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Bacterial meningitis in adults: Host and pathogen factors, treatment and outcome

Heckenberg, S.G.B.

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Citation for published version (APA):Heckenberg, S. G. B. (2013). Bacterial meningitis in adults: Host and pathogen factors, treatment and outcome.

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Download date: 01 Jul 2019

Chapter 8

General discussion

Bacterial meningitis:

epidemiology, pathophysiology and treatment

Adapted from: Bacterial meningitis: epidemiology, pathophysiology and

treatment. Sebastiaan G.B. Heckenberg, Matthijs C. Brouwer, D van de Beek

Handbook of Clinical Neurology 2013 (in press).

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Introduction

Community-acquired bacterial meningitis exacts a heavy toll, even in developed

countries. It is a neurological emergency and these patients require immediate

evaluation and treatment. The incidence of bacterial meningitis is about 5 cases

per 100,000 adults per year in developed countries and may be 10 times higher

in less developed countries.1, 2 The predominant causative pathogens in adults

are Streptococcus pneumoniae (pneumococcus) and Neisseria meningitidis

(meningococcus) which are responsible for about 80% of all cases.1, 2

Epidemiology

The incidence of acute bacterial meningitis is 5–10/100,000 persons per year in

high income countries, resulting in 15,000–25,000 cases in the USA annually.1,

3, 4 Vaccination strategies have substantially changed the epidemiology of

community-acquired bacterial meningitis during the past two decades.1, 3,

5 The routine vaccination of children against Haemophilus influenzae type B

has virtually eradicated H. influenzae meningitis in the developed world.1, 6

As a consequence, S. pneumoniae has become the most common pathogen

beyond the neonatal period and bacterial meningitis has become a disease

predominantly of adults. The introduction of conjugate vaccines against seven

serotypes of S. pneumoniae that are among the most prevalent in children aged

6 months to 2 years has reduced the rate of invasive pneumococcal infections

in young children and in older persons.5 The integration of the meningococcal

protein–polysaccharide conjugate vaccines into vaccination programs in

several countries further reduced the disease burden of bacterial meningitis in

high- and medium-income countries.7

S. pneumoniae affects all ages and causes the most severe disease in the very

young and the very old.8 Of the >90 pneumococcal serotypes, a few dominate

as the causes of meningitis. The increase of drug-resistant strains of S.

pneumoniae, is an emerging problem worldwide. The prevalence of antibiotic-

resistant strains in some parts of the US is as high as 50–70% with important

consequences for treatment.9

N. meningitidis is mainly responsible for bacterial meningitis in young adults;

it causes sporadic cases and epidemics.10 Its incidence shows a peak in winter

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and early spring and varies greatly around the world. Small outbreaks typically

occur in young adults living in close quarters, such as dormitories of military

camps or schools. Major epidemics have occurred periodically in sub-Saharan

Africa (the so-called ‘meningitis belt’), Europe, Asia and South America.1 During

these epidemics, attack rates can reach several hundred per 100,000, with

devastating consequences.

Meningococcal serogroups are determined by structural differences in

the capsular polysaccharide. Serogroups A, B, C, X, Y and W-135 are most

commonly associated with invasive disease worldwide, with regional variation

in the distribution.10 In the Netherlands, serogroup B and C account for >95%

of disease.chapter 2 Serogroup A meningococci cause epidemic disease in the

‘meningitis belt’ every 5-10 years, emphasising the importance of vaccination

in these parts of Africa.10 Multilocus sequence typing (MLST) has provided

an additional typing method based on the sequencing of 6 meningococcal

housekeeping genes.11 This unambiguous method allows for international

monitoring of meningococcal epidemiology through an online database

(pubmlst.org). In chapter 2, we described the relation of meningococcal clonal

complex with clinical characteristics. Meningococcal meningitis caused by

meningococci belonging to cc11 was associated with sepsis and poor outcome.

Clonal complex 11 was strongly associated with serogroup C and since our

study, the implementation of serogroup C vaccination in the Netherlands has

all but eradicated serogroup C disease. As serogroup B disease also reduced,

the share of meningococcal meningitis in all adult bacterial meningitis has

decreased from 37% (1998-2002) to 14% (2006-2009).chapter 5

The group B streptococcus (S. agalactiae) is a pathogen of neonates and often

causes a devastating sepsis and meningitis.1, 12 It colonizes the maternal birth

canal, and is transmitted to the child during delivery. The colonized newborn

can develop group B streptococcal disease of early onset (developing at less

than 7 days of age; median 1 day) or late onset (developing later than 7 days

of age). Listeria monocytogenes causes meningitis preferentially in neonates, in

adults with alcoholism, immunosupression, or iron overload, pregnant women

or the elderly.13 There is often an encephalitic component to presentation, with

early mental status alterations, neurologic deficits and seizures. In countries

with routine vaccination against H. influenzae type B it has become a rare

disease.6 In large parts of the world H. influenzae type b remains a major cause

of paediatric meningitis, with high rates of mortality and hearing loss.1

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Bacterial meningitis also occurs in hospitalized patients (“physician associated

meningitis” or “nosocomial meningitis”). In a large city hospital, almost 40%

of cases may be nosocomial.4 Most cases occur in patients undergoing

neurosurgical procedures, including implanting of neurosurgical devices,

and in patients with focal infections of the head. Furthermore, patients with

cerebrospinal fluid shunts are at continuous risk of developing drain associated

meningitis.14 The organisms causing nosocomial meningitis differ markedly

from those causing community-acquired meningitis and include Gram-

negative rods (e.g. Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa,

Acinetobacter spp., Enterobacter spp.), staphylococci and streptococci other

than S. pneumoniae.14-16

Since the early antibiotic era, the emergence of antimicrobial resistance has

been a continuing problem. Pneumococcal resistance to penicillin, due to

changes in its penicillin binding proteins, started to appear in the 1960s and

has since developed worldwide, often necessitating initial therapy with a

combination of a third-generation cephalosporin with vancomycin, instead of

monotherapy with penicillin.1

Genetics

Host genetic factors are major determinants of susceptibility to infectious

diseases. A cause of these differences in susceptibility are single base-pair

variations, also known as single-nucleotide polymorphisms (SNPs), in genes

controlling the host response to microbes. Patients with recurrent or familial

meningitis or sepsis due to S. pneumoniae or N. meningitidis are often found

to have rare mutations that cause a substantial increase in susceptibility

to infection.17 These mutations are mostly founding genes coding for the

complement system or Toll like receptor (TLR) pathways. In the general

population identified alterations include SNPs in the complement system,

cytokines and TLRs.17 A genome wide association study has shown complement

factor H SNPs decrease the risk of meningococcal disease.18 In patients with

sepsis due to N. meningitidis, SNPs in cytokine and fibrinolysis genes have been

reported to influence mortality.19

In bacterial meningitis research on genetic factors is lacking but may provide

important pathophysiological insights. Bacterial meningitis is a complex

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disorder in which injury is caused, in part, by the causative organism and, in

part, by the host’s own inflammatory response. Recognition of particular

subgroups of patients with a genetic predisposition to more severe illness may

help to individualize treatment and improve prognosis.

