Bacterial meningitis: current therapy and possible future treatment options

Despite targeted therapy, case-fatality rates and neurologic sequelae of bacterial meningitis remain unacceptably high. The poor outcome is mainly due to secondary systemic and intracranial complications. These complications seem to be both a consequence of the inflammatory response to the invading pathogen and release of bacterial components by the pathogen itself. Therefore, within the last decades, research has focused on the mechanism underlying immune regulation and the inhibition of bacterial lysis in order to identify new targets for adjuvant therapy. The scope of this article is to give an overview on current treatment strategies of bacterial meningitis, to summarize new insights on the pathophysiology of bacterial meningitis, and to give an outlook on new treatment strategies derived from experimental models.

Bacterial meningitis impairs hippocampal neurogenesis

Bacterial meningitis causes persisting neurofunctional sequelae. Theoccurrence of apoptotic cell death in the hippocampal subgranular zone of the dentate gyrus characterizes the disease in patients and relates to deficits in learning and memory in corresponding experimental models. Here, we investigated why neurogenesis fails to regenerate the damage in the hippocampus associated with the persistence of neurofunctional deficits. In an infant rat model of bacterial meningitis, the capacity of hippocampal-derived cells to multiply and form neurospheres was significantly impaired comparedto that in uninfected littermates. In an in vitro model of differentiating hippocampal cells, challenges characteristic of bacterial meningitis (i.e. bacterial components, tumor necrosis factor [20 ng/mL], or growth factor deprivation) caused significantly more apoptosis in stem/progenitor cells and immature neurons than in mature neurons. These results demonstrate that bacterial meningitis injures hippocampal stem and progenitor cells, a finding that may explain the persistence of neurofunctional deficits after bacterial meningitis.

SNPs in DNA repair genes associated to meningitis and host immune response

In vitro and in animal models, APE1, OGG1, and PARP-1 have been proposed as being involved with inflammatory response. In this work, we have investigated if the SNPs APE1 Asn148Glu, OGG1 Ser326Cys, and PARP-1 Val762Ala are associated to meningitis. The patient genotypes were investigated by PIRA-PCR or PCR-RFLP. DNA damages were detected in genomic DNA by Fpg treatment. IgG and IgA were measured from plasma and the cytokines and chemokines were measured from cerebrospinal fluid samples using Bio-Plex assays. A higher frequency (P<0.05) of APE1 Glu allele in bacterial meningitis (BM) and aseptic meningitis (AM) patients was observed. The genotypes Asn/Asn in control group and Asn/Glu in BM group was also higher. For the SNP OGG1 Ser326Cys, the genotype Cys/Cys was more frequent (P<0.05) in BM group. The frequency of PARP-1 Val/Val genotype was higher in control group (P<0.05). The occurrence of combined SNPs is significantly higher in BM patients, indicating that these SNPs may be associated to the disease. Increasing in sensitive sites to Fpg was observed in carriers of APE1 Glu allele or OGG1 Cys allele, suggesting that SNPs affect DNA repair activity. Alterations in IgG production were observed in the presence of SNPs APE1 Asn148Glu, OGG1 Ser326Cys or PARP-1 Val762Ala. Moreover, reduction in the levels of IL-6, IL-1Ra, MCP-1/CCL2 and IL-8/CXCL8 was observed in the presence of APE1 Glu allele in BM patients. In conclusion, we obtained indications of an effect of SNPs in DNA repair genes on the regulation of immune response in meningitis.

Association of kynurenine aminotransferase II gene C401T polymorphism with immune response in patients with meningitis

The kynurenine (KYN) pathway has been shown to be altered in several diseases which compromise the central nervous system (CNS) including infectious diseases such as bacterial meningitis (BM). The aim of this study was to assess single nucleotide polymorphisms (SNPs) in four genes of KYN pathway in patients with meningitis and their correlation with markers of immune response in BM.

The formyl peptide receptor like-1 and scavenger receptor MARCO are involved in glial cell activation in bacterial meningitis

Recent studies have suggested that the scavenger receptor MARCO (macrophage receptor with collagenous structure) mediates activation of the immune response in bacterial infection of the central nervous system (CNS). The chemotactic G-protein-coupled receptor (GPCR) formyl-peptide-receptor like-1 (FPRL1) plays an essential role in the inflammatory responses of host defence mechanisms and neurodegenerative disorders such as Alzheimer's disease (AD). Expression of the antimicrobial peptide cathelicidin CRAMP/LL-37 is up-regulated in bacterial meningitis, but the mechanisms underlying CRAMP expression are far from clear.

