Fisiopatología de La Meningitis Bacteriana

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New understandings on the pathophysiology of

bacterial meningitis
Uwe Koedel, Matthias Klein and Hans-Walter Pfister
Department of Neurology, Klinikum Grosshadern, Purpose of review
Ludwig Maximilians University, Munich, Germany
Currently, dexamethasone is the only adjuvant of proven benefit in bacterial meningitis.
Correspondence to Uwe Koedel, Clinics of the Dexamethasone halves the risk of poor outcome, but only in selected patient groups.
Ludwig-Maximilians-University, Department of
Neurology, Marchioninistr. 15, D-81377 Munich, New therapies based upon an understanding of the pathophysiology are needed.
Germany This article summarizes our knowledge on the pathophysiology of bacterial meningitis
Fax: +49 89 7095 5561;
e-mail: Uwe.Koedel@med.uni-muenchen.de with special emphasis on pneumococcal meningitis, the experimentally best
characterized subtype.
Current Opinion in Infectious Diseases 2010,
23:217–223
Recent findings
Experimental studies made clear that the harmful inflammatory reaction is initiated by the
interaction of bacterial products with host pattern recognition receptors (PRRs) such as
Toll-like receptors. PRR signalling leads to MyD88-dependent production of
proinflammatory cytokines of the interleukin-1 family. Secretion of interleukin-1 family
cytokines forms a positive feedback loop that boosts MyD88-dependent production of
proinflammatory mediators. As a consequence, great numbers of neutrophils are
recruited to the subarachnoid space. Activated neutrophils release many potentially
cytotoxic agents including oxidants and matrix metalloproteinases that can cause
collateral damage to brain tissue. Additionally to the inflammatory response, direct
bacterial cytotoxicity has been identified as a contributor to tissue damage.
Summary
Promising pathophysiologically targeted approaches for adjunctive therapy of acute
bacterial meningitis include limiting the release of toxic bacterial products (e.g.
nonbacteriolytic antibiotics) and interfering in the generation of host-derived cytotoxins.

Keywords
daptomycin, rifampicin, roscovitine, Streptococcus pneumoniae

Curr Opin Infect Dis 23:217–223


ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
0951-7375

with adjunctive anti-inflammatory steroids in pneumo-


Introduction coccal meningitis. Nowadays, corticosteroids are recom-
Even though antibiotic therapy has made acute bacterial mended for adjunctive therapy in selected patients,
meningitis curable, it remains a life-threatening disease namely adults in high-income countries and areas with
with high case fatality rates of up to 34% for Streptococcus a low HIV prevalence [11,12]. Apart from applicability
pneumoniae and 10% for Neisseria meningitidis, the two restrictions, adjunctive corticosteroids also do not give
most common pathogens of such infections beyond the complete protection. Still, every seventh adult patient
neonatal period [1–3]. Long-term neuropsychological with pneumococcal meningitis dies, and each fourth
and otological sequelae are also a major concern, affecting patient remains with neurological and/or otological def-
up to 50% of survivors [4,5]. Clinical and neuropatho- icits [13]. Also noteworthy in this respect, Schut et al.
logical studies have indicated that an unfavourable out- [14] recently described the occurrence of delayed
come of bacterial meningitis is often caused by intracra- cerebral thrombosis after primary good recovery in six
nial complications, including raised intracranial pressure, patients receiving corticosteroids during initial therapy of
brain oedema formation, and cerebrovascular ischaemia pneumococcal meningitis. The authors suggested that
[6,7,8]. Fifty years ago, Johnson and colleagues [9] cerebral thrombosis might have occurred as a late com-
already hypothesized that ‘the majority of the changes plication of corticosteroid therapy. Altogether, there is
producing death are related primarily to the exudative still the urgent need for novel adjunctive treatment
response of the host and the acute and chronic inflam- strategies for bacterial meningitis. In an Editorial Com-
matory changes that follow’. In line with this hypothesis, ment in Neurology [15], K.L. Tyler wrote that ‘it is likely
Ribble and Braude [10] reported first promising results that the key to further reductions in mortality and
0951-7375 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/QCO.0b013e328337f49e