We performed a nationwide genetic association study in adults with bacterial

meningitis on common variants in the complement system and selected

all SNPs with a minor allele frequency of more than 5% in genes coding for

complement components (C1QA, C1QB, C1QC, C2, C3, C5, C6, C7, C8B, C9, CFD,

CFH, CFI, and CFP) for which a commercial genotyping assay was available.

We identified rs17611 in complement component 5 (C5; GG genotype) to be

associated with unfavorable outcome in patients of mixed European descent

with pneumococcal meningitis (OR, 2.25; 95% CI, 1.33–3.81; p=0.002). chapter 7

Pathophysiology and pathology

Specific bacterial virulence factors for meningeal pathogens include specialized

surface components that are crucial for adherence to the nasopharyngeal

epithelium, the evasion of local host defense mechanisms and subsequent

invasion of the bloodstream.20 In pneumococcal disease, presence of the

polymeric immunoglobulin A receptor on human mucosa, which binds to a

major pneumococcal adhesin, CbpA, correlates with the ability of pneumococci

to invade the mucosal barrier. Viral infection of the respiratory tract may also

promote invasive disease.21 From the nasopharyngeal surface, encapsulated

organisms cross the epithelial cell layer and invade the small subepithelial

blood vessels.

Binding of bacteria to upregulated receptors (e.g., platelet activating-factor

receptors) promotes migration through the respiratory epithelium and vascular

endothelium, resulting in blood stream invasion.

In the bloodstream, bacteria must survive host defenses, including circulating

antibodies, complement-mediated bactericidal mechanisms and neutrophil

phagocytosis. Encapsulation is a shared feature of the principal meningeal

pathogens. To survive the various host conditions they encounter during

infection, pneumococci undergo spontaneous and reversible phase variation,

which involves changes in the amount of important surface components.21,

22 The capsule is instrumental in inhibiting neutrophil phagocytosis and

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complement-mediated bactericidal activity. Several defense mechanisms

counteract the antiphagocytic activity of the bacterial capsule. Activation of

the alternative complement pathway results in cleavage of C3 with subsequent

deposition of C3b on the bacterial surface, thereby facilitating opsonization,

phagocytosis and intravascular clearance of the organism.23 Impairment of the

alternative complement pathway occurs in patients with sickle-cell disease

and those who have undergone splenectomy, and these groups of patients

are predisposed to the development of pneumococcal meningitis. Functional

deficiencies of several components involved in the activation and function of

complement-mediated defences have been identified (i.e., mannose-binding

lectin, properdin, terminal complement components), which increase the

susceptibility for invasive meningococcal infections.17 In our studies following

the discovery of the role of the rs17611-SNP in pneumococcal meningitis,

the anaphylatoxin C5a was identified as a crucial complement product in

pneumococcal meningitis. Neutralization experiments showed that adjunctive

treatment with C5-Ab improved outcome in mice with pneumococcal

meningitis. chapter 7

The blood–brain barrier is formed by cerebromicrovascular endothelial cells,

which restrict blood-borne pathogen invasion. Cerebral capillaries, as opposed

to other systemic capillaries, have adjacent endothelial cells fused together

by tight junctions that prevent intercellular transport.24 Bacteria are thought

to invade the subarachnoid space via transcytosis. Nonhaematogenous

invasion of the CSF by bacteria occurs in situations of compromised integrity

of the barriers surrounding the brain. Direct communication between the

subarachnoid space and the skin or mucosal surfaces as a result of malformation

or trauma gives rise to meningeal infection. Bacteria can also reach the CSF as

a complication of neurosurgery or spinal anesthesia.14

Physiologically, concentrations of leucocytes, antibodies, and complement

components in the subarachnoid space are low, which facilitates rapid

multiplication of bacteria. In the CSF pneumococcal cell-wall products,

pneumolysin, and bacterial DNA induce a severe inflammatory response via

binding to Toll-like receptor-2 (TLR).24 Once engaged, this signaling receptor

transmits the activating signal into the cell, which initiates the induction of

inflammatory cytokines.25 In N. meningitidis, lipopolysaccharide (LPS) is a

major component of the outer membrane. LPS is sensed by mammalian cells

through Toll-like receptor 4 (TLR4), in combination with coreceptors MD-2 and

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CD14. The host responds to bacterial endotoxin with proinflammatory gene

expression and activation of coagulation pathways in sepsis and meningitis.10

The discovery of meningococcal lpxL1 mutants and the associated reduced

induction of pro-inflammatory cytokines prompted our investigation of

the clinical fenotype caused by meningococcal lpxL1 mutants in adults with

meningococcal meningitis. chapter 3 Infection with lpxL1-mutant meningococcal

strains is associated with less systemic inflammation and reduced activation of

the coagulant system, reflected in less fever, higher serum platelet counts, and

lower numbers with rash.

The subarachnoid inflammatory response is accompanied by production of

multiple mediators in the CNS. Tumour necrosis factor α (TNFα), interleukin

1β, and interleukin 6 are regarded as the major early response cytokines that

trigger the inflammatory cascade, which induces various pathophysiological

alterations implicated in pneumococcal meningitis (Figure 1).20 TNFα and

interleukin 1β stimulate the expression of chemokines and adhesion molecules,

which play an important part in the influx of leucocytes from the circulation

to the CSF. Upon stimulation with bacterial components, macrophages and

granulocytes release a broad range of potentially tissue-destructive agents,

which contribute to vasospasm and vasculitis, including oxidants (e.g.,

peroxynitrite) and proteolytic enzymes such as matrix metalloproteinases

(MMP). Matrix metalloproteinases (MMP), zinc-dependent enzymes produced

as part of the immune response to bacteria that degrade extracellular matrix

proteins, also contribute to the increased permeability of the blood–brain

barrier.