Meningitis caused by Mycoplasma mycoides subspecies capri in a goat

A 2-year-old, female goat from Connecticut was submitted for necropsy with a 5-day history of pyrexia and intermittent neurologic signs, including nystagmus, seizures, and circling. Postmortem examination revealed suppurative meningitis. Histologic examination of the brain revealed that the meninges were diffusely infiltrated by moderate numbers of lymphocytes, macrophages, and fibrin, with scattered foci of dense neutrophilic infiltrate. Culture of pus and brainstem yielded typical mycoplasma colonies. DNA sequencing of the 16S ribosomal RNA gene revealed 99% sequence homology with Mycoplasma mycoides subspecies capri and Mycoplasma mycoides subspecies mycoides Large Colony biotype, which are genetically indistinguishable and likely to be combined as a single subspecies labeled M. mycoides subsp. capri. The present case is unusual in that not only are mycoplasma an uncommon cause of meningitis in animals, but additionally, in that all other reported cases of mycoplasma meningitis in goats, systemic lesions were also present. In the present case, meningitis was the only lesion, thus illustrating the need to consider mycoplasma as a differential diagnosis for meningitis in goats.

Inflammasome-dependent IFN-γ drives pathogenesis in Streptococcus pneumoniae meningitis

The pathology associated with Streptococcus pneumoniae meningitis results largely from activation of immune-associated pathways. We systematically investigated the production of IFN subtypes, as well as their influence on pathology, in a mouse model of S. pneumoniae meningitis. Despite the occurrence of a mixed IFN type I/II gene signature, no evidence for production or involvement of type I IFNs in disease progression was found. In contrast, type II IFN (IFN-γ) was strongly induced, and IFN-γ(-/-) mice were significantly protected from severe disease. Using intracellular cytokine staining and targeted cell-depletion approaches, NK cells were found to be the dominant source of IFN-γ. Furthermore, production of IFN-γ was found to be dependent upon ASC and IL-18, indicating that an ASC-dependent inflammasome pathway was responsible for mediating IFN-γ induction. The influence of IFN-γ gene deletion on a range of processes known to be involved in bacterial meningitis pathogenesis was examined. Although neutrophil numbers in the brain were similar in infected wild-type and IFN-γ(-/-) mice, both monocyte recruitment and CCL2 production were less in infected IFN-γ(-/-) mice compared with infected wild-type controls. Additionally, gene expression of NO synthase was strongly diminished in infected IFN-γ(-/-) mice compared with infected controls. Finally, bacterial clearance was enhanced in IFN-γ(-/-) mice, although the underlying mechanism remains unclear. Together, these data suggest that inflammasome-dependent IFN-γ contributes via multiple pathways to pathology during S. pneumoniae meningitis.

Daptomycin is more efficacious than vancomycin against a methicillin-susceptible Staphylococcus aureus in experimental meningitis

OBJECTIVES: To test the efficacy of daptomycin, a cyclic lipopeptide antibiotic, against a methicillin-susceptible Staphylococcus aureus strain in experimental rabbit meningitis and to determine its penetration into non-inflamed and inflamed meninges RESULTS: Over a treatment period of 8 h, daptomycin (15 mg/kg) was significantly superior to the comparator regimen vancomycin (-4.54 +/- 1.12 log(10)/mL for daptomycin versus -3.43 +/- 1.17 log(10)/mL for vancomycin). Daptomycin managed to sterilize 6 out of 10 CSFs compared with 4 out of 10 for vancomycin. The penetration of daptomycin into inflamed meninges was approximately 5% and approximately 2% into non-inflamed meninges. CONCLUSIONS: The superior bactericidal activity of daptomycin was confirmed in vivo and in time-killing assays in vitro.

Gelatinase B [matrix metalloproteinase (MMP)-9] and collagenases (MMP-8/-13) are upregulated in cerebrospinal fluid during aseptic and bacterial meningitis in children

