-
hospital antibiotic use, high HIV rates and malnutrition [7, 19].
A Vietnamese study of adults and adolescents found that dexametha-
sone only improved outcome (reduced death or disability) for those
with microbiologically-proven disease, which, of course, is not known
at the point of treatment [20, 21]. Dexamethasone was associated
with increased one-month mortality in those with probable menin-
gitis (possibly owing to tuberculous meningitis cases in that group).
The most commonly isolated pathogen was S. suis [1, 20]. A study of
Malawian adults showed no improved outcome with adjuvant dex-
amethasone [7]. HIV prevalence was 90%, compared with 1% in the
Vietnamese study [7]. Thus, a recent review of acute bacterial menin-
gitis in resource-poor settings was only able to recommend steroid
use for HIV-negative adults with microbiologically-proven disease
(presumably a positive Gram stain on initial lumbar puncture) [1]. A
recent meta-analysis of individual patient data from one European
and four developing country trials appears to support this [22], while
a recent Cochrane review demonstrated no beneficial effect of dex-
amethasone in low-income countries [19].
Glycerol (1,2,3-propanetriol) is a naturally occurring osmotic agent
[23] that reduces cerebral edema and improves brain perfusion. Glyc-
erol may also reduce brain inflammation by scavenging oxygen free
radicals. It is attractive to the low-income setting as it is cheap, easily
available and administered orally [8, 23]. Although one study sug-
gested that oral glycerol therapy prevented severe neurologic sequelae
in childhood bacterial meningitis [23], other studies showed no
benefit [24, 25].
FLUID MANAGEMENT
Routine fluid restriction is not recommended and may be detrimental
[15]. A Cochrane review of three trials comparing unrestricted and
restricted fluid regimens recommended maintenance of intravenous
fluids in settings where children present late and where acute bacterial
meningitis mortality is high [26]. A third of children with acute bacte-
rial meningitis are hyponatremic; therefore, resuscitation with isot-
onic fluids is advocated where appropriate. Intravenous fluids are
preferable to the nasogastric route but may be expensive and the
expertise required to deliver them may be lacking in some settings. A
trial in Papua New Guinea showed no significant difference in mortal-
ity whether children with acute bacterial meningitis were resuscitated
with intravenous or nasogastric fluids, although other complications
were higher in the nasogastric fluids group [1].
VACCINATION
Conjugate vaccines have substantially reduced the incidence of
Hib, pneumococcus and Group C meningococcus meningitis in
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high-income countries, and of Hib and pneumococcal meningitis in
the African countries where these have been introduced [1]. Conju-
gate vaccines are the most effective form of immunization for those
under two years of age who are particularly vulnerable to bacterial
meningitis. High-income countries have reported an increase in inva-
sive pneumococcal disease from non-vaccine serotypes with the intro-
duction of conjugate vaccines. Therefore, enhanced surveillance will
be necessary for resource-poor countries when pneumococcal conju-
gate vaccines are introduced. Single (Group A) and quadrivalent cap-
sular polysaccharide meningococcal vaccines have been used in the
African meningitis belt; a conjugate meningococcus group A vaccine
(MenAfriVacTM) has been rolled out in several African countries in the
meningitis belt (www.meningvax.org) [1, 7].
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