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Figure 1. Multiple complications in a patient with pneumococcal meningitis

(A) T2-proton-density-weighted MRI of the brain shows a transverse view of a hyperintense signal (arrows) in the globus pallidus, putamen and thalamus that indicates bilateral edema. (B) A postmortem view of the brain of the same patient shows yellowish-colored meninges as a result of extensive inflammation. (C) Confirmation of the bilateral infarction of globus pallidus, putamen and thalamus (arrows). The microscopic substrate in the same patient shows a meningeal artery with (D) lymphocytic infiltration in and around the vessel wall, (E) extensive subpial necrotizing cortical inflammation, and (F) edema in the white matter.

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A major contributor to increased intracranial pressure in bacterial meningitis

is the development of cerebral oedema, which may be vasogenic, cytotoxic or

interstitial in origin. Vasogenic cerebral oedema is a consequence of increased

blood–brain barrier permeability.26 Cytotoxic edema results from an increase

in intracellular water following alterations of the cell membrane and loss of

cellular homeostasis. Cytotoxic mechanisms include ischemia and the effect of

excitatory amino acids. Secretion of antidiuretic hormone also contributes to

cytotoxic oedema by making the extracellular fluid hypotonic and increasing

the permeability of the brain to water. Interstitial oedema occurs by an increase

in CSF volume, either through increased CSF production via increased blood

flow in the choroid plexus, or decreased resorption secondary to increased CSF

outflow resistance.

The exact mechanisms that lead to permanent brain injury are incompletely

understood. Cerebral ischemic necrosis probably contributes to damage to

the cerebral cortex (Figure 1). Cerebrovascular complications occur in 15–20%

of patients with bacterial meningitis.2 Other abnormalities include subdural

effusion or empyema, septic sinus thrombosis, subarachnoid hematomas,

compression of intracranial structures due to intracranial hypertension,

and herniation of the temporal lobes or cerebellum. Gross changes, such as

pressure coning, are rare.27

There is diffuse acute inflammation of the pia-arachnoid, with migration of

neutrophil leucocytes and exudation of fibrin into the CSF. Pus accumulates

over the surface of the brain, especially around its base and the emerging

cranial nerves, and around the spinal cord. The meningeal vessels are dilated

and congested and may be surrounded by pus (Figure 1). Pus and fibrin

are found in the ventricles and there is ventriculitis, with loss of ependymal

lining and subependymal gliosis. Infection may block CSF circulation, causing

obstructive hydrocephalus or spinal block. In many cases death may be

attributable to related septicaemia, although bilateral adrenal haemorrhage

(Waterhouse–Friederichsen syndrome) may well be a terminal phenomenon

rather than a cause of fatal adrenal insufficiency as was once imagined. Patients

with meningococcal septicaemia may develop acute pulmonary oedema.

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Clinical presentation

Community-acquired bacterial meningitis

Early diagnosis and rapid initiation of appropriate therapy are vital in the

treatment of patients with bacterial meningitis. A recent study provided a

systematic assessment of the sequence and development of early symptoms

in children and adolescents with meningococcal disease (encompassing

the spectrum of disease from sepsis to meningitis) before admission to the

hospital.28 Classic symptoms of rash, meningismus, and impaired consciousness

develop late in the pre-hospital illness, if at all. Early signs before admission

in adolescents with meningococcal disease were leg pain and cold hands and

feet.

Bacterial meningitis is often considered but may be difficult to recognize. The

clinical presentation of a patient with bacterial meningitis may vary depending

on age, underlying conditions and severity of illness. Clinical findings of

meningitis in young children are often minimal and in childhood bacterial

meningitis and in elderly patients’ classical symptoms such as headache, fever,

nuchal rigidity and altered mental status may be less common than in younger

and middle-aged adults.1, 29 Infants may become irritable or lethargic, stop

feeding, and are found to have a bulging fontanel, separation of the cranial

sutures, meningism, and opisthotonos, and they may develop convulsions.

These findings are uncommon in neonates, who sometimes present with

respiratory distress, diarrhoea, or jaundice.1, 12 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.30 Certain clinical features may predict the bacterial cause of

meningitis. Predisposing conditions like ear or sinus infections, pneumonia,

immunocompromise, and dural fistulae are estimated to be present in 68-92%

of adults with pneumococcal meningitis.8, 31 Rashes occur more frequently in

patients with meningococcal meningitis, with reported sensitivities of 63–80%

and with specificities of 83–92%.1, 32

Post-traumatic bacterial meningitis

This is often indistinguishable clinically from spontaneous meningitis.14, 16

However, in obtunded or unconscious patients who have suffered a recent or

previous head injury, few clinical signs may be present. A fever and deterioration

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in the level of consciousness or loss of vital functions may be the only signs of

meningitis. Finding a CSF leak adds support to the possibility of meningitis in

such patients, but this is undetectable in most cases. The range of bacteria

causing meningitis in these patients is broad and consideration should be

given to broad spectrum antibiotics including metronidazole for anaerobic

pathogens.

Infections of CSF shunts

Patients may present with clinical features typical of spontaneous meningitis,

especially if virulent organisms are involved.14 The more usual presentation is

insidious, with features of shunt blockage such as headache, vomiting, fever,

and a decreasing level of consciousness. Fever is a helpful sign, but is not a

constant feature and may be present in as few as 20 per cent of cases. Shunts

can be infected without causing meningitis, in which event the features

of the infection will be determined by where the shunt drains. Infection of

shunts draining into the venous system produces a disease similar to chronic

right-sided infective endocarditis together with glomerulonephritis (shunt

nephritis), while infection of shunts draining into the peritoneal cavity produces

peritonitis.

Management

Given the high mortality of acute bacterial meningitis, starting treatment

and completing the diagnostic process should be carried out simultaneously

in most cases (Figure 2).2 The first step is to evaluate vital functions, obtain

two sets of blood cultures, and blood tests which typically should not take

more than one or two minutes. At the same time, the severity of the patient’s

condition and the level of suspicion for the presence of bacterial meningitis

should be determined.

