Efficacy of usual and high doses of daptomycin in combination with rifampin versus alternative therapies in experimental foreign-body infection by methicillin-resistant Staphylococcus aureus.

摘要

The treatment of prosthetic joint infections caused by methicillin-resistant Staphylococcus aureus (MRSA) continues to be a challenge for the clinician. The aim of this study was to evaluate the efficacies of daptomycin at usual and high doses (equivalent to 6 and 10 mg/kg of body weight/day, respectively, in humans) and in combination with rifampin and to compare the activities to those of conventional anti-MRSA therapies. We used MRSA strain HUSA 304, with the following MICs and minimal bactericidal concentrations (MBCs), respectively: daptomycin, 1 mug/ml and 4 mug/ml; vancomycin, 2 mug/ml and 4 mug/ml; linezolid, 2 mug/ml and >32 mug/ml; and rifampin, 0.03 mug/ml and 0.5 mug/ml. In time-kill curves, only daptomycin and its combinations with rifampin achieved a bactericidal effect in log and stationary phases. For in vivo studies, we used a rat foreign-body infection model. Therapy was administered for 7 days with daptomycin at 100 mg/kg/day and 45/mg/kg/day, vancomycin at 50 mg/kg/12 h, rifampin at 25 mg/kg/12 h, and linezolid at 35 mg/kg/12 h, and each antibiotic was also combined with rifampin. Among monotherapies, daptomycin at 100 mg/kg/day and rifampin performed better than vancomycin and linezolid. In combination with rifampin, both dosages of daptomycin were significantly better than all other combinations, but daptomycin at 100 mg/kg/day plus rifampin achieved better cure rates at day 11 (P < 0.05) than daptomycin at 45 mg/kg/day plus rifampin. Resistant strains were found in monotherapies with rifampin and daptomycin at 45 mg/kg/day. In conclusion, daptomycin at high doses was the most effective monotherapy and also improved the efficacy of the combination with rifampin against foreign-body infections by MRSA. Clinical studies should confirm whether this combination may be considered the first-line treatment for foreign-body infections by MRSA in humans.