JAC Advance Access originally published online on November 25, 2005
Journal of Antimicrobial Chemotherapy 2006 57(1):116-121; doi:10.1093/jac/dki422
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Evaluation of daptomycin activity against Staphylococcus aureus in an in vitro pharmacodynamic model under normal and simulated impaired renal function
1 Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; 2 Detroit Medical Center, Detroit, MI 48201, USA; 3 School of Medicine, Wayne State University, Detroit, MI 48201, USA
Received 8 March 2005; returned 2 August 2005; revised 11 August 2005; accepted 27 October 2005
* Correspondence address. Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA. Tel: +1-313-577-4376; Fax: +1-313-577-8915; E-mail: m.rybak{at}wayne.edu
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).
Keywords: bactericidal activity , dose fractionation , lipopeptides
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