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Sequential combination of rifampicin and ceftriaxone for bacterial meningitis treatment reduced the release of bacterial compounds by Streptococcus pneumoniae in vitro and attenuated inflammation and neuronal damage in vivo

Abstract number: O338

Spreer A., Lugert R., Stoltefaut V., Hoecht A., Eiffert H., Nau R.

Objectives: In bacterial meningitis, severe systemic and local inflammatory processes cause long-term impairment and death. Current standard therapy relies on members of the group of b-lactam antibiotics such as ceftriaxone. By inhibition of cell wall synthesis these antibiotics induce bacteriolysis, which leads to a sudden release of high amounts of proinflammatory and toxic bacterial products including bacterial DNA and haemolysins (e.g. pneumolysin produced by S. pneumoniae). Bactericidal protein-synthesis inhibiting antibiotics like rifampicin prevent bacteriolysis and the resulting burst of inflammation. With respect to a certain risk of secondary resistance development during rifampicin monotherapy, combination of rifampicin with other antibiotics is mandatory. Therefore, we evaluated a sequential combination regimen with a short-time rifampicin pretreatment followed by the addition of ceftriaxone.

Methods: In vitro we analysed the release of pneumolysin and bacterial DNA from pneumococcal broth culture by quantitative immunoblotting and real-time-PCR. In vivo, we evaluated in a rabbit model of pneumococcal meningitis the influence of rifampicin pretreatment on cerebrospinal fluid (CSF) inflammation and on hippocampal neuronal damage.

Results: In pneumococcal broth culture, rifampicin pretreatment for only 30 minutes significantly reduced the ceftriaxone-induced release of pneumolysin and bacterial DNA. Likewise, in vivo, rifampicin pretreatment for 1 hour followed by the addition of ceftriaxone significantly reduced markers of neuroinflammation in the CSF, i.e. prostaglandin E2 and total protein 2 hours after initiation of antibiotic therapy. Reduced inflammation resulted in a significantly reduced density of apoptotic neurons in the hippocampal dentate gyrus compared to animals treated with ceftriaxone alone. The combined antibiotic treatment resulted in a slight decrease in the speed of bacterial killing, but was nevertheless rapidly bactericidal.

Conclusion: A pretreatment of only 1 hour with the bactericidal broad-spectrum antibiotic rifampicin prior to therapy with a b-lactam antibiotic reduced the release of proinflammatory bacterial products in vitro and attenuated inflammation and neuronal damage in vivo. This concept holds promise to reduce inflammation-associated damage in severe bacterial infections and should therefore be evaluated for meningitis therapy in clinical trials.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Barcelona, Spain
Presentation type:
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