Journal Article

Evaluation of daptomycin activity against <i>Staphylococcus aureus</i> in an <i>in vitro</i> pharmacodynamic model under normal and simulated impaired renal function

Vanthida Huang and Michael J. Rybak

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 57, issue 1, pages 116-121
Published in print January 2006 | ISSN: 0305-7453
Published online November 2005 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dki422
Evaluation of daptomycin activity against Staphylococcus aureus in an in vitro pharmacodynamic model under normal and simulated impaired renal function

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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

Journal Article.  3469 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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