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Antimicrobial Agents and Chemotherapy, September 2008, p. 3061-3067, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00102-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Evaluation of Daptomycin Pharmacodynamics and Resistance at Various Dosage Regimens against Staphylococcus aureus Isolates 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,¹ School of Medicine, Wayne State University,² Detroit Receiving Hospital, Detroit, Michigan 48201,³ University of Wisconsin, School of Pharmacy, Madison, Wisconsin 53705⁴

Received 24 January 2008/ Returned for modification 29 April 2008/ Accepted 22 June 2008

The need to investigate novel dosing regimens and combinations is essential in combating poor treatment outcomes for Staphylococcus 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/liter) and four nonsusceptible isolates (MICs, 2 to 4 mg/liter). Daptomycin regimens of 6 and 10 mg/kg of body weight daily alone and in combination with gentamicin at 5 mg/kg daily or rifampin at 300 mg every 8 h were evaluated using an in vitro model with simulated endocardial vegetations over 96 h. 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 for only one of the nonsusceptible isolates and for only two isolates with increased doses of 10 mg/kg/day. Combination regimens demonstrated improvement with 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 therapy 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 with nonsusceptible isolates.

Published ahead of print on 30 June 2008.