Recommendations for cranial CT and fears of herniation are based on the

observed clinical deterioration of a few patients in the several to many hours

after lumbar puncture and the perceived temporal relationship of lumbar

puncture and herniation, but proving a cause and effect association is very

difficult based on the available data. Therefore, it is reasonable to proceed with

lumbar puncture without a CT scan if the patient does not meet any of the

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following: patients who have new-onset seizures (suggestive of focal brain

lesions), an immunocompromised state, signs suspicious for space-occupying

lesions (papilledema or focal neurological signs - not including cranial nerve

palsy), or moderate-to-severe impairment of consciousness (score on the

Glasgow Coma Scale below 11).2, 27 Other contraindications to lumbar puncture

include local skin sepsis at the site of puncture, a clinically instable patient, and

any clinical suspicion of spinal cord compression. Lumbar puncture may also

be harmful in patients with coagulopathy, because of the chance of needle-

induced subarachnoid hemorrhage or of the development of spinal subdural

and epidural hematomas. Contraindications for (immediate) lumbar puncture

are provided in Table 1.2 In patients with suspected bacterial meningitis who

receive a CT scan before lumbar puncture, initial therapy consisting of adjunctive

dexamethasone (10 mg iv) and empirical antimicrobial therapy (Figure 2, Table

1) should always be started without delay, even before sending the patient to

the CT scanner. Several studies have reported a strong increase in mortality due

to a delay in treatment caused by cranial imaging.33 In chapter 2 we described

adults with meningococcal meningitis and neuroimaging preceded lumbar

puncture in 85 of 92 (92%) patients; antibiotics were administered before CT in

only 15 of 88 (17%) of these patients. Therefore, 83% of these patients suffered

a delay of administration of adequate therapy.

Table 1. Contra-indications for immediate lumbar puncture

Signs suspect for space occupying lesion: PapilledemaFocal neurologic signs (excluding isolated cranial nerve palsies)

Score on Glasgow Coma Scale <10

Severe immunodeficiency (such as HIV)

New onset seizures

Skin infection puncture site

Coagulopathy, e.g. use of anticoagulant medication or clinical signs of diffuse intravascular coagulation

Septic shock

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Figure 2. Algorithm for the management of the patient with suspected community-bacterial meningitis

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Laboratory diagnosis

When CSF analysis shows increased white blood cell counts, confirming

a diagnosis of meningitis,it is important to discriminate between the

usually harmless viral and the life-threatening bacterial meningitis. The CSF

abnormalities of bacterial meningitis include raised opening pressure in almost

all patients, polymorphonuclear leukocytosis, decreased glucose concentration,

and increased protein concentration. In bacterial meningitis, the white blood

cell count is typically >1000 cells/μl, while in viral meningitis it is <300 cells/

μl, although there is considerable overlap.1, 27 The neutrophil count is higher

in bacterial than in viral meningitis. More than 90% of cases present with CSF

white cell counts of more than 100/μl. In immunocompromised patients, CSF

white blood cell counts may be lower, although acellular CSF is exceedingly

rare, except in patients with tuberculous meningitis.34 The normal CSF glucose

concentration is between 2.5 and 4.4 mmol/l which is approximately 65% of the

serum glucose. In bacterial meningitis the glucose concentration is usually less

than 2.5 mmol/l, or < 40% of the serum glucose. The CSF protein in bacterial

meningitis is usually increased >50 mg/dl.1, 30

The CSF Gram stain identifies the cauasative micro-organism in 50–90% of

cases and CSF culture is positive in 80% of untreated patients, depending on

the pathogen.1, 30 Gram’s staining of CSF permits the rapid identification of the

causative organism (sensitivity, 60-90%; specificity, >97%). The yield of CSF

Gram staining is only marginally decreased if the patient received antibiotic

treatment prior to the lumbar puncture.1 Latex particle agglutination tests that

detect antigens of N. meningitidis, S. pneumoniae, H. influenzae and S. agalactiae

have been tested in bacterial meningitis patients. No incremental yield of this

method was observed in several cohort studies. Therefore these tests are no

longer advised.1 In the past decade PCR has proven to provide additional yield

in recognizing the causative pathogen in bacterial meningitis patients from

CSF. The reported sensitivities and specificities are high for different organisms

and therefore PCR can be used to detect patients in whom cultures remain

negative or those who were pre-treated with antitbiotics. However, CSF culture

will remain the “gold standard” for diagnosis as it is obligatory to obtain the

in vitro susceptibility of the causative microorganism and to rationalize

treatment.1

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When to repeat a lumbar puncture

A repeat analysis of the cerebrospinal fluid should only be carried out in

patients whose condition has not responded clinically after 48 hours of

appropriate antimicrobial and adjunctive dexamethasone treatment.30 It

is essential when pneumococcal meningitis caused by penicillin-resistant

or cephalosporin-resistant strains is suspected. Gram staining and culture

of the cerebrospinal fluid should be negative after 24 hours of appropriate

antimicrobial therapy.

Serum markers of inflammation

In the distinction between viral and bacterial meningitis, serum inflammatory

markers may suggest the diagnosis.1, 30 Retrospective studies showed that

increased serum procalcitonin levels (>0.5 ng/ml) and C-reactive protein levels

(>20 mg/liter) were associated with bacterial meningitis.35, 36 Although elevated

concentrations can be suggestive of bacterial infection, they do not establish

the diagnosis of bacterial meningitis.

Blood Culture

Blood cultures are valuable to detect the causative organism and establish

susceptibility patterns if CSF cultures are negative or unavailable. Blood culture

positivity differs for each causative organism and varies between 50 and 90%.

The yield of blood cultures is decreased by 20% for patients who received

pretreatment with antibiotics.1

Skin biopsy

Microbiological examination of skin lesions is routine diagnostic work-up

in patients with suspected meningococcal infection. It differentiates well

between meningitis with and without haemodynamic complications, and the

result is not affected by previous antibiotic treatment.37, 38

Antimicrobial therapy

The choice of initial antimicrobial therapy is based on the most common

bacteria causing the disease according to the patient’s age, the clinical setting

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and on patterns of antimicrobial susceptibility (Table 2). Once the pathogen

has been isolated, specific treatment based on the susceptibility of the isolate

can replace the empirical regimen (Table 3).

