Matrix Metalloproteinase Inhibition Lowers Mortality and Brain Injury in Experimental Pneumococcal Meningitis

Liechti, Fabian D.; Grandgirard, Denis; Leppert, David; Leib, Stephen L.

doi:10.1128/iai.00073-14

Cited by 51 publications

(89 citation statements)

References 58 publications

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“…The second-generation MMP inhibitors Ro 32-3555 and Ro 32-7315 started 3 h after infection (antibiotic treatment started 15 h later) decreased hippocampal apoptosis and cortical injury in the infant rat model of Str. pneumoniae meningitis [191]. Moreover, Ro 32-3555 reduced mortality.…”

Section: Inhibitors Of Matrix Metalloproteinases (Mmps)mentioning

confidence: 97%

“…pneumoniae meningitis, subcutaneous injections of lithium chloride started 5 days prior to infection reduced neuronal apoptosis in the dentate gyrus and improved spatial memory function as assessed by Morris water maze 3 weeks after infection [191]. In the same model, intraperitoneal treatment with fluoxetine (10 mg/kg/day) reduced the number of animals with relevant hippocampal apoptosis when compared to untreated infected littermates and also tended to reduce neocortical injury without influencing the parameters of inflammation [190].…”

Section: Rehabilitationmentioning

confidence: 98%

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Bacterial meningitis: an update of new treatment options

Nau

Djukic

Spreer

et al. 2015

Expert Review of Anti-infective Therapy

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The outcome of bacterial meningitis critically depends on the rapid initiation of bactericidal antibiotic therapy and adequate management of septic shock. In community-acquired meningitis, the choice of an optimum initial empirical antibiotic regimen depends on the regional resistance patterns. Pathogens resistant to antibacterials prevail in nosocomial bacterial meningitis. Dexamethasone is recommended as adjunctive therapy for community-acquired meningitis in developed countries. In comatose patients, aggressive measures to lower intracranial pressure <20 mmHg (in particular, external ventriculostomy, osmotherapy and temporary hyperventilation) were effective in a case-control study. Although many experimental approaches were protective in animal models, none of them has been proven effective in patients. Antibiotics, which are bactericidal but do not lyse bacteria, and inhibitors of matrix metalloproteinases or complement factor C5 appear the most promising therapeutic options. At present, vaccination is the most efficient method to reduce disease burden. Palmitoylethanolamide appears promising to enhance the resistance of the brain to infections.

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Section: Inhibitors Of Matrix Metalloproteinases (Mmps)mentioning

confidence: 97%

Section: Rehabilitationmentioning

confidence: 98%

Bacterial meningitis: an update of new treatment options

Nau

Djukic

Spreer

et al. 2015

Expert Review of Anti-infective Therapy

View full text Add to dashboard Cite

show abstract

“…To date, however, little is known about possible interactions between ceftriaxone and MMPs since current experiments are mainly on rodent models of meningitis experimenting the effect of other MMP inhibitors (e.g. Ro 32-3555 or GM6001) on neuronal loss or learning abilities with ceftriaxone only as a comedication [31,32,33,34,35,36,37]. Since studies on minocycline show a 2-fold decrease and ceftriaxone in current analysis showed a 3-fold increase in post-IVT-sICH rate, an identical effect of ceftriaxone on MMPs seems unlikely.…”

Section: Discussionmentioning

confidence: 99%

Preventive Ceftriaxone in Patients with Stroke Treated with Intravenous Thrombolysis: Post Hoc Analysis of the Preventive Antibiotics in Stroke Study

et al. 2016

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Background: The Preventive Antibiotics in Stroke Study (PASS), a randomized open-label masked endpoint trial, showed that preventive ceftriaxone did not improve functional outcome at 3 months in patients with acute stroke (adjusted common OR 0.95; 95% CI 0.82-1.09). Post-hoc analyses showed that among patients who received intravenous thrombolysis (IVT), patients who received ceftriaxone had a significantly better outcome as compared with the control group. This study aimed to gain more insight into the characteristics of these patients. Methods: In PASS, 2,550 patients were randomly assigned to preventive antibiotic treatment with ceftriaxone or standard care. In current post-hoc analysis, 836 patients who received IVT were included. Primary outcome included functional status on the modified Rankin Scale, analyzed with adjusted ordinal regression. Secondary outcomes included infection rate and symptomatic intracerebral hemorrhage (sICH) rate. Results: For all patients in PASS, the p value for the interaction between IVT and preventive ceftriaxone regarding functional outcome was 0.03. Of the 836 IVT-treated patients, 437 were administered ceftriaxone and 399 were allocated to the control group. Baseline characteristics were similar. In the IVT subgroup, preventive ceftriaxone was associated with a significant reduction in unfavorable outcome (adjusted common OR 0.77; 95% CI 0.61-0.99; p = 0.04). Mortality at 3 months was similar (OR 0.75; 95% CI 0.48-1.18). Preventive ceftriaxone was associated with a reduction in infections (OR 0.43; 95% CI 0.28-0.66), and a trend towards an increased risk for sICH (OR 3.09; 95% CI 0.85-11.31). Timing of ceftriaxone administration did not influence the outcome (aOR 1.00; 95% CI 0.98-1.03; p = 0.85). Conclusions: According to the post-hoc analysis of PASS, preventive ceftriaxone may improve the functional outcome in IVT-treated patients with acute stroke, despite a trend towards an increased rate of post-IVT-sICH.

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“…This adult rat model with intracisternal infection was then adapted to neonatal rats for GBS and pneumococci [37][38][39]. In this model, 10 μl containing log 10 5-6 cfu/ml of live S. pneumoniae serotype 3 (depending on the disease severity aimed for) are injected intrathecally into the cisterna magna, which leads to symptomatic meningitis in infant rats around 18 h later [39][40][41].…”

Section: Experimental Models To Study Bacterial Meningitismentioning

confidence: 99%

Bacterial Meningitis: Insights Into Pathogenesis and Evaluation of New Treatment Options: A Perspective from Experimental Studies

2015

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Bacterial meningitis is associated with high mortality and morbidity rates. Bacterial components induce an overshooting inflammatory reaction, eventually leading to brain damage. Pathological correlates of neurofunctional deficits include cortical necrosis, damage of the inner ear and hippocampal apoptosis. The hippocampal dentate gyrus is important for memory acquisition and harbors a neuronal stem cell niche, thus being potentially well equipped for regeneration. Adjuvant therapies aimed at decreasing the inflammatory reaction, for example, dexamethasone, and those protecting the brain from injury have been evaluated in animal models of the disease. They include nonbacteriolytic antibiotics (e.g., daptomycin), metalloproteinase inhibitors and modulators of the immunological response, for example, granulocyte colony-stimulating factor. Increasing research interest has recently been focused on interventions aimed at supporting regenerative processes.

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Matrix Metalloproteinase Inhibition Lowers Mortality and Brain Injury in Experimental Pneumococcal Meningitis

Cited by 51 publications

References 58 publications

Bacterial meningitis: an update of new treatment options

Bacterial meningitis: an update of new treatment options

Preventive Ceftriaxone in Patients with Stroke Treated with Intravenous Thrombolysis: Post Hoc Analysis of the Preventive Antibiotics in Stroke Study

Bacterial Meningitis: Insights Into Pathogenesis and Evaluation of New Treatment Options: A Perspective from Experimental Studies

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