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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,¹ School of Medicine, Wayne State University, Detroit, Michigan,² Detroit Receiving Hospital, Detroit, Michigan 48201,³ Department of Medicine, Division of Infectious Diseases, New York Medical College, Munger Pavilion 245, Valhalla, New York 10595,⁴ John D. Dingell Department of Veterans Affairs Medical Center, Detroit, Michigan,⁵ Henry Ford Hospital, Detroit, Michigan,⁶ William Beaumont Hospital, Royal Oak, Michigan⁷

Received 3 July 2007/ Returned for modification 15 September 2007/ Accepted 31 October 2007

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.

Published ahead of print on 12 November 2007.