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Bactericidal antibiotics which inhibit bacterial protein synthesis release smaller quantities of proinflammatory\/toxic bacterial compounds than \u0392-lactams and other cell wall-active drugs. Among the \u0392-lactams, compounds binding to penicillin-binding protein 2 (PBP-2) release smaller amounts of bacterial substances than antibacterials inhibiting PBP-3. Generally, high antibiotic concentrations (more than 10 times the MIC) induce the release of fewer bacterial proinflammatory\/toxic compounds than concentrations close to the MIC. In several in vitro and in vivo systems, bacteria treated with protein synthesis inhibitors or \u0392-lactams inhibiting PBP-2 induce less inflammation than bacteria treated with PBP-3-active \u0392-lactams. In mouse models of Escherichia coli peritonitis sepsis and of Streptococcus pneumoniae meningitis, lower release of proinflammatory bacterial compounds was associated with reduced mortality. In conclusion, sufficient evidence for the validity of the concept of modulating the release of proinflammatory bacterial compounds by antibacterials has been accumulated in vitro and in animal experiments to justify clinical trials in sepsis and meningitis. A properly conducted study addressing the potential benefit of bacterial protein synthesis inhibitors versus \u0392-lactam antibiotics will require both strict selection and inclusion of a large number of patients. 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