Bactericidal activity and kinetics of RP 59500 in a mouse model of Staphylococcus aureus septicaemia

Abstract

The bactericidal activity of RP 59500, a semisynthetic streptogramin, was compared with that of vancomycin against Staphylococcus aureus. This activity was evaluated in vitro by the kill curve method and in vivo using a model of mouse septicaemia. In vitro, RP 59500 (MIC = 0.12 mg/L) was more rapidly bactericidal against S. aureus IP 8203 than was vancomycin (MIC = 1 mg/L). In vivo, RP 59500 (120 mg/kg) was bactericidal against staphylococci in the blood of infected mice 1 h after administration, an effect which lasted for up to 7 h, whereas vancomycin at the same dose was bactericidal only 4 h after administration. The serum concentrations of vancomycin were higher than those of RP 59500 for at least 4 h after administration, and the C_max and AUC of vancomycin were 4.8 and 8.3 times higher, respectively, than those of RP 59500 (C_max= 13.2 mg/L; AUC_o−t= 15.2 mg/L/h), although the agents had similar elimination half-lives (about 0.5 h). RP 59500 was also administered to mice as a fractionated dose (30 mg/kg × 4, 40 mg/kg × 3, 60 mg/kg × 2). The onset of its bactericidal effect was delayed by fractionating the dose, but the suppression of bacteria in the blood was prolonged.