Meningitis Bacteriana Clinicas 2018

A c u t e C o m m u n i t y - A c q u i red
Bacterial Meningitis
Ana Helena A. Figueiredo, MD, Matthijs C. Brouwer, MD, PhD,
Diederik van de Beek, MD, PhD*
KEYWORDS
Community-acquired bacterial meningitis Lumbar puncture Antimicrobial therapy
Conjugate vaccines Dexamethasone Epidemiology
KEY POINTS
Bacterial meningitis is a disease with high mortality and morbidity. The epidemiology has
changed due to the introduction of conjugate vaccines.
The clinical presentation may vary depending on age, underlying conditions, and severity
of illness and lumbar puncture is the procedure of choice for the diagnosis.
Empirical antibiotic treatment depends on local antibiotic susceptibility patterns of com-
mon pathogens.
Use of adjunctive dexamethasone is recommended in patients with suspected or proven
bacterial meningitis in high- or medium-income countries.
About half of the individuals who survived bacterial meningitis suffer from neurologic def-
icits, including cognitive impairment.
INTRODUCTION
Bacterial meningitis is an impacting disease with substantial mortality and morbidity

worldwide.1 The introduction of conjugate vaccines and the improvement of treatment
over the years reduced the burden of the disease, although it remains a concern in
both high- and low-income countries.2 Community-acquired bacterial meningitis is
a neurologic emergency, and early diagnosis and treatment can reduce morbidity
and mortality.3 Here, the authors provide an update on the changing epidemiology
Study Funding: This study has been funded by grants from the Netherlands Organization for
Health Research and Development (ZonMw; NWO-Vidi grant 2017.[016.176.308] to M.C.
Brouwer, NWO-Vidi grant 2011.[016.116.358] to D. van de Beek), the Academic Medical Center
(AMC Fellowship 2008 to D. van de Beek), and the European Research Council (ERC Starting
Grant [261178] to D. van de Beek).
Conflicts of Interest: All authors no conflicts.
Amsterdam UMC, University of Amsterdam, Neurology, Amsterdam Neuroscience, Meiberg-
dreef 9, Amsterdam, 1105 AZ Amsterdam, The Netherlands
* Corresponding author.
E-mail address: [email protected]
Neurol Clin 36 (2018) 809–820

