Pathogenesis of bacterial meningitis: contributions by experimental models in rabbits

Rabbits models of bacterial meningitis have contributed substantially to our understanding of the disease, although the technical characteristics of these models only allow the study of specific aspects of the disease. Bacterial multiplication in the subarachnoidal space is not substantially influenced by host defense mechanisms, mainly because of the lack of sufficient amounts of specific antibodies and functional complement in infected CSF. The multiplying bacteria induce profound changes in the blood-brain barrier, an influx of serum proteins into the CSF and the invasion of polymorphonuclear leukocytes at the site of the infection. The presence of polymorphonuclear leukocytes in CSF not only appears to be of limited value in combating the infection, but also seems to produce deleterious effects on the central nervous system. Components of the leukocytes, such as unsaturated fatty acids, arachidonic metabolites and free oxygen radicals, may contribute to the profound hydrodynamic, structural and metabolic changes that are currently under study in experimental models of the disease. A better understanding of the pathophysiology of bacterial meningitis may allow us to design more effective therapeutic strategies and improve the outcome of this disease.

Brain levels of neuropeptide Y in experimental pneumococcal meningitis

Neuropeptide Y (NPY), which is found in high concentrations in several regions of the brain including nuclei of the brain stem and in nerve fibers surrounding cerebral vessels, has been proposed to play a role in regulating cerebral blood flow (CBF) and systemic vegetative functions. Since CBF is altered during meningitis, we examined whether NPY concentrations changed in various regions of the rabbit brain in response to experimental pneumococcal meningitis. Changes were most pronounced in the medulla, where NPY concentration increased threefold after 48 h of infection. Concomitantly, there was an increase in NPY immunoreactive fibers surrounding small vessels in the dorsolateral medulla, especially in the nucleus tractus solitarius. These results suggest that NPY may play a role in inducing some of the hemodynamic changes seen during pneumococcal meningitis.

Oral SCH 39304 as primary, salvage, and maintenance therapy for cryptococcal meningitis in AIDS

To determine the efficacy and toxicity of SCH 39304 in the treatment and suppression of cryptococcal meningitis, we conducted a prospective, noncomparative study in three groups of patients: patients with acute cryptococcal meningitis, patients with acute cryptococcal meningitis in whom other therapies have failed (salvage), and patients who required maintenance therapy. As primary therapy, the patients received up to 14 days or 1 g of amphotericin B followed by SCH 39304 200 mg once daily for 12 weeks. As maintenance therapy, the patients received SCH 39304 600 mg once weekly for 12 months. Of five salvage patients, none completed the study. Two patients died, two patients clinically deteriorated, and one patient was noncompliant. Two of three patients with acute cryptococcal meningitis completed the 12-week primary therapy, and one patient was discontinued from therapy because of a skin rash (95% confidence interval, 14-100%). All four patients who were receiving weekly maintenance therapy followed up to 27 weeks were clinically stable with no change in their serum cryptococcal antigen titer from baseline when the study was prematurely terminated. Elevation of liver function test results developed in three patients and skin rash developed in one patient. The unique pharmacologic and pharmacokinetic properties of SCH 39304 (low incidence of toxicity, long serum half-life, and good penetration into the cerebrospinal fluid) lend promise to pursue other triazole antifungals at higher doses as primary therapy and less frequent dosing for maintenance therapy.

Pharmacodynamics of antibiotics in experimental bacterial meningitis--two sides to rapid bacterial killing in the cerebrospinal fluid

In bacterial meningitis, several pharmacodynamic factors determine therapeutic success--when defined as sterilization of the cerebrospinal fluid (CSF); (i) local host defense deficits require the use of bactericidal antibiotics; (ii) CSF antibiotic concentrations that are at least 10-fold above the MBC are necessary for maximal bactericidal activity; (iii) high CSF peak concentrations that lead to rapid bacterial killing appear more important than prolonged suprainhibitory concentrations, probably because very low residual levels in the CSF prevent bacterial regrowth even during relatively long dosing intervals; (iv) penetration of antibiotics into the CSF is significantly impaired by the blood-brain barrier, thus requiring high serum levels to achieve the CSF concentrations necessary for rapid bacterial killing. Beyond these principles, recent data suggest that rapid lytic killing of bacteria in the CSF may have harmful effects on the brain because of the release of biologically active bacterial products. The conflict between the need for rapid CSF sterilization and the harmful consequences of bacterial lysis must be addressed in the therapy of meningitis.

