JAC Advance Access published online on November 25, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki422
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1 Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; Detroit Medical Center, Detroit, MI 48201, USA; Present address. Department of Clinical and Administrative Sciences, Southern School of Pharmacy, Mercer University, Atlanta, GA 30341, USA
* To whom correspondence should be addressed. Objectives: Daptomycin is a lipopeptide antimicrobial that is primarily excreted by the kidney. We examined daptomycin bactericidal activity in an in vitro pharmacodynamic model (IVPM) under normal and simulated impaired renal function against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Methods: Two clinical strains MSSA-1199 and MRSA-494 were used in an IVPM. MICs and MBCs were determined according to CLSI. Daptomycin free concentrations were simulated that corresponded to dose regimens of 4, 6 and 8 mg/kg every 24 h at 8 h t1/2 (Scheme I) and every 48 h at 30 h t1/2 (Scheme II). In addition, we simulated daptomycin free concentrations corresponding to fractional dose regimens of 2, 3 and 4 mg/kg every 24 h at 30 h t1/2 (Scheme III). The targeted Cmax free/MIC for 2, 3, 4, 6 and 8 mg/kg against MSSA-1199 ranged from 5.2 to 21.2. The targeted Cmax free/MIC for 2, 3, 4, 6 and 8 mg/kg against MRSA-494 ranged from 10.4 to 42.2. The targeted AUCfree/MIC for Schemes I, II and III against MSSA-1199 ranged from 94 to 392. The targeted AUCfree/MIC for Schemes I, II and III against MRSA-494 ranged from 188 to 581. Bactericidal activity and the potential for resistance were determined over 96 h. All models were completed in triplicate. Results: Daptomycin MICs (MBCs) for MSSA-1199 and MRSA-494 were 0.5 (1.0) mg/L and 0.25 (0.25) mg/L, respectively. Daptomycin 6 and 8 mg/kg at both 8 and 30 h t1/2 achieved 99.9% kill as early as 1 h. Daptomycin 4 mg/kg achieved 99.9% kill as early as 1 h when given at 8 and 30 h t1/2 but was not maintained to an endpoint of 96 h (P > 0.05). Conclusions: Overall, there was no difference in kill noted for daptomycin regimens at 4, 6 and 8 mg/kg every 24 h at 8 h t1/2 versus every 48 h at 30 h t1/2. Fractional doses of daptomycin at 30 h t1/2 were inferior to daptomycin regimens of 4, 6 and 8 mg/kg administered every 48 h (P = 0.03).
Received March 8, 2005
Revised August 11, 2005
Accepted October 27, 2005
Original article
Evaluation of daptomycin activity against Staphylococcus aureus in an in vitro pharmacodynamic model under normal and simulated impaired renal function
Vanthida Huang 1
and
Michael J. Rybak 2 *
2 Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; Detroit Medical Center, Detroit, MI 48201, USA; School of Medicine, Wayne State University, Detroit, MI 48201, USA
Michael J. Rybak, E-mail: m.rybak{at}wayne.edu
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