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Antimicrob. Agents Chemother. doi:10.1128/AAC.00869-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Evaluation of daptomycin activity against Staphylococcus aureus following vancomycin exposure in an in vitro pharmacodynamic model with simulated endocardial vegetations

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, and School of Medicine, Wayne State University; Detroit Receiving Hospital Detroit, MI 48201.; Department of Medicine, Division of Infectious Diseases, New York Medical College, Munger Pavilion 245, Vahalla, NY, 10595; John D. Dingell Department of Veterans Affairs Medical Center, Detroit, MI; Henry Ford Hospital, Detroit, MI; and William Beaumont Hospital, Royal Oak, MI

^* To whom correspondence should be addressed. Email: m.rybak{at}wayne.edu.

	Abstract

Recently, emergence of reduced susceptibility to daptomycin has been linked to reduced vancomycin susceptibility occurring after vancomycin exposure in S. 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 (SEV) model over 8 days. Five clinical isolates (4 MRSA and 1 MSSA) all reported to become nonsusceptible to daptomycin were evaluated. The following regimens were evaluated: vancomycin 1 g every 12 h x 4 d followed by daptomycin 6 mg/kg daily x 4 d; daptomycin 6 mg/kg daily x 8 d. If nonsusceptibility was detected, the following regimens were evaluated: no treatment x 4 d followed by daptomycin 6 mg/kg daily x 4 d; vancomycin 1 g every 12 h x 4 d followed by daptomycin 10 mg/kg daily x 4 d; daptomycin 10 mg/kg daily x 8 d. The emergence of daptomycin nonsusceptibility (12-16 fold MIC increase) was detected only with the MSSA isolate with daptomycin 6 mg/kg daily x 4 d post vancomycin exposure. However, daptomycin bactericidal activity was still maintained and the MIC increases of these isolates were unstable to serial passage on antibiotic-free agar with no mprF or yycG mutations. 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.