The pharmacokinetics and dynamics of antimicrobial agents are important

drug characteristics to base the empirical regimen on. Penetration of the

BBB into the subarachnoid space is the first pharmacological factor that

determines whether an antimicrobial agent is able to clear bacteria from the

CSF. BBB penetration is affected by lipophility, molecular weight and structure,

and protein-bound fraction. Bacterial meningitis is a dynamic process and

CSF penetration of antimicrobials is highly dependent on the breakdown of

the BBB. Anti-inflammatory drugs such as dexamethasone might influence

the breakdown of the BBB and thereby interfere with CSF penetration of

antimicrobial agents.

The activity of antimicrobial drugs in infected purulent CSF depends on

a number of factors, such as activity in the environment of decreased pH,

protein-bound fraction, bacterial growth rate and density, and clearance in

the CSF. Mechanisms of antibiotic action are targeting of the bacterial cell wall,

targeting of the bacterial cell membrane or targeting biosynthetic processes.

Whereas bacteriostatic activity involves inhibition of growth of microorganisms,

bactericidal antimicrobials cause bacterial cell death. Antibiotic-induced lysis of

bacteria leads to the release of immunostimulatory cell-wall components and

toxic bacterial products, which induce a severe inflammatory response that

mainly occurs through binding to Toll-like receptors and the complement system.

Neonatal meningitis is largely caused by group B streptococci, E. coli, and L.

monocytogenes. Initial treatment, therefore, should consist of penicillin or

ampicillin plus a third-generation cephalosporin, preferably cefotaxime or

ceftriaxone, or penicillin or ampicillin and an aminoglycoside.1, 26, 39

In the community, children are at risk of meningitis caused by N. meningitidis

and S. pneumoniae, and, rarely in Hib-vaccinated children, H. influenzae.

Antimicrobial resistance has emerged among the three major bacterial

pathogens causing meningitis. Although intermediate penicillin resistance

is common in some countries, the clinical importance of penicillin resistance

in the meningococcus has yet to be established. Because of the resistance

patterns of these bacteria third-generation cephalosporins cefotaxime or

ceftriaxone should be used in children. 1, 12, 26, 39

Spontaneous meningitis in adults is usually caused by S. pneumoniae or N.

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meningitidis. Due to the worldwide emergence of multidrug-resistant strains

of S. pneumoniae, some experts recommend to add vancomycin to the initial

empiric antimicrobial regimen in adult patients. 1, 26, 39 Additionally, in patients

aged over 50 years treatment with ampicillin should be added to the above

antibiotic regimen for additional coverage of L. monocytogenes, which is more

prevalent among this age group. Although no clinical data on the efficacy of

rifampin in patients with pneumococcal meningitis are currently available,

some experts would recommend the use of this agent 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 cephalosporin. S.

suis remains sensitive to the β-lactams and should be treated with penicillin,

cefotaxime, or ceftriaxone. Fluoroquinolones may be an alternative.

Nosocomial post-traumatic meningitis is mainly caused by multiresistant

hospital-acquired organisms such as K. pneumoniae, E. coli, Pseudomonas

aeruginosa, and S. aureus. Depending on the pattern of susceptibility in a

given hospital unit, ceftazidime (2 g intravenously, every 8 h), cefotaxime,

ceftriaxone, or meropenem should be chosen. If P. aeruginosa infection seems

likely, ceftazidime or meropenem is the preferred antibiotic.14, 39

Device- and shunt-associated meningitis is caused by a wide range of

organisms, including methicillin-resistant staphylococci (mostly coagulase-

negative staphylococci) and multiresistant aerobic bacilli. Cases with shunts

and an insidious onset are probably caused by organisms of low pathogenicity,

and empirical therapy is a less urgent requirement. For postoperative

meningitis the first-line empirical therapy should be cefotaxime, or ceftriaxone,

or meropenem. If the patient has received broad-spectrum antibiotics recently

or if P. aeruginosa is suspected, ceftazidime or meropenem should be given.

Meropenem should be used if an extended-spectrum, β-lactamase organism

is suspected, and flucloxacillin or vancomycin if S. aureus is likely. The infected

shunt or drain will almost certainly have to be removed urgently.14

Once the aetiological agent has been isolated and its susceptibilities determined,

the empirical treatment should be changed, if necessary, to an agent or agents

specific for the isolate (Table 4). The optimal duration of treatment has not been

determined by rigorous scientific investigation; however, treatment regimens

that are probably substantially in excess of the minimum necessary to achieve

cure have been based on wide clinical experience.

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General recommendations for empirical antibiotic treatment have included

ceftriaxone administered intravenously every 12 h or intravenous cefotaxime

every 4 to 6 h, and/or ampicillin at 4-h intervals, or penicillin G every 4 h. There

are no randomized comparative clinical studies of the various dosing regimens.

In general, 7 days of antimicrobial therapy are given for meningitis caused by N.

meningitidis and H. influenzae, 10 to 14 days for S. pneumoniae, and at least 21

days for L. monocytogenes. As these guidelines are not standardized it must be

emphasized that the duration of therapy may need to be individualized on the

basis of the patient’s response. 1, 26, 39

Table 2. Recommendations for empirical antimicrobial therapy in suspected bacterial meningitis

Predisposing factor Common bacterial pathogens Initial intravenous antibiotic therapy

Age

<1 month Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes

Ampicillin plus cefotaxime or an aminoglycoside

1-3 months S. pneumoniae, Neisseria meningitidis, S. agalactiae, Haemophilus influenzae, E. coli, L. monocytogenes

Ampicillin plus vancomycine plus ceftriaxone or cefotaxime†

4-23 months S. pneumoniae, N. meningitidis, S. agalactiae, H. influenzae, E. coli

Vancomycine plus ceftriaxone or cefotaxime†

2-50 years N. meningitidis, S. pneumoniae Vancomycine plus ceftriaxone or cefotaxime†

>50 years N. meningitidis, S. pneumoniae, L. monocytogenes, aerobic gram-negative bacilli

Vancomycine plus ceftriaxone or cefotaxime plus ampicillin‡

With risk factor present¶

S. pneumoniae, L. monocytogenes, H. influenza

Vancomycine plus ceftriaxone or cefotaxime plus ampicillin

Posttraumatic S. pneumoniae, H. influenzae Vancomycine plus ceftriaxone or cefotaxime plus ampicillin