We investigated the protein expression of gelatinases [matrix metalloproteinase (MMP)-2 and -9] and collagenases (MMP-8 and -13) in cerebrospinal fluid (CSF) from patients with bacterial (BM, n = 17) and aseptic (AM, n = 14) meningitis. In both, MMP-8 and -9 were increased in 100% of patients, whereas MMP-13 was detectable in 53% and 82% respectively. Three patients with clinical signs of meningitis, without CSF pleocytosis, scored positive for all three MMPs. MMP-8 appeared in two isoforms, granulocyte-type [polymorphonuclear cell (PMN)] and fibroblast/macrophage (F/M) MMP-8. Analysis of kinetic changes from serial lumbar punctures showed that these MMPs are independently regulated, and correlate only partly with CSF cytosis or levels of the endogenous inhibitor, tissue inhibitor of matrix metalloproteinase-1. In vitro, T cells, peripheral blood mononuclear cells (PBMCs) and granulocytes (PMN) release MMP-8 and -9, whereas MMP-13 could be found only in the former two cell types. Using models of exogenous (n-formyl-Met-Leu-Phe, T cell receptor cross-linking) and host-derived stimuli (interleukin-2), the kinetics and the release of the MMP-8, -9 and -13 showed strong variation between these immune cells and suggest release from preformed stocks. In addition, MMP-9 is also synthesized de novo in PBMCs and T cells. In conclusion, invading immune cells contribute only partially to MMPs in CSF during meningitis, and parenchymal cells are an equally relevant source. In this context, in patients with clinical signs of meningitis, but without CSF pleocytosis, MMPs seem to be a highly sensitive marker for intrathecal inflammation. The present data support the concept that broad-spectrum enzyme inhibition targeting gelatinases and collagenases is a potential strategy for adjunctive therapy in infectious meningitis.

Temporal expression of inflammatory mediators in brain basilar artery vasculitis and cerebrospinal fluid of rabbits with coccidioidal meningitis

Strokes due to transmural vasculitis associated with coccidioidal meningitis result in significant morbidity and mortality. The immunological and inflammatory processes responsible are poorly understood. To determine the inflammatory mediators, i.e. cytokines, chemokines, iNOS, matrix metalloproteinase-9 (MMP-9), that possibly contribute to vasculitis, temporal mRNA expression in brain basilar artery samples and MMP-9 protein in the CSF of male NZW rabbits infected intracisternally with 6.5 x 10(4) arthroconidia of Coccidioides immitis were assessed. Five infected and 3 sham-injected rabbits at each time point were euthanized 4, 9, 14 and 20 days post infection. All infected rabbits had neurological abnormalities and severe vasculitis in the basilar arteries on days 9-20. In basilar arteries of infected animals versus controls, mRNAs encoding for IL-6, iNOS, IFN-gamma, IL-2, MCP-1, IL-1beta, IL-10, TNF-alpha, CCR-1, MMP-9, TGF-beta, as well as MMP-9 protein in CSF, were found to be significantly up-regulated. Thus, this study identified inflammatory mediators associated with CNS vasculitis and meningitis due to C. immitis infection. Assessment of the individual contribution of each mediator to vasculitis may offer novel approaches to the treatment of coccidioidal CNS infection. This study also provides unique methodology for immunology studies in a rabbit model.

No temporal association between influenza outbreaks and invasive pneumococcal infections

OBJECTIVE: To assess whether the influenza peak in populations precedes the annual peak for invasive pneumococcal infections (IPI) in winter. DESIGN: Ecological study. Active surveillance data on influenza A and IPI in children up to 16 years of age collected from 1997 to 2003 were analysed. SETTING: Paediatric hospitals in Germany. Patients: Children under 16 years of age. RESULTS: In all years under study, the influenza A season did not appear to affect the IPI season (p = 0.49). Specifically, the influenza peak never preceded the IPI peak. CONCLUSION: On a population level there was no indication that the annual influenza epidemic triggered the winter increase in the IPI rate or the peak of the IPI distribution in children.

Cerebral vasculature is the major target of oxidative protein alterations in bacterial meningitis

We have previously shown that antioxidants such as a-phenyl-tert-butyl nitrone or N-acetylcysteine attenuate cortical neuronal injury in infant rats with bacterial meningitis, suggesting that oxidative alterations play an important role in this disease. However, the precise mechanism(s) by which antioxidants inhibit this injury remain(s) unclear. We therefore studied the extent and location of protein oxidation in the brain using various biochemical and immunochemical methods. In cortical parenchyma, a trend for increased protein carbonyls was not evident until 21 hours after infection and the activity of glutamine synthetase (another index of protein oxidation) remained unchanged. Consistent with these results, there was no evidence for oxidative alterations in the cortex by various immunohistochemical methods even in cortical lesions. In contrast, there was a marked increase in carbonyls, 4-hydroxynonenal protein adducts and manganese superoxide dismutase in the cerebral vasculature. Elevated lipid peroxidation was also observed in cerebrospinal fluid and occasionally in the hippocampus. All of these oxidative alterations were inhibited by treatment of infected animals with N-acetylcysteine or alpha-phenyl-tert-butyl nitrone. Because N-acetylcysteine does not readily cross the blood-brain barrier and has no effect on the loss of endogenous brain antioxidants, its neuroprotective effect is likely based on extraparenchymal action such as inhibition of vascular oxidative alterations.