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Elsevier en noviembre 03, 2019. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2019.
Elsevier Inc. Todos los derechos reservados.
810 Figueiredo et al
and predisposing factors and provide a clinical approach on patients presenting with
community-acquired bacterial meningitis.
EPIDEMIOLOGY
In the past 30 years, the epidemiology of bacterial meningitis has changed substantially
with a shift in causative pathogens and affected age groups.2,4 These changes were in
part due to the large-scale introduction of conjugated vaccines against Haemophilus
influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis, but also sto-
chastic changes in N meningitidis resulted in a sharp decrease in incidence.5 The major
burden of disease is still in sub-Saharan Africa with incidence rates varying between 10
and 40 per 100,000 inhabitants, whereas in the United States and Europe, incidence
rate varied between 0.7 and 7.1 per 100,000.4,6,7 Currently, the predominant causative
bacteria worldwide in neonatal meningitis are Streptococcus agalactiae (group B strep-
tococcus) and Escherichia coli, whereas in children outside the neonatal age, S pneu-
moniae and N meningitidis cause most cases.8 In adults, pneumococcus and
meningococcus cause 85% of cases, whereas Listeria monocytogenes is the third
most common cause, which is most commonly found in the elderly and patients with
immunodeficiency, for instance, alcoholics, patients with cancer, and patients using
immunosuppressive medication.9,10 Pneumococcus is now the most common cause
of community-acquired bacterial meningitis outside of the neonatal age and is found
in 50% to 70% of cases.4,11 To reduce the burden of pneumococcal disease in general,
vaccines have been developed covering a limited number of the more than 90 sero-
types that can cause disease in humans. Since 1983, a pneumococcal polysaccharide
vaccine including 23 serotypes is available, but because polysaccharide antigens are
poorly immunogenic in young children and the elderly, this vaccine had limited effect
in the at-risk population.2 In the early 2000s, a conjugated vaccine containing 7 pneu-
mococcal serotypes (PCV7) was introduced, resulting in a decreased incidence of
meningitis caused by vaccine serotypes. This decreased incidence was first observed
in children, followed by a decrease in adults caused by herd immunity.12 Regrettably,
following the reduction in vaccine serotype disease, an increase in meningitis due to
nonvaccine serotype was observed, reducing the efficacy of the vaccination.12 Subse-
quently, 10- and 13-valent vaccines were marketed, which were projected to cover
more than 70% of pneumococcal serotypes causing meningitis.13 Following PCV13
introduction, no dramatic decline in incidence has been observed in the United States
and France. The introduction did result in a shift in serotypes toward nonvaccine sero-
types.14,15 Novel approaches to prevention of pneumococcal meningitis are needed,
such as a pan-serotype vaccine, because currently available vaccines are not ex-
pected to result in a further reduction in incidence.
The meningococcus is the second-most common pathogen in bacterial meningi-
tis in children beyond the neonatal age and adults and is infamous for major
outbreaks in sub-Saharan Africa.1,16 The predominant serogroup differs per conti-
nent with serogroup B being the most common in Europe, serogroup Y most com-
mon in the United States, and the second in Europe and serogroup A the most
common in Africa. Vaccination against serogroup C was started in several countries
in Europe following a sharp increase in incidence.5,17 This vaccine introduction
resulted in the virtual disappearance of serogroup C meningitis in these countries.17
Recent surges in serogroup W disease in the United Kingdom and the Netherlands
were observed after which the conjugated serogroup C vaccine was replaced with
the tetra-valent serogroup A,C,W,Y vaccine and incidence decreased again.18 Sub-
stantial efforts have been made to reduce the serogroup A meningococcal
Acute Community-Acquired Bacterial Meningitis 811
meningitis incidence in the “meningitis belt,” referring to sub-Saharan Africa, where

