Rifampin in experimental endocarditis due to Staphylococcus aureus in rabbits

Rifampin possesses unique activity against Staphylococcus aureus. It is the most active antistaphylococcal antibiotic currently available and has been shown to be particularly effective in eradicating S. aureus from abscess cavities in experimental infections. However, resistance develops rapidly in vitro and in vivo when large numbers of organisms (10(6)-10(7)) are present, and use of combination therapy has been recommended. The use of combination therapy is complicated by the finding that in vitro the addition of rifampin may reduce (antagonize) the bactericidal effect of the beta-lactam antibiotics. This study examines the in vivo effect of treatment with a beta-lactam agent (cloxacillin), rifampin, or the combination on the eradication of S. aureus from cardiac vegetations in experimental endocarditis. Five different dosage combinations of the beta-lactam agent and rifampin were administered for a three-day period, and an attempt was made to correlate peak serum bactericidal titers with results of quantitative cultures of vegetations after therapy. In two of five regimens the combination of rifampin and cloxacillin produced enhanced efficacy in vivo (synergism); in two regimens the effect was no greater than the effect of either drug alone (indifference), and in one regimen the combination was less effective than either single-drug regimen alone (antagonism). Peak serum bactericidal titers often were predictive of the in vivo effect when high doses of cloxacillin were used but were not consistently predictive of in vivo results when rifampin was the agent responsible for the major therapeutic effect. Rifampin-resistant strains did not emerge in animals receiving combination therapy but were isolated from vegetations from several animals receiving rifampin alone.