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Antimicrob. Agents Chemother. doi:10.1128/AAC.00102-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Evaluation of daptomycin pharmacodynamics and resistance at varying dosage regimens against Staphylococcus aureus with reduced susceptibilities to daptomycin 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; University of Wisconsin, School of Pharmacy, Madison, WI 53705

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

	Abstract

The need to investigate novel dosing regimens and combinations is essential in combating poor treatment outcomes for S. aureus bacteremia and endocarditis. We evaluated the impact of simulated standard and high dose daptomycin in combination with gentamicin or rifampin against daptomycin susceptible and nonsusceptible matched strains of S. aureus. These strains were collected from the daptomycin bacteremia and endocarditis clinical trial and consisted of three susceptible strains (MIC 0.25 mg/L) and four nonsusceptible isolates (MIC 2-4). Daptomycin regimens of 6 and 10 mg/kg daily alone and in combination with gentamicin 5 mg/kg daily or rifampin 300 mg q8h were evaluated in an in vitro model with simulated endocardial vegetations over 96 hours. Rapid bactericidal activity identified by time to 99.9% kill was displayed in all regimens with the daptomycin susceptible strains. Concentration-dependent activity was noted by more rapid killing with the 10 mg/kg/day dose. The addition of gentamicin improved activity in the majority of susceptible isolates. Daptomycin 6 mg/kg/day monotherapy displayed bactericidal activity in only one of the nonsusceptible isolates, and only two isolates with increased doses of 10 mg/kg/day. Combination regimens demonstrated improvement in some but not all nonsusceptible isolates. Three isolates developed a reduction in daptomycin susceptibility with 6 mg/kg/day monotherapy, but this was suppressed with both combination and high dose daptomycin. These results suggest that high dose daptomycin therapy and combination therapy may be reasonable treatment options for susceptible isolates; however more investigations are needed to confirm the variability of these regimens on nonsusceptible isolates.