most cases occur. A sharp decrease in serogroup A disease has been observed
following the stepwise serogroup A conjugate vaccine introduction in these African
countries.16 The total incidence of meningococcal disease was down by 57%,
and serogroup A disease almost completely disappeared.16 An increase in
serogroup W incidence in 2010 and serogroup C in 2015, however, caused a similar
number of cases as seen prior during the serogroup A epidemics.16 Continuous
monitoring of meningococcal disease epidemiology and adequate response in
vaccination policy are vital to reduce the burden of meningococcal disease. The
Advisory Committee on Immunization Practices in the United States recommends
that persons aged 16 to 23 years may receive meningococcal vaccine for short-
term protection for serogroup B in situational potential exposure, which is not
covered in the quadrivalent vaccine (A,C,W,Y) used for routine immunization in
the United States.
Other pathogens in bacterial meningitis occurring in less than 10% of adult men-
ingitis cases are L monocytogenes, H influenzae, and Staphylococcus aureus.19 Lis-
teria meningitis typically occurs in older adults with an immunocompromised
state.10 A longitudinal study of Listeria epidemiology showed the incidence in neo-
nates and pregnant woman has decreased, potentially due to public education on
food-borne infections during pregnancy.20 Furthermore, this study showed the pre-
dominant genotype of Listeria is clonal complex 6, which has been associated with
poor disease outcome. The proposed mechanism of this clonal expansion was se-
lection of this Listeria genotype through use of industrial disinfectants.21 H influen-
zae type b has virtually disappeared as an important cause of meningitis, and
nowadays other serotypes and nontypeable H influenzae strains are found as inci-
dental causes of bacterial meningitis. It has been associated with ear or sinus infec-
tion as predisposing condition and generally has a good outcome.22 S aureus is
found in approximately 2% of adult meningitis cases and is frequently associated
with concomitant endocarditis.19,23 Streptococcus suis is the major pathogen of
bacterial meningitis in South-East Asia and has been associated with contact
with pigs.24
PREDISPOSING FACTORS
Bacterial meningitis occurs more frequently in persons with defects of the immune
system, both inborn and acquired, and anatomic defects of the natural barriers of
the central nervous system.25 Immunodeficiency can be due to an immature immune
system in children under 2 years of age, immunosenescence in the elderly, but also
comorbid conditions such as splenectomy or asplenic states, diabetes mellitus, in-
fections with human immunodeficiency virus, alcoholism, cancer, and use of immu-
nosuppressive drugs.25–30 Genetic association studies have identified several
genetic deficiencies increasing the susceptibility to pneumococcal and meningo-
coccal infections.31 Rare genetic variations were found to result in a high risk of
recurrent infections due to these pathogens, whereas population-based studies
showed common genetic variants in the complement system result in a moderately
increased susceptibility to meningitis.31,32 Leakage of cerebrospinal fluid (CSF),
either following surgery, after trauma, or due to inborn anatomic defects, poses a
high risk of meningitis, causing an easy entry to the central nervous system for bac-
teria from the nasopharynx. In patients with recurrent meningitis, the search for CSF
leaks should involve ears, nose, and throat consultation and cranial imaging to iden-
tify bony defects.33
CLINICAL PRESENTATION
Early diagnosis and rapid initiation of appropriate therapy are the keys in patients with
suspected community-acquired bacterial meningitis. The clinical presentation may
vary depending on age, underlying conditions, and severity of illness.1,34,35 Infants
may become irritable or lethargic, may stop feeding, and are found to have a bulging
fontanelle, separation of the cranial sutures, meningism, and opisthotonos, and they
may develop convulsions.11 These findings are uncommon in neonates, who some-
times present only with respiratory distress, diarrhea, or jaundice.11 Clinical findings
of meningitis in young children are often minimal, and in childhood bacterial meningi-
tis, classical symptoms, such as headache, fever, nuchal rigidity, and altered mental
status, may be less common than in younger and middle-aged adults.19,36 Elderly pa-
tients with bacterial meningitis often present with classic symptoms of bacterial men-
ingitis.35 However, in a prospective study on adults with bacterial meningitis, the
classic triad of signs and symptoms consisting of fever, nuchal rigidity, and altered
mental status was present in only 44% of the patients.36 Certain clinical features
may predict the bacterial cause of meningitis.37 Rashes occur more frequently in pa-
tients with meningococcal meningitis, with reported sensitivities of 63% to 80% and
with specificities of 83% to 92%.1,38,39
THERAPEUTIC APPROACH
Dilemmas remain for physicians who need to accurately diagnose patients with bac-
terial meningitis and administer antibiotics and adjunctive therapies rapidly for this life-
threatening disease.3 Once an initial patient evaluation has been completed with his-
tory and physical findings, lumbar puncture is the diagnostic procedure of choice for
diagnosis of bacterial meningitis.40 The diagnostic accuracy of the findings in history
and physical examinations is reviewed elsewhere.41 Fever, stiff neck, and change in
mental status are the classic triad. About 95% will have 2 of the 4 of fever, stiff
neck, altered mental status, or headache. Characteristic findings in the CSF are typi-
cally used to make the diagnosis of meningitis. Classically described, the white blood
cell count in bacterial meningitis is typically greater than 1000 cells/mL, whereas in viral
meningitis, it is less than 300 cells/mL, although considerable overlap exists.42
The measurement of protein and glucose is an important aspect of CSF analysis
because abnormal protein and glucose levels are typically found in bacterial disease
but are relatively normal in many cases of viral meningitis.41 However, data in the liter-
ature concerning guidelines for predicting bacterial disease are derived mainly from
pediatric patients, with several multiple retrospective models using logistic equations
and other mathematical modeling43; however, none have yet proved robust enough
for widespread clinical practice.3
With the urgent nature of this testing to make the diagnosis of meningitis, one of the
issues physicians are faced with in an emergency department setting is whether neu-
roimaging is required before lumbar puncture.34 A recent study showed that lumbar
puncture can be performed safely in the large majority of patients with bacterial men-
ingitis, because it is only very rarely complicated by cerebral herniation.44 One set of
recommendations for emergency department brain computed tomographic (CT)
scanning before lumbar puncture is based on a prospective study from the United
States involving 301 adult patients with suspected meningitis.45 Items associated
with abnormal CT scan included age greater than 60, altered mental status, gaze or
facial palsy, abnormal language or inability to answer 2 questions or follow 2 com-
mands, immunocompromised status, history of central nervous system disease,
recent seizure, visual field abnormalities, and arm or leg drift. This study showed
that if none of these features were present, there was a negative predictive value of
97% for an intracranial abnormality, confirming that clinical features can be used to
identify patients who are unlikely to have abnormal findings on brain CT.
The authors think it is reasonable proceed with lumbar puncture without a CT scan if
the patient does not meet any of the following: patients who have new-onset seizures,
an immunocompromised status, signs that are suspicious for space-occupying le-
sions (papilledema or focal neurologic signs, not including cranial nerve palsy), or
moderate to severe impairment of consciousness.8,40 In other patients, cranial CT
can be considered a screening method for contraindications for lumbar puncture,
but one should realize that the interrater reliability of this assessment is moderate
only.44
Gram staining and culture of CSF can identify the causative pathogen in approxi-
mately 80% of the patients.1 The sensitivity of bacterial antigen tests is limited.1 A
promising diagnostic tool in cases of suspected bacterial meningitis and negative
CSF cultures is the amplification of bacterial DNA by polymerase chain reaction.1 A
recent development is the introduction of multiplex kits for pathogen detection.
Although high diagnostic sensitivity and specificity have been reported, further refine-
ments and particularly a reduction of the false-positive rates and cost-effectiveness
studies are needed before these kits are recommended in the diagnosis of bacterial
meningitis.46
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of the triad of fever, headache, and stiff neck is bacterial or
viral meningitis, fungal meningitis, tuberculous meningitis, drug-induced aseptic men-
ingitis, carcinomatous or lymphomatous meningitis, aseptic meningitis associated
with inflammatory diseases (systemic lupus erythematosus, sarcoidosis, Behçet dis-
ease, Sjögren syndrome), and, when temperature is only moderately elevated and
onset of headache is acute, subarachnoid hemorrhage.47 When an impaired level of
consciousness, focal neurologic deficits, or new-onset seizure activity are added to
the classic triad, the differential diagnosis includes viral encephalitis, venous sinus
thrombosis, tick-borne bacterial infections depending on geographic area (Borrelia
and Ehrlichia infections in North America and Europe, Rocky Mountain spotted fever
in North America), brain abscess, and subdural empyema.48,49
TREATMENT
Antibiotics
A delay in antimicrobial therapy (eg, due to cranial CT or transfer to another hospital)
has been associated with an increased risk for adverse clinical outcome in
community-acquired bacterial meningitis.50,51 Therefore, if imaging precedes lumbar
puncture, blood cultures should be drawn and antimicrobial therapy with adjunctive
dexamethasone initiated before imaging is performed.
Empirical antibiotic treatment should be based on the most common bacterial spe-
cies that cause the disease according to the patient’s age group, clinical setting,
epidemiology, and local antibiotic susceptibility patterns of the predominant patho-
gens (Table 1).52 Neonatal meningitis is largely caused by group B streptococci,
E coli, and L monocytogenes.20,52,53 Initial treatment, therefore, should consist of peni-
cillin or ampicillin plus a third-generation cephalosporin, preferably cefotaxime or cef-
triaxone, or penicillin or ampicillin and an aminoglycoside.8 Empirical coverage with a
third-generation cephalosporin (cefotaxime or ceftriaxone) at appropriate doses for
meningitis is recommended based on a broad spectrum of activity and excellent
814
Figueiredo et al
Table 1
Recommendations for empiric antimicrobial therapy in suspected community-acquired bacterial meningitis
Predisposing Factor Common Bacterial Pathogens Initial Intravenous Antibiotic Therapy