Postneurosurgery Coagulase-negative staphylococci, Staphylococcus aureus, aerobic gram-negative bacilli (including Pseudomonas aeruginosa)

Vancomycin plus ceftazidime

CSF shunt Coagulase-negative staphylococci, S. aureus, aerobic gram-negative bacilli (including Pseudomonas aeruginosa), Propionibacterium acnes

Vancomycin plus ceftazidime

†Footnote: †In areas with very low penicillin-resistance rates (as in such as the Netherlands) monotherapy penicillin may be considered. ‡In areas with very low penicillin-resistance and cephalosporin-resistance rates (as in such as the Netherlands) combination therapy of amoxicillin and third-generation cephalosporin may be considered. ¶Alcoholism, altered immune status. General recommendations for intravenous empirical antibiotic treatment have included penicillin, 2 million units every 4 hours; amoxicillin or ampicillin, 2 g every 4 hours; vancomycin, 15 mg/kg every 6-8 hours; third-generation cephalosporin: ceftriaxone, 2 g every 12 hours, or cefotaxime, 2 g every 4-6 hours; ceftazidime, 2 g every 8 hours. This material was published previously by 2 articles by van de Beek et al as part of an online supplementary appendix to reference 1 and 24. Copyright 2006 and 2010 Massachusetts Medical Society.2, 14 All rights reserved.

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Table 3. Recommendations for specific antimicrobial therapy in suspected bacterial meningitis

Micro-organism Antimicrobial therapy Duration of therapy

H. influenzae

β-lactamase negative Amoxicilline 7 days

β-lactamase positive Ceftriaxone or cefotaxime 7 days

N. meningitidis

Penicillin MIC <0.1 μg/ml Penicillin G or amoxicilline 7 days

Penicillin MIC 0.1–1.0 μg/ml Ceftriaxone or cefotaxime 7 days

S. pneumoniae

Penicillin MIC <0.1 μg/ml Penicillin G or amoxicilline 10-14 days

Penicillin MIC 0.1–1.0 μg/ml Ceftriaxone or cefotaxime 10-14 days

Penicillin MIC >2.0 μg/ml or cefotaxime / ceftriaxone MIC >1.0 mg/ml

Vancomycin plus ceftriaxone or cefotaxime

10-14 days

L. monocytogenes Penicillin G or amoxicilline >21 days

S. agalactiae Penicillin G or amoxicilline 7 days

Adjunctive dexamethasone treatment

Animal models of bacterial meningitis showed that bacterial lysis, induced

by antibiotic therapy, leads to inflammation in the subarachnoid space. The

severity of this inflammatory response is associated with outcome and can be

attenuated by treatment with steroids.40 On basis of experimental meningitis

studies, several clinical trials have been undertaken to determine the effects of

adjunctive steroids in children and adults with bacterial meningitis.41, 42

Of several corticosteroids, the use of dexamethasone in bacterial meningitis has

been investigated most extensively. Dexamethasone is a glucocorticosteroid

with anti-inflammatory as well as immunosuppressive properties and has

excellent penetration in the CSF. In a meta-analysis of randomized trials since

1988, adjunctive dexamethasone was shown to reduce meningitis-associated

hearing loss in children with meningitis due to H. influenzae type B.43

As most available studies on adjunctive dexamethasone therapy in adults with

bacterial meningitis were limited by methodological flaws, its value in adults

remained a subject of debate for a long time. In 2002, results of a European

randomized placebo-controlled trial showed that adjunctive treatment with

dexamethasone, given before or with the first dose of antimicrobial therapy,

was associated with a reduction in the risk of unfavorable outcome in adults

with bacterial meningitis (relative risk [RR] 0.59; 95 per cent confidence interval

[CI] 0.37-0.94) and with a reduction in mortality (RR 0.48; CI 0.24-0.96).44 This

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beneficial effect was most apparent in patients with pneumococcal meningitis,

in whom mortality was decreased from 34 to 14%. The benefits of adjunctive

dexamethasone therapy were not undermined by an increase of severe

neurological disability in patients who survived or by any corticosteroid-

induced complication. In a post-hoc analysis, which included only patients

with pneumococcal meningitis who died within 14 days after admission, the

mortality benefit of dexamethasone therapy was entirely due to reduced

mortality from systemic causes such as septic shock, pneumonia or acute

respiratory distress syndrome; there was no significant reduction in mortality

due to neurological causes.45

Results of a subsequent quantitative review on this topic in adults, which

included five clinical trials, confirmed that treatment with corticosteroids was

associated with a significant reduction in mortality (RR 0.6; CI 0.4-0.8) and in

neurological sequelae (RR 0.6; CI 0.4-1). The reduction in case fatality in patients

with pneumococcal meningitis was 21% (RR 0.5; CI 0.3-0.8).46 In meningococcal

meningitis, in which the number of events was smaller, there were favorable

point estimates for preventing mortality (RR 0.9; CI 0.3-2.1) and neurological

sequelae (RR 0.5; CI 0.1-1.7), but these effects did not reach statistical

significance. Adverse events were equally divided between the treatment and

placebo groups. Treatment with adjunctive dexamethasone did not worsen

long-term cognitive outcome in adults after bacterial meningitis.47 Since the

publication of these results, adjunctive dexamethasone has become routine

therapy in most adults with suspected bacterial meningitis.31

Randomized studies in adults with bacterial meningitis from Malawi and

Vietnam have been published.48, 49 In the Malawi study dexamethasone was not

associated with any significant benefit, 49 whilst in Vietnam a significant benefit

in mortality (RR 0.43, CI 0.2–0.94) was seen in patients with confirmed bacterial

meningitis only.48 A recent meta-analysis of individual patient data of 5 recent

randomized controlled trials showed no effect of adjunctive dexamethasone in

meningitis.50 Guidelines recommend routine use of adjunctive dexamethasone

in adults with pneumococcal meningitis in high-income countries.2, 39

Dexamethasone therapy has been implemented on a large scale as adjunctive

treatment of adults with pneumococcal meningitis in the Netherlands.31 The

prognosis of pneumococcal meningitis on a national level has substantially

improved after the introduction of adjunctive dexamethasone therapy with a

reduction in mortality from 30 to 20%.

