Daptomycin Activity against Staphylococcus aureus following Vancomycin Exposure in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations

ABSTRACT Recently, the emergence of reduced susceptibility to daptomycin has been linked to the reduced vancomycin susceptibility that occurs after vancomycin exposure in Staphylococcus aureus in vivo and in vitro. This study evaluated this propensity in clinical isolates of S. aureus using an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations over 8 days. Five clinical isolates (four methicillin-resistant S. aureus isolates and one methicillin-susceptible S. aureus [MSSA] isolate), all of which were reported to have become nonsusceptible to daptomycin, were evaluated. The following regimens were evaluated: vancomycin 1 g every 12 h for 4 days followed by daptomycin 6 mg/kg of body weight daily for 4 days and daptomycin 6 mg/kg daily for 8 days. If nonsusceptibility was detected, the following regimens were evaluated: no treatment for 4 days followed by daptomycin 6 mg/kg daily for 4 days, vancomycin 1 g every 12 h for 4 days followed by daptomycin 10 mg/kg daily for 4 days, and daptomycin 10 mg/kg daily for 8 days. The emergence of daptomycin nonsusceptibility (12- to 16-fold MIC increase) was detected only with the MSSA isolate with daptomycin 6 mg/kg daily for 4 days after vancomycin exposure. However, the bactericidal activity of daptomycin was maintained and the MIC increases of these isolates, which had no mprF or yycG mutations, were unstable to serial passage on antibiotic-free agar. Subsequent regimens did not demonstrate nonsusceptibility to daptomycin. These findings suggest that reduced daptomycin susceptibility can be a strain-specific and unstable event. Further evaluation of the susceptibility relationship between daptomycin and vancomycin is necessary to understand the factors involved and their clinical significance.