JNK is activated but does not mediate hippocampal neuronal apoptosis in experimental neonatal pneumococcal meningitis

Pneumococcal meningitis is associated with caspase 3-dependent apoptosis of recently post-mitotic immature neurons in the dentate gyrus of the hippocampus. The death of these cells is implicated in the learning and memory deficits in patients surviving the disease. The stress-activated protein kinase c-Jun N-terminal kinase (JNK) has been shown to be an important mediator of caspase 3-dependent neuronal apoptosis. However, whether JNK is involved in hippocampal apoptosis caused by pneumococcal meningitis has so far not been investigated. Here we show in a neonatal rat model of pneumococcal meningitis that JNK3 but not JNK1 or JNK2 is activated in the hippocampus during the acute phase of infection. At the cellular level, JNK3 activation was accompanied in the dentate gyrus by markedly increased phosphorylation of its major downstream target c-Jun in early immature (Hu-positive) neurons, but not in migrating (doublecortin-positive) neurons, the cells that do undergo apoptosis. These findings suggested that JNK may not be involved in pneumococcal meningitis-induced hippocampal apoptosis. Indeed, although intracerebroventricular administration of D-JNKI-1 or AS601245 (two highly specific JNK inhibitors) inhibited c-Jun phosphorylation and protein expression in the hippocampus, hippocampal apoptosis was unaffected. Collectively, these results demonstrate that JNK does not mediate hippocampal apoptosis in pneumococcal meningitis, and that JNK may be involved in processes unrelated to apoptosis in this disease.

General laboratory diagnostics of eosinophilic GI diseases

Eosinophils and gastrointestinal tract interact in an intimate and enigmatic relationship. Under inflammatory conditions, eosinophil infiltration in the gastrointestinal tract is a common feature of numerous eosinophilic gastrointestinal disorders (EGIDs). EGIDs are disorders, for which the diagnosis is relatively difficult. Nevertheless, some common laboratory techniques are currently used for their diagnosis and disease monitoring. Besides eosinophils, mast cells and T cells have also been suggested to play a role in the pathogenesis of these disorders. Here, we review the pathogenesis and common laboratory approaches applied for their diagnosis, in particular eosinophil and mast cell markers.

Eosinophilic esophagitis: analysis of food impaction and perforation in 251 adolescent and adult patients

BACKGROUND ; AIMS: Eosinophilic esophagitis is a rapidly emerging, chronic inflammatory disorder. Prolonged inflammation evokes structural alterations and a fragile esophageal wall prone to perforation/rupture and food impaction. This report assesses the risk of spontaneously arising and procedure-induced complications and proposes practical recommendations. METHODS: The Swiss Esophageal Esophagitis Database documented 251 confirmed cases. A chart review identified which patients had required endoscopic bolus removal and/or experienced transmural esophageal perforation/rupture. In addition, a MEDLINE search for "eosinophilic esophagitis" with "esophageal perforation" or "esophageal rupture" was undertaken. RESULTS: During an 18-year period, 87 patients (34.7%) experienced 134 food impactions requiring flexible (124, 92.5%) or rigid (10, 7.5%) endoscopic bolus removal. Transmural perforation occurred in 20% (2/10) of rigid procedures, and 1 esophageal rupture (Boerhaave's syndrome) was observed. CONCLUSIONS: Bolus removal by rigid endoscopy is a high-risk procedure and should be avoided in eosinophilic esophagitis patients who require a gentler approach. Whether food impaction and esophageal wall remodeling can be prevented with anti-inflammatory medication is still undetermined. All Boerhaave's syndrome cases should be evaluated for underlying eosinophilic esophagitis.