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Despite these encouraging results, the use of adjunctive dexamethasone

in bacterial meningitis remains controversial in certain patients. Clearly the

results from studies in children and adults from Malawi suggests that there is

no benefit in patients in that setting compared with the results from Europe

and Vietnam and further work is needed to determine if these differences in

the efficacy of dexamethasone can be explained. Secondly, patients with

septic shock and adrenal insufficiency benefit from corticosteroid therapy in

physiological doses and for >4 days; however, when there is no evidence of

relative adrenal insufficiency, therapy with corticosteroids may be detrimental.

Results of a subsequent quantitative review on this topic that included nine

studies comparing mortality rates of corticosteroid treatment in sepsis or

septic shock showed a trend towards increased mortality associated with their

administration.51 As controlled studies of the effects of corticosteroid therapy in

a substantial number of patients with both meningitis and septic shock are not

available at present, treatment with corticosteroids cannot be recommended

unequivocally for such patients. Third, corticosteroids may potentiate ischemic

and apoptotic injury to neurons. In animal studies of bacterial meningitis

corticosteroids aggravated hippocampal neuronal apoptosis and learning

deficiencies in dosages similar to those used in clinical practice. Therefore,

concerns existed about the effects of steroid therapy on long-term cognitive

outcome. To examine the potential harmful effect of treatment with adjunctive

dexamethasone on long-term neuropsychological outcome in adults with

bacterial meningitis a follow-up study of the European Dexamethasone Study

was conducted.52 In 87 of 99 eligible patients, 46 (53%) of whom were treated

with dexamethasone and 41 (47%) of whom received placebo, no significant

differences in outcome were found between patients in the dexamethasone

and placebo groups (median time between meningitis and testing was 99

months). Therefore, treatment with adjunctive dexamethasone does not

worsen long-term cognitive outcome in adults after bacterial meningitis.

By reducing permeability of the BBB, steroids can impede penetration of

antibiotics into the CSF, as was shown for vancomycin in animal studies,53 which

can lead to treatment failures, especially in patients with meningitis due to drug-

resistant pneumococci in whom antibiotic regimens often include vancomycin.

However, an observational study, which included 14 adult patients admitted

to the intensive care unit because of suspected pneumococcal meningitis,

appropriate concentrations of vancomycin in CSF were obtained even when

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concomitant steroids were used.54 The dose of vancomycin used in this study

was 60 mg/kg/day. Although these results suggest that dexamethasone can

be used without fear of impeding vancomycin penetration into the CSF of

patients with pneumococcal meningitis (provided that vancomycin dosage is

adequate), it is recommended that patients with bacterial meningitis due to

non-susceptible strains, treated with adjunctive dexamethasone, are carefully

monitored throughout treatment.

We compared 2 cohorts of adults with culture proven bacterial meningitis:

patients from the Dutch Bacterial Meningitis Cohort Study (1998-2002),

before routine treatment with dexamethasone, with patients enrolled in

the MeninGene study (2006-2009).Chapter 4,5 In adults with meningococcal

meningitis, adjunctive dexamethasone did not influence rates of unfavorable

outcome. However, there was a favorable trend for death and hearing loss in

the meningococcal subgroup in the absence of any excess adverse events. We

therefore concluded that when the patient is identified to have meningococcal

meningitis there is no obvious reason to discontinue dexamethasone.

In pneumococcal meningitis, the outcome of adults with community-acquired

pneumococcal meningitis on a national level has significantly improved over

the last few years. We found a decline in unfavorable outcome from 50 to

39%. We used a historical cohort design to evaluate the treatment effect in

pneumococcal en meningococcal meningitis. Unknown differences between

treatment groups may have existed. However, we have corrected for known

prognostic factors and the treatment effect was consistent with the results of

the European Dexamethasone Study.44

Other adjunctive therapies

Glycerol is a hyperosmolar agent that has been used in several neurological and

neurosurgical disorders to decrease intracranial pressure. Although glycerol

has no beneficial effect in experimental meningitis models, a small randomised

clinical trial in Finland suggested that this drug might protect against sequelae

in children with bacterial meningitis.55, 56 A large study in children with bacterial

meningitis in several South American countries showed a significant decrease

in sequelae, but there were several questions about the methodology of the

trial.57 A recent trial in Malawi in adults however showed that adjuvant glycerol

was harmful and increased mortality.58 Therefore, there appears to no role for

treatment with adjuvant glycerol in bacterial meningitis in adults. For children

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the evidence is currently insufficient to justify routine glycerol treatment.

The management of adults with bacterial meningitis can be complex and

common complications are meningoencephalitis, systemic compromise, stroke

and raised intracranial pressure (Figure 2). Various adjunctive therapies have been

described to improve outcome in such patients, including anti-inflammatory

agents, anticoagulant therapies, and strategies to reduce intracranial pressure

(ICP).26 Few randomized clinical studies are available for other adjunctive

therapies than corticosteroids in adults with bacterial meningitis.

Recently a randomized controlled trial was published on adjuvant high dose

paracetamol in children with bacterial meningitis in Luanda. The trial was

performed in a 2x2 design in which simultaneously slow infusion of antibiotics

was compared to bolus injection of antibiotics. No benefit on the primary

endpoints were observed in any of the treatment groups.59

A Dutch cohort study evaluated the effects of complications on mortality in

patients with pneumococcal meningitis and compared these findings among

different age-groups. In older patients (≥60 years), death was usually a result

of systemic complications, whereas death in younger patients (<60 years) was

predominantly due to neurological complications such as brain herniation.29

This observation may be explained by age-related cerebral atrophy, which

allows elderly patients to tolerate brain swelling. These findings suggest that

supportive treatments that aim to reduce ICP could be most beneficial in

younger adults with pneumococcal meningitis. Methods available to reduce

intracranial pressure range from simple (e.g., elevation of the head of the bed

to 30°) to aggressive strategies (e.g., “Lund concept”).26, 60 However, there is no

evidence that ICP monitoring and treatment of increased ICP is beneficial in

patients with bacterial meningitis.

The rationale of hyperventilation in patients with bacterial meningitis is the

relation between cerebral arteriolar dilation, increased cerebral blood flow

(CBF) and a subsequent rise in ICP. Hyperventilation-induced hypocapnia

causes (cerebral) vasoconstriction and a reduction in CBF, resulting in lowering

of ICP.26 This approach has been used in patients with traumatic brain injury

as well; however, the enthusiasm for hyperventilation was greatly tempered

after a study on prophylactic hyperventilation in patients with severe brain

injury showed a worse outcome.26 In bacterial meningitis, patients are often

hypocapneic at the time of admission suggesting that there is spontaneous

hyperventilation.