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
218 Paediatric and neonatal infections

morbidity will lie with more pathophysiologically tar- Immune activation in the CSF space
geted approaches’. Here, we give an overview of the When S. pneumoniae arrive unscathed at the stationary
current knowledge on the pathophysiology of bacterial phase or are damaged by a harsh environment (such as
meningitis, using the example of pneumococcal menin- exposure to antibiotics), the pathogens undergo autolysis
gitis, the experimentally best characterized subtype. We [29]. Autolysis results in the release of subcapsular bac-
further describe two potentially promising targets for terial components including peptidoglycan, lipoteichoic
adjunctive therapy of meningitis. acid (LTA), pneumolysin (PLY), and bacterial DNA
[30,31]. Pneumococcal cell wall products were indicated
to be the key triggers of the host inflammatory response
Molecular pathophysiology of pneumococcal during meningitis [32,33]. Intracisternal inoculation of
meningitis cell wall components was shown to be sufficient for
Pneumococcal meningitis typically develops when the triggering meningeal inflammation and also for inducing
subarachnoid space becomes infected, either from pneu- clinical symptoms of meningitis [34]. The greater the
mococci spread haematogenously from the nasopharynx amount of cell wall components in the CSF, the worse the
(predominant route in neonates and children) or con- clinical outcome of the disease [35]. All in all, it is
tinuously from focal infections in the vicinity of the virtually certain that bacterial products ‘can do it all’
subarachnoid space (e.g. mastoiditis, the mostly used when it comes to initiation of the host immune response
route in adults). in meningitis (Fig. 1). The essential question, however, is
how bacterial products can trigger meningeal inflam-
Survival of pathogens in the cerebrospinal fluid mation. First insight into the underlying mechanisms
From an immunological point of view, the subarachnoid has been provided by overexpression assays in vitro.
space is a unique site of the body. It has several features When cell lines were transfected with TLR2, they
in common with other so-called immune-privileged became responsive to S. pneumoniae [36,37]. The cell
organs like the brain [16]. First, the subarachnoid cavity wall components, peptidoglycan and LTA, were ident-
lacks a fully organized drainage by lymphatic vessels ified as the main pneumococcal ligands for TLR2 [38,39].
[17]. Second, soluble pattern recognition receptors TLR2 was reported to recognize LTA in cooperation
(PRRs, e.g. complement factors) that recognize bacteria with TLR1 [40] and with the help of CD14 [39]. More-
and enhance their uptake by phagocytes are largely over, the pneumococcal toxin PLY was described to
absent [18,19]. Third, specialized blood–cerebrospinal engage and signal trough TLR4 [36]. In addition,
fluid (CSF) barriers seclude the CSF space from circu- TLR9 was reported to interact with isolated genomic
lating blood and prevent most blood components from DNA from S. pneumoniae [41]. Further studies using
entering [20]. Fourth, normal CSF contains an array of primary immune cells from gene-deficient mice
anti-inflammatory and immunosuppressive factors that [42,43] pointed out that a single deficiency of TLR2,
actively suppress the immune reactivity [16]. However, TLR4 or TLR9 caused only selective and relatively
in contrast to the brain, functionally active macrophages modest reductions in cytokine production, whereas the
and dendritic cells are present in tissues lining the CSF, combined loss of TLR2, TLR4 and TLR9 led to a nearly
namely the leptomeninges, the perivascular spaces, and complete cellular unresponsiveness to S. pneumoniae. All
the choroid plexus [21,22]. These cells can function as this suggests that distinct TLRs have to synergize to fully
sentinel cells and recognize bacteria in the CSF through activate an immune response to S. pneumoniae.
PRRs. Among the PRRs expressed there are macrophage
scavenger receptors, the mannose receptor, and comp- Substantial evidence for the involvement of TLRs in
lement receptors which bind to bacteria and mediate vivo in pneumococcal meningitis came from studies in
their internalization by phagocytes [23–25]. Moreover, mice lacking functional MyD88 which is used by all
signalling PRRs, such as Toll-like receptors (TLRs), are TLRs except TLR3. In experimental pneumococcal
present on and in immunocompetent cells within the meningitis, MyD88-deficient mice showed a dramatic-
brain [26,27]. All in all, these properties make the CSF ally impaired host defence, as evidenced by substantially
space a body compartment with normally suppressed higher bacterial loads in the brain or blood [44].
(but inducible) immune reactivity. As a consequence, This higher susceptibility was due to a defective host
when bacteria enter the CSF, they can multiply easily, immune response inside the CSF. Compared to infected
reaching similar high titres as under bacterial culture wild-type mice, MyD88-deficient mice showed a 80%
conditions [28]. Once high densities are reached, resi- reduction in CSF leukocyte counts, which was associated
dent immunocompetent cells are activated. The delay of with a nearly complete abrogation of the expression
the immune response seems to be primarily due to a local of proinflammatory cytokines and chemokines in the
lack of soluble PRRs that flag pathogens for recognition brain. By utilizing mice with single or combined
by immune cells, as well as the local expression of deficiencies of TLR2, TLR4 and TLR9, we were able
immunosuppressive factors. to demonstrate that both TLR2 and TLR4 play a crucial

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
New therapies for bacterial meningitis Koedel et al. 219

Figure 1 Schematic diagram of the major pathogenic steps of pneumococcal meningitis

