JAC Advance Access originally published online on May 31, 2007
Journal of Antimicrobial Chemotherapy 2007 60(2):334-340; doi:10.1093/jac/dkm170
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Evaluation of daptomycin treatment of Staphylococcus aureus bacterial endocarditis: an in vitro and in vivo simulation using historical and current dosing strategies
1 Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA 2 Detroit Receiving Hospital, Detroit, MI 48201, USA 3 School of Medicine, Wayne State University, Detroit, MI 48201, USA 4 John D. Dingell Department of Veteran's Affairs Medical Center, Detroit, MI 48201, USA
Received 22 March 2007; returned 17 April 2007; revised 20 April 2007; accepted 21 April 2007
* Corresponding author. Tel: +1-313-577-4376; Fax: +1-313-577-8915; E-mail: m.rybak{at}wayne.edu
Objectives: A failure to daptomycin therapy and subsequent emergence of a daptomycin non-susceptible isolate occurred during the 1990 clinical investigation of daptomycin for the treatment of Staphylococcus aureus bacteraemia and endocarditis. We attempted to determine if this occurrence was reproducible in vitro and if it could be prevented by various daptomycin dosing strategies.
Methods: The daptomycin susceptible parent strain (SA-675) and the subsequent non-susceptible derivative (SA-684) were evaluated. In the rabbit endocarditis model, daptomycin 3 mg/kg every 8 h for 4 days was administered to simulate the study patient's pharmacokinetic exposure. Daptomycin doses of 1.5 and 3 mg/kg every 12 h and 6 and 10 mg/kg every 24 and 48 h were simulated in the in vitro model with simulated endocardial vegetations (SEVs).
Results: Daptomycin significantly reduced bacterial counts of SA-675 in rabbits, but one in 105–106 organisms from vegetations of one animal had an 8-fold increase in MIC. Daptomycin 1.5 mg/kg every 12 h in the in vitro model demonstrated no activity against either strain; reduced susceptibility emerged in SA-675 (4-fold increase in MIC). Bactericidal activity was noted with 6 and 10 mg/kg dosing against SA-675 with no resistance detected. The activity of the 6 mg/kg regimen was reduced against SA-684 but significantly improved activity was noted with 10 mg/kg daily.
Conclusions: The emergence of resistance was successfully recreated at suboptimal dosing regimens while the current recommended regimen of 6 mg/kg/day prevented the emergence of non-susceptible mutants. Daptomycin 10 mg/kg/day demonstrated even more enhanced killing. Further investigation with daptomycin 10 mg/kg is warranted.
Keywords: pharmacodynamics , pharmacokinetics , daptomycin non-susceptibility
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