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In patients with traumatic brain injury, studies have shown that mannitol

decreases blood viscosity and reduces the diameter of pial arterioles in a

manner similar to the vascoconstriction produced by hyperventilation.26

Although osmotic tissue dehydration may still play some role, mannitol works

primarily through its immediate rheological effect, by diluting the blood

and increasing the deformability of erythrocytes, thereby decreasing blood

viscosity ad increased CBF. This sudden increase in CBF causes autoregulatory

vasoconstriction of cerebral arterioles, decreasing the intracerebral blood

volume and lowering ICP. In bacterial meningitis, because BBB permeability has

been increased, the effect of mannitol is uncertain. There is little information

from clinical and experimental studies concerning the use of mannitol in

bacterial meningitis. A single dose of mannitol reduced ICP for approximately

3 hours in a meningitis model.(Lorenz CCM 1996) Continuous intravenous

infusion of mannitol attenuated the increases of regional CBF, brain water

content and ICP in a pneumococcal meningitis model.

Seizures occur frequently in patients with bacterial meningitis.61 These patients

tend to be older, are more likely to have focal abnormalities on brain CT and to

have S. pneumoniae as the causative micro-organism, and they have a higher

mortality. The high mortality warrants a low threshold for starting antiepileptic

therapy in those with clinical suspicion of seizures.

Recurrent bacterial meningitis

Recurrent bacterial meningitis occurs in 5% of community-acquired bacterial

meningitis cases, and most patients have a predisposing condition, particularly

head injury and CSF leak, only occasionally impairment of humoral immunity.62,

63 In patients with no apparent cause of recurrent meningitis or known history

of head trauma, the high prevalence of remote head injury and CSF leakage

justifies an active search for anatomical defects and CSF leakage. Detection of

β-2 transferrine in nasal discharge is a sensitive and specific method to confirm

a CSF leak and thin-slice CT of the skull base is best to detect small bone defects.

It should be kept in mind though that the detection of a small bone defect does

not prove CSF leakage. 3D-CISS MRI images may show CSF flow into the nasal

cavity or paranasal sinuses and may provide additional evidence for CSF leakage.

Surgical repair has a high success rate with low mortality and morbidity.

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Outcome

Community-acquired bacterial meningitis in adults is a severe disease with

high fatality and morbidity rates. Meningitis caused by S. pneumoniae has the

highest case fatality rate, reported from 19 to 37%.1, 2, 8 Whereas neurological

complications are the leading cause of death in younger patients, elderly

patients die predominantly from systemic complications. Of those who

survive, up to 50% develop long-term neurologic sequelae, including

cognitive impairment.64 Hearing loss commonly complicates pneumococcal

meningitis and is present in ~25% of patients. Serotype 23F is associated with a

significant lower risk of hearing loss, as compared with the serotype 3. Otitis on

presentation is a risk factor for developing hearing loss and otolaryngological

evaluation in these patients should be performed on admission. chapter 6

For meningococcal meningitis mortality and morbidity rates are lower, with

rates up to 5 and 7 percent, respectively. The strongest risk factors for an

unfavorable outcome in patients with bacterial meningitis are those indicative

of systemic compromise, impaired consciousness, low cerebrospinal fluid white-

cell count, and infection with S. pneumoniae.30 Recently, we have constructed

and validated a simple model for predicting outcome, using six variables that

are routinely available within one hour of admission.65 This helps to identify

high-risk individuals and provides important information for patients and their

relatives (Figure 3).

Recommendations for future research

Vaccination strategies have greatly reduced the incidence of meningococcal

disease, and the implementation of the PCV7 pneumococcal vaccine has

reduced incidence of pneumococcal meningitis in children and is beginning

to show effect of herd immunity, reducing invasive pneumococcal disease

in adults. The development of additional meningococcal vaccines, such as

meningococcal group B vaccine, will further reduce the burden of disease in

developed countries. However, acces to already existing vaccines in low-income

countries is currently the single most important factor for the reduction of the

global burden of disease in bacterial meningitis.

The importance of national and international scientific collaboration, as

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illustrated in chapters 3 and 7, is essential to the advance of clinical medicine

through translational research. Translational medicine is the integration of

basic and clinical sciences to improve diagnosis and treatment in patients.

Sharing data internationally will contribute to developing new treatments

for bacterial meningitis. As bacterial meningitis continues to cause severe

disease, further research into elucidating the mechanisms of damage caused

by inflammatory response will reveal new strategies for reducing morbidity

and mortality in bacterial meningitis. The implementation of dexamethasone

in high-income countries has been an important step in this process. Further

research into clinical applicabililty of C5-specific monoclonal antibodies is

warranted. Determining of genetic polymorphisms in individual patients may

influence vaccination and treatment strategies in the future.

Figure 3. Prediction rule for risk for unfavorable outcome in adults with bacterial meningitis

% unfavorableoutcome:

TOTAL points:

age: 20 30 40 50 60 70 80

points: 0 2 4 6 8 10 12

points: 0 1 2 4 5 6 8 9 10 12 13 14 16

Glasgow Coma Scale: 15 14 13 12 11 10 9 8 7 6 5 4 3

points: 0 10

tachycardia: No Yes

points: 0 9

cranial nerve palsy: No Yes

points: 0 13

CSF leukocyte count: High Low

points: 0 1 2 12

CSF Gram’s stain: G- No Other G+

0 5 10 15 20 25 30 35 40 45 50 55 60 65

3.2 5.1 8.2 13 20 29 40 52 64 75 83 89 93 96

Tachycardia was defined as a heart rate greater than 120 beats/min. low cerebrospinal fluid (CSF) leukocyte count was defined as <1,000 cells/mm3. Result of CSF Gram’s stain: G– = gram-negative cocci; No = no bacteria; Other = other bacterial species; G+ = grampositive cocci. Instruction: Locate the age of the patient on the top axis and determine how many points the patient receives. Repeat this for the remaining five axes. Sum the points for all six predictors and locate the total sum on the total point axis. Draw a line straight down to the axis labeled “% unfavourable outcome” to find the estimated probability of an unfavourable outcome for this patient.

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