Age
<1 mo S agalactiae, E coli, L monocytogenes Ampicillin plus cefotaxime or an aminoglycoside
1–3 mo S pneumoniae, N meningitidis, S agalactiae, H influenzae, E coli, L Ampicillin plus vancomycin plus ceftriaxone or cefotaximea
monocytogenes
3–23 mo S pneumoniae, N meningitidis, S agalactiae, H influenzae, E coli Vancomycin plus ceftriaxone or cefotaximea
2–50 y N meningitidis, S pneumoniae Vancomycin plus ceftriaxone or cefotaximea
>50 y N meningitidis, S pneumoniae, L monocytogenes, aerobic gram- Vancomycin plus ceftriaxone or cefotaxime plus ampicillinb
negative bacilli
With risk factor presentc S. pneumoniae, L monocytogenes, H influenzae Vancomycin plus ceftriaxone or cefotaxime plus ampicillinb
a
In areas with very low penicillin-resistance rates, monotherapy penicillin may be considered.
b
In areas with very low penicillin-resistance and cephalosporin-resistance rates, combination treatment of amoxicillin and third-generation cephalosporin may be
considered.
c
Alcoholism, altered immune status.
Adapted from van de Beek D, Brouwer MC, Thwaites GE, et al. Advances in treatment of bacterial meningitis. Lancet 2012;380(9854):1694; with permission.
penetration into the CSF during inflammatory conditions.52 Because of the worldwide
emergence of multi-drug-resistant strains of S pneumoniae, vancomycin is added to
the initial empirical antimicrobial regimen in adult patients.8,54 In addition, in patients
aged greater than 50 years, treatment with ampicillin should be added to the above
antibiotic regimen for additional coverage of L monocytogenes, which is more preva-
lent among this age group.10 Although no clinical data on the efficacy of rifampin in
patients with pneumococcal meningitis are available, some experts would recom-
mend the use of rifampicin, based on its susceptibility, in combination with a third-
generation cephalosporin, with or without vancomycin, in patients with pneumococcal
meningitis caused by bacterial strains that, on the basis of local epidemiology, are
likely to be highly resistant to penicillin or cephalosporins.
Adjunctive Dexamethasone Therapy

