Influence of resistance to streptogramin A type antibiotics on the activity of quinupristin-dalfopristin in vitro and in experimental endocarditis due to Staphylococcus aureus

We evaluated the activity of quinupristin-dalfopristin (Q-D) against three clinical strains of Staphylococcus aureus susceptible to Q (MIC, 8 mu g/ml) and Q-D (MICs, 0.5 to 1 mu g/ml) but displaying various levels of suscepti bility to D. D was active against S. aureus HM 1054 (MIC, 4 mu g/ml) and ha d reduced activity against S. aureus RP 13 and S. aureus N 95 (MICs, 32 and 64 mu g/ml, respectively). In vitro, Q-D at a concentration two times the MTC (2xMIC) produced reductions of 4.3, 3.9, and 5.8 log(10) CFU/ml after 2 4 h of incubation for HM 1054, RP 13,and N 95, respectively. Comparable kil ling was obtained at 8xMIC. Q-D-resistant mutants were selected in vitro at a frequency of 2 x 10(-8) to 2 x 10(-7) for the three strains on agar cont aining 2xMIC of Q-D; no resistant bacteria were detected at 4xMIC. Rabbits with aortic endocarditis were treated for 4 days with Q-D at 30 mg/kg of bo dy weight intramuscularly (i.m.) three times a day (t.i.d.) or vancomycin a t 50 mg/kg i.m. t.i.d. In vivo, Q-D and vancomycin were similarly active an d bactericidal against the three tested strains compared to the results for control animals (P < 0.01). Among animals infected with RP 13 and treated with Q-D, one rabbit retained Q-D-resistant mutants that were resistant to Q and to high levels of D (MICs, 64, >256, and 8 mu g/ml for Q, D, and Q-D, respectively). We conclude that the bactericidal activity of Q-D against s trains with reduced susceptibility to D and susceptible to Q-D is retained and is comparable to that of vancomycin. Acquisition of resistance to both Q and D is necessary to select resistance to Q-D.