Protein synthesis inhibiting clindamycin improves outcome in a mouse model of Staphylococcus aureus sepsis compared with the cell wall active ceftriaxone

Abstract

Objective: The release of proinflammatory components from bacteria depends on the mode of action of the antibacterial therapy used. We studied whether this influences mortality in experimental sepsis. Design. In a lethal murine model of Staphylococcus aureus sepsis, animals were randomly assigned to receive the protein synthesis inhibitor clindamycin (CLI) or the beta-lactam ceftriaxone (CRO). Setting. Therapy was introduced subcutaneously 5 hrs after intraperitoneal injection of 107 colony forming units of S. aureus American Type Culture Collection 29213 and was continued every 8 hrs for 3 days. Measurements and Results: Survival was higher in mice receiving CLI (29/50 animals [58%]) than in mice receiving CRO (16/50 animals [32%]; p = 015). Mice treated with CRO died earlier than mice receiving CLI (p = .002). Eight hours after the first antibiotic dose, the motor performance of mice receiving CRO had deteriorated more than it did for mice receiving CLI (p = .009). Higher levels of tumor necrosis factor-alpha were measured in serum (p = .027) and peritoneal fluid (p = .001) of CRO-treated mice. In vitro, CLI released smaller amounts of staphylococcal enterotoxin A than CRO. Conclusions: Antibiotic treatment of Gram-positive sepsis with a protein synthesis inhibitor decreases morbidity and mortality compared with a bacteriolytic compound. This may be caused by a reduction of the concentrations of proinflammatory/toxic bacterial components and cytokines.