Activities of the combination of quinupristin-dalfopristin with rifampin in vitro and in experimental endocarditis due to Staphylococcus aureus strains with various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics

We evaluated the activities of quinupristin-dalfopristin (Q-D), alone or in combination with rifampin, against three strains of Staphylococcus aureus susceptible to rifampin (MIC, 0.06 mug/ml) and to Q-D (MICs, 0.5 to 1 mug/m l) but displaying various phenotypes of resistance to macrolide-lincosamide -streptogramin antibiotics: S. aureuu HM1053 was susceptible to quinupristi n and dalfopristin (MICs of 8 and 4 mug/ml, respectively); for S, aureus RP 13, the MIC of dalfopristin was high (MICs of quinupristin and dalfopristin for strain RP13, 8 and 32 mug/ml, respectively); and S, aureus HM1054R was obtained after conjugative transfer of macrolide-lincosamide-streptogramin B constitutive resistance to HM1054, and the MIC of quinupristin for this strain was high (MICs of quinupristin and dalfopristin, 64 and 4 mug/ml, re spectively). In vitro time-kill curve studies showed no difference between Q-D and rifampin, at a concentration of four times the MIG, against the thr ee strains. Rabbits with aortic endocarditis were treated 4 days with Q-D, rifampin, or their combination. In vivo, the combination was highly bacteri cidal and synergistic against strains susceptible to quinupristin (HM1054 a nd RP13) and sterilized 94% of the animals. In contrast, the combination wa s neither synergistic nor bactericidal against the quinupristin-resistant s train (HM1054R) and did not prevent the emergence of mutants resistant to r ifampin, We conclude that the in vive synergistic and bactericidal activity of the combination of Q-D and rifampin against S, aureus is predicted by t he absence of resistance to quinupristin but not by in vitro combination st udies.