Pneumococcal meningitis develops when the pathogen reaches the cerebrospinal fluid (CSF)-filled subarachnoid space either by a haematogenous
route or by direct migration from nearby infection (e.g. sinusitis, mastoiditis). Autolysis of Streptococcus pneumoniae results in the release of
subcapsular bacterial components like lipoteichoic acid or pneumolysin. The presence of these bacterial products is recognized by resident
immunocompetent cells by means of pattern recognition receptors which leads to cell activation and the production of cytokines and chemokines (like
IL-1ß or CXCL1,2,5). Consequently, large numbers of neutrophils are recruited into the CSF, which also liberate proinflammatory and chemotactic
agents, thereby exaggerating and perpetuating inflammation. Among the factors released by neutrophils are also numerous cytotoxic products such as
oxidants that can cause collateral damage of brain tissue (by inducing apoptosis or necrosis). Host-derived cytotoxins can also induce vascular injury,
leading to, for example, the formation of vasogenic brain oedema or blood clots with subsequent cerebral hypoperfusion. In addition to inflammation-
induced damage, pneumococci-derived cytotoxic products like pneumolysin or hydrogen peroxide can contribute to vascular and neuronal injury in
meningitis. RBC, red blood cell.

role in pneumococcal meningitis [43]: Infected MyD88-dependent production of IL-1 family cytokines.
TLR2–TLR4-double-deficient mice developed a 50% Secretion of IL-1 family cytokines forms a positive feed-
reduction of CSF pleocytosis and a selective inhibition of back loop that boosts the MyD88-dependent production
cytokine production, whereas the single deficiency of inflammatory mediators. As a consequence, large
either of TLR2 or TLR4 had no impact on meningeal numbers of blood-borne leukocytes, predominantly
inflammation. Moreover, additional TLR9 deficiency neutrophils, are recruited into the CSF.
did not result in further attenuation of the inflammatory
reaction observed in TLR2–TLR4-double-deficient Neutrophil and pathogen-dependent mechanisms of
mice [43]. The observation that TLR2–TLR4- tissue injury
double-deficient mice were less severely impaired in The hypothesis that the inflammatory response does
their immune response than MyD88-deficient mice more harm than good [9] was clearly validated by mouse
suggests that the MyD88 phenotype may be – at least studies that demonstrated substantial reductions in vas-
partly – due to the blocking of secondary autocrine cular and neuronal injury when neutrophils had been
effects of interleukin (IL)-1 family cytokines. This con- depleted [48,49].
cept is supported by studies in mice with deficiencies of
individual genes of the IL-1/IL-18 pathway. For If activated neutrophils do not quickly encounter their
example, mice lacking caspase-1, which is crucial for microbial targets, they respond by releasing all their
the generation of active IL-1 and IL-18, showed a antimicrobial weapons into the extracellular space.
strongly diminished inflammatory host response to pneu- Among the major effector molecules in the neutrophils’
mococci in the CSF [45]. Moreover, IL-1R and IL-18 arsenal are strong oxidants like peroxynitrite. Peroxyni-
deficiency was associated with a suppressed inflamma- trite can exert a vast variety of cytotoxic effects, for
tory response [46,47]. example through lipid peroxidation, DNA strand break-
age, or matrix metalloproteinase (MMP) activation [50].
Combined, TLR2 and TLR4 act as sensors of pneumo- Oxidative alterations to vital macromolecules were
coccal infection of the CSF. Their activation leads to repeatedly demonstrated in CSF and brain samples of

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
220 Paediatric and neonatal infections

