Ex vivo study of serum bactericidal titers and killing rates of daptomycin (LY146032) combined or not combined with amikacin compared with those of vancomycin

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Abstract
Twelve volunteers, in two groups of six, received daptomycin at a dose of 1 or 2 mg/kg. In addition, they received in a randomly allocated order amikacin (500 mg), daptomycin-amikacin, and vancomycin (500 mg). Thirty-five clinical isolates, including Staphylococcus aureus, S. epidermidis, Corynebacterium sp. group JK, and Enterococcus faecalis, were tested in vitro for the measure of the serum bactericidal titers and killing rates. The mean peak concentrations of daptomycin in serum 1 h after the administration of 1 and 2 mg/kg were 11 and 20 micrograms/ml, respectively. At 24 h after the administration of 2 mg/kg, the mean level in serum was 1.9 micrograms/ml, which is higher than the MICs for susceptible pathogens. Daptomycin and amikacin provided identical concentrations in serum whether given alone or in combination. Among the six regimens tested, those including daptomycin provided the highest and the most prolonged serum bactericidal titers against S. aureus, S. epidermidis, and E. faecalis. The killing rates measured by the killing curves were correlated with the concentration/MIC and concentration/MBC ratios of daptomycin for all strains tested. Significant killing occurred once the concentration of daptomycin in the serum 4- to 6-fold the MIC or 1- to 1.2-fold the MBC. The combination of daptomycin and amikacin had no effect on either the serum bactericidal titers or the rates of killing. Only vancomycin provided significant killing of the strains of Corynebacterium sp. group JK.