Experimental animal models have shown that dexamethasone inhibits the production
of tumor necrosis factor-a and interleukin-1, reverses development of brain edema,
and limits the increase in CSF lactate and leukocyte concentrations.55 Since publica-
tion of the experimental studies, several controlled randomized clinical trials have
been performed to determine whether adjunctive steroid therapy is beneficial in chil-
dren with bacterial meningitis. Initial results showed that the main beneficial effect of
dexamethasone was to reduce the risk of hearing loss in children with H influenzae
type b meningitis.56 Additional data extended the likely benefit to children with pneu-
mococcal meningitis.57 Subsequent large randomized controlled trials in Malawian
and South American children did not show benefit of this adjunctive therapy.58,59 A
Cochrane meta-analysis showed that adjunctive dexamethasone treatment did not in-
fluence overall mortality but did decrease hearing loss in surviving children with bac-
terial meningitis. In low-income countries, no benefit of dexamethasone was
established in this meta-analysis.60
For adults with bacterial meningitis, results of a European randomized controlled
trial showed that adjunctive dexamethasone, given before or with the first dose of anti-
microbial therapy, was associated with a reduced risk of unfavorable outcome and
mortality.61 The beneficial effect was most apparent in adults with pneumococcal
meningitis, in whom mortality was decreased from 34% to 14%. In this subgroup,
dexamethasone prevented death due to a reduction of systemic and cerebral compli-
cations.62 A follow-up study showed that the survival benefit from adjunctive dexa-
methasone therapy is obtained in the acute phase of the disease and remains for
years.63
In 2004, a meta-analysis of 5 randomized controlled trials showed that treatment
with corticosteroids reduced both mortality and neurologic sequelae in adults with
bacterial meningitis.64 However, subsequent randomized controlled trials from Malawi
and Vietnam did not show that dexamethasone benefited adults.65,66 In Vietnam,
dexamethasone was associated with a decreased rate of mortality for patients with
microbiologically confirmed disease.66 An individual patient data meta-analysis
showed that dexamethasone treatment reduced the rate of hearing loss irrespective
of antibiotic pretreatment.67
European Society of Clinical Microbiology and Infectious Diseases/Infections Dis-
eases Society of America guidelines recommend the use of adjunctive dexametha-
sone in patients with suspected or proven bacterial meningitis, but only in high-
income countries.8,54 The advised dexamethasone regimen is 0.6 mg/kg of body
weight intravenously (IV) daily for children, and 10 mg IV given every 6 hours for adults,
with the first dose being preferably given before or with the first dose of antimicrobials,
for 4 days.8,54
The implementation of adjunctive dexamethasone therapy has led to decreased