Effects of EDP-420 on penicillin-resistant and quinolone- and penicillin-resistant pneumococci in the rabbit meningitis model

OBJECTIVES: To test the efficacy of EDP-420, a new ketolide, in experimental pneumococcal meningitis and to determine its penetration into the CSF. METHODS: The experimental rabbit model was used in this study and EDP-420 was tested against a penicillin-resistant and a penicillin- and quinolone-resistant mutant. EDP-420 was also tested against both strains in time-killing assays over 8 h in vitro. RESULTS: In experimental meningitis, EDP-420 produced a bactericidal activity comparable to the standard regimen based on a combination of vancomycin with ceftriaxone against a penicillin-resistant Streptococcus pneumoniae and a penicillin- and quinolone-resistant S. pneumoniae isolate. The penetration of EDP-420 into inflamed meninges was 38% after an i.v. injection of 10 mg/kg. The bactericidal activity of EDP-420 was also confirmed in in vitro time-killing assays. CONCLUSIONS: EDP-420 is an efficacious alternative treatment in pneumococcal meningitis, especially when resistant strains are suspected.

Esophageal strictures in adult eosinophilic esophagitis: dilation is an effective and safe alternative after failure of topical corticosteroids

Strictures are a frequent complication of eosinophilic esophagitis. The efficacy and safety of topical corticosteroids and of dilation of eosinophilic esophagitis-associated strictures have not yet been thoroughly clarified. We present a retrospective analysis of 10 adult patients with eosinophilic esophagitis who had symptomatic esophageal stenosis that was unresponsive to topical corticosteroids, and who were treated using bougienage. Eight patients had one single stricture, one patient had two, and another had three strictures; mean stricture length was 2.1 cm (range 1 - 6 cm). Bougienage led to prompt symptom relief. Apart from transient postprocedural odynophagia, no severe complications occurred. During the follow-up (mean 6 months; range 2 - 11 months), all patients enjoyed sustained treatment response.

Role of glial cells in the functional expression of LL-37/rat cathelin-related antimicrobial peptide in meningitis

Antimicrobial peptides are intrinsic to the innate immune system in many organ systems, but little is known about their expression in the central nervous system. We examined cerebrospinal fluid (CSF) and serum from patients with active bacterial meningitis to assess antimicrobial peptides and possible bactericidal properties of the CSF. We found antimicrobial peptides (human cathelicidin LL-37) in the CSF of patients with bacterial meningitis but not in control CSF. We next characterized the expression, secretion, and bactericidal properties of rat cathelin-related antimicrobial peptide, the homologue of the human LL-37, in rat astrocytes and microglia after incubation with different bacterial components. Using real-time polymerase chain reaction and Western blotting, we determined that supernatants from both astrocytes and microglia incubated with bacterial component supernatants had antimicrobial activity. The expression of rat cathelin-related antimicrobial peptide in rat glial cells involved different signal transduction pathways and was induced by the inflammatory cytokines interleukin 1beta and tumor necrosis factor. In an experimental model of meningitis, infant rats were intracisternally infected with Streptococcus pneumoniae, and rat cathelin-related antimicrobial peptide was localized in glia, choroid plexus, and ependymal cells by immunohistochemistry. Together, these results suggest that cathelicidins produced by glia and other cells play an important part in the innate immune response against pathogens in central nervous system bacterial infections.

Phage lytic enzyme Cpl-1 for antibacterial therapy in experimental pneumococcal meningitis

Treatment of bacterial meningitis caused by Streptococcus pneumoniae is increasingly difficult, because of emerging resistance to antibiotics. Recombinant Cpl-1, a phage lysin specific for S. pneumoniae, was evaluated for antimicrobial therapy in experimental pneumococcal meningitis using infant Wistar rats. A single intracisternal injection (20 mg/kg) of Cpl-1 resulted in a rapid (within 30 min) decrease in pneumococci in cerebrospinal fluid (CSF) by 3 orders of magnitude lasting for 2 h. Intraperitoneal administration of Cpl-1 (200 mg/kg) led to an antibacterial effect in CSF of 2 orders of magnitude for 3 h. Cpl-1 may hold promise as an alternative treatment option in pneumococcal meningitis.