PHARMACODYNAMICS OF RP-59500 ALONE AND IN COMBINATION WITH VANCOMYCIN AGAINST STAPHYLOCOCCUS-AUREUS IN AN IN VITRO-INFECTED FIBRIN CLOT MODEL

The bactericidal activity and emergence of resistance to RP 59500 (quinupristin/dalfopristin) when it was administered alone and in combination with vancomycin against fibrin clots that have been infected with methicillin-susceptible Staphylococcus aureus ATCC 25923 or methicillin-resistant S. aureus (MRSA) 67 were evaluated in an in vitro pharmacodynamic infected fibrin clot model, Fibrin clots were infected with S. aureus to achieve an inoculum of approximately 10(9) CFU/g. Antibiotics were administered to simulate pharmacokinetics in humans: RP 59500 (7.5 mg/kg of body weight) every 8 h and vancomycin (15 mg/kg) every 12 h over 72 h, Preliminary test tube time-kill experiments with an inoculum of similar to 10(5) CPU/ml suggested that RP 59500 was more rapid in achieving a 99.9% reduction in the number of CFU per milliliter than vancomycin against ATCC 25923 (6.94 versus 24 h; P = 0.0003) and MRSA 67 (6.77 versus 17.03 h; P = 0.004), At a higher inoculum (similar to 10(8) CPU/ml), 99.9% kill was achieved only with the combination regimen against ATCC 25923 and MRSA 67 (10.9 and 10.5 h, respectively), with total reductions of 6.35 and 6.33 log(10) CPU/ml over 24 h, respectively, In the fibrin clot model, RP 59500 was: more effective than vancomycin in reducing organism titers over 72 h, However, the combination regimen was the most effective therapy, with a total reduction of colony count against ATCC 25923 (total reduction of 1.24 log(10) CFU/g for RP 59500, 0.56 log(10) CFU/g for vancomycin, and 3.3 log(10) CFU/g for the combination; P < 0.002) and MRSA 67 (total reduction of 1.66 log(10) CFU/g for RP 59500, 0.50 log(10) CFU/g for vancomycin, and 2.48 log(10) CFU/g for the combination; P < 0.04), Resistance of both strains of S. aureus was noted in the model only after exposure to RP 59500 (32-fold increase in the MIG), as was a simultaneous increase in the erythromycin MIC (32-fold) for ATCC 25923, but no changes in the lincomycin MIC were noted, Overall, RP 59500 demonstrated more potent bactericidal activity than vancomycin against S. aureus over 72 h, In the fibrin clot model, the most optimal therapy was the combination regimen.