rates of unfavorable outcome and death throughout Europe and the United
States.6,19,39,68 In a prospective nationwide cohort study in the Netherlands, the
drug was administered in 92% of meningitis episodes, in the period 2006 to 2009.
An observational study reported a decline of mortality from 30% to 20% after the intro-
duction of adjunctive dexamethasone therapy (P 5 .001).68 The decline in mortality
was observed across the whole study population but was more prominent in patients
who received dexamethasone.19
Use of adjunctive dexamethasone has been reported to predispose patients with
bacterial meningitis to a new complication, delayed cerebral thrombosis.69,70 Pa-
thology suggests an immunologic reaction targeting cerebral blood vessels, possibly
complement mediated,70,71 with vascular inflammation, thromboembolism of large
arteries, and infectious intracranial aneurysms.72 Pneumococcal cell wall compo-
nents can be observed for weeks after pneumococcal meningitis and may be a
source of resurging inflammation after the initial immunosuppression by
dexamethasone.72
OUTCOME
Reported case fatality rates vary with age, causative pathogen, and income status.73
Meningitis caused by S pneumoniae has the highest case fatality rates: 20% to 37%
for high-income countries and up to 50% for low-income countries.73,74 Meningo-
coccal meningitis fatality rates are much lower: between 3% and 10% for high- and
low-income countries.74 Neurologic sequelae have been estimated to occur in a sub-
stantial number of surviving patients: about half of survivors suffer from focal neuro-
logic deficits.73 Most frequently reported sequelae are focal neurologic deficits,
hearing loss, cognitive impairment, and epilepsy. Adults with pneumococcal meningi-
tis have the highest risk of developing focal neurologic deficits, commonly caused by
cerebral infarction,75 but can also be due to subdural empyema,49 cerebral abscess,76
or intracerebral bleeding.77 Focal deficits may improve during clinical course and even
after discharge, but a proportion of patients will have persisting focal neurologic def-
icits that often interfere in the patient’s daily life. Hearing loss occurs in a high propor-
tion of patients with pneumococcal meningitis and has been associated with
coexisting otitis.78 Children and adults recovering from bacterial meningitis are at
risk for long-term cognitive deficits.79,80 Although corticosteroids may potentiate
ischemic and apoptotic injury to neurons, treatment with adjunctive dexamethasone
did not increase risk for long-term cognitive impairment.81 Costs associated with
post–meningitis sequelae have an important economic impact on health care
systems.2,82
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Meningitis Bacteriana Clinicas 2018

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Meningitis Bacteriana Clinicas 2018

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A c u t e C o m m u n i t y - A c q u i red

Bacterial meningitis is an impacting disease with substantial mortality and morbidity

Neurol Clin 36 (2018) 809–820

meningitis incidence in the “meningitis belt,” referring to sub-Saharan Africa, where

Predisposing Factor Common Bacterial Pathogens Initial Intravenous Antibiotic Therapy

Adjunctive Dexamethasone Therapy

The implementation of adjunctive dexamethasone therapy has led to decreased

5. Bijlsma MW, Bekker V, Brouwer MC, et al. Epidemiology of invasive meningo-

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