patients and rodents who died of meningitis [51–54]. In have been evaluated in animal models of pneumococcal
humans suffering from meningitis, high-grade oxidative meningitis. Rifampicin inhibits DNA-dependent RNA
stress was also associated with an unfavourable outcome polymerase in bacterial cells by binding its ß-subunit,
[51]. Moreover, animal studies have provided evidence thus preventing transcription to RNA and subsequent
that antioxidant therapy (e.g. N-acetyl-L-cysteine) can translation to proteins [67]. Daptomycin, on the contrary,
be protective against vascular, neuronal, and cochlear is inserted into the bacterial cell wall, resulting in con-
injury in pneumococcal meningitis [54–56]. Apart from secutive pore formation, loss of electrical membrane
oxidants, potent proteolytic enzymes such as MMPs are potential, and inhibition of peptidoglycan synthesis
released from granules of activated neutrophils. MMPs, [68,69]. Due to its lipophilic nature, rifampicin diffuses
in particular MMP-9, were found in high concentrations efficiently into the CSF, even in the presence of steroids
in CSF samples obtained either from patients with bac- [70,71]. Data on the CSF penetration of daptomycin are
terial meningitis or animals with experimental meningitis limited and inconclusive [72,73]. However, in an infant
[57]. CSF levels of MMP-9 were reported to be higher in rat model of pneumococcal meningitis, daptomycin
patients with hearing impairment and/or epileptic sei- monotherapy was found to clear bacteria more efficiently
zures than in those who recovered without any neuro- from the CSF than ceftriaxone, to reduce the inflamma-
logical deficits [58]. Studies with pharmacologic inhibi- tory host reaction, and to prevent the development of
tors revealed that MMPs contribute to blood–brain cortical injury [74]. Similar protective effects were also
barrier breaching and neuronal injury in experimental obtained with rifampicin monotherapy in rabbit and
meningitis [59,60]. mouse meningitis models [75,76]. Since neither rifampi-
cin (due to the rapid development of bacterial resistance)
In addition to inflammation-induced collateral damage, nor daptomycin (due to a lack of efficacy against pneu-
direct bacterial toxicity was implicated as a factor driving mococcal pneumonia) can be used as a single agent for
cochlear and neuronal damage in meningitis [61]. Incu- the treatment, recent studies assessed whether combin-
bation of brain cells with strains defective in pneumo- ing these drugs with ceftriaxone is superior to ceftriaxone
lysin and/or hydrogen peroxide production was associ- monotherapy. In a rabbit model, short-term pretreatment
ated with a reduction of cellular damage [62,63]. In with rifampicin reduced the b-lactam-induced release of
addition, application of these toxins in purified form bacterial products, attenuated inflammation, and thereby
induced neuronal and endothelial cell death in vitro decreased neuronal cell loss [77,78]. In an infant rat
[63]. Finally, intracisternal inoculation of strains model, co-therapy of rifampicin with ceftriaxone also
deficient in pneumolysin, autolysin or hydrogen per- lowered CSF inflammation, but did not attenuate brain
oxide production significantly lowered cochlear and damage and hearing loss. In contrast, the combination of
neuronal injury, compared with the sufficient strain daptomycin with ceftriaxone led to less neuronal injury
[63,64,65]. and improved hearing capacity [79]. This discrepancy,
and also open questions such as the comparison of anti-
All in all, meningitis-induced tissue injury is dependent biotic co-therapies with standard therapy (antibiotics
on the release of both host-derived and bacterial toxins, and dexamethasone) underline the need for further
suggesting that an ideal therapy for bacterial meningitis experimental investigations before clinical trials can be
should interfere with both kinds of toxins. attempted.

Removing neutrophils safely


Promising targets for adjunctive therapy Experimental data suggested that an enhanced lifespan
Experimental work in animals suggests great potential for of activated neutrophils in the CSF substantially contrib-
nonbacteriolytic killing of pathogens and/or for silent utes to massive leukocyte accumulation and, thus,
removal of neutrophils from the CSF in the adjunctive meningitis-induced tissue injury [48,80]. Recently, Rossi
therapy of bacterial meningitis. and colleagues [81] made the interesting observation that
cyclin-dependent kinase inhibitors like roscovitine can
Killing bacteria softly induce caspase-dependent apoptosis in neutrophils and
ß-Lactam antibiotics which belong to the standard thera- are capable of overriding powerful antiapoptosis signals
peutic regimen in pneumococcal meningitis activate a from survival factors. Using an adult mouse model of
crucial pneumococcal autolysin, resulting in an abrupt pneumococcal meningitis, our group demonstrated that
release of subcapsular bacterial components [66]. This adjunctive therapy with roscovitine significantly attenu-
causes a strong, albeit transient, boost of meningeal ated CSF pleocytosis without affecting antibiotic-
inflammation and cytotoxicity. (Highly) bacteriocidal induced bacterial clearance [49]. Analysis of cell com-
but nonbacteriolytic antibiotics may therefore represent position in the CSF of roscovitine-treated mice revealed
a major chance for meningitis therapy. Up till now, two increased numbers of apoptotic neutrophils, suggesting
nonbacteriolytic antibiotics, rifampicin and daptomycin, apoptosis induction as the likely mechanism underlying

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
New therapies for bacterial meningitis Koedel et al. 221

the reduction of CSF pleocytosis. These effects were


associated with an improved recovery, as evidenced by References and recommended reading
Papers of particular interest, published within the annual period of review, have
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rating scales, and a lower mortality rate. Thus, limiting  of special interest
 of outstanding interest
the lifespan of neutrophils in the inflamed CSF seems to Additional references related to this topic can also be found in the Current
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The authors’ research is funded by the Deutsche Forschungs- Study of six selected patients with stroke complicating pneumococcal meningitis,
Gemeinschaft, the Else Kroener-Fresenius-Foundation, and the Menin- pointing at delayed stroke as a possible side effect of corticosteroid therapy in
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