In Vitro Activities of Daptomycin, Arbekacin, Vancomycin, and Gentamicin Alone and/or in Combination against Glycopeptide Intermediate-Resistant Staphylococcus aureus in an Infection Model

Abstract

ABSTRACT Daptomycin, a lipopeptide antibiotic, has broad activity against gram-positive organisms, similar to vancomycin; however, its mechanism of action differs, resulting in interference with cell membrane transport and a more rapid bactericidal activity. In light of increasing need for alternative treatments against intermediate-resistant Staphylococcus aureus , there is revitalized interest in this antibiotic. We, therefore, evaluated the activity of daptomycin alone or in combination in an in vitro infection model against two glycopeptide intermediate-resistant S. aureus (GISA) isolates. Newly designed regimens of daptomycin at 4 and 6 mg/kg of body weight every 24 h (q24h) were compared to the previous regimen of 3 mg/kg q12h. Daptomycin MICs and minimal bactericidal concentrations (MBCs) (MIC/MBC) for Mu-50, HIP5836 (992), and MRSA-67 were 0.5/1.0, 0.5/1.0, and 0.125/0.5 μg/ml, respectively. MICs and MBCs of arbekacin for the three strains were 2.0/8.0, 0.125/0.5, and 0.125/0.25 μg/ml, respectively. Vancomycin and gentamicin MICs and MBCs for the three strains were 8.0/8.0, 8.0/8.0, and 0.5/1.0 μg/ml and 128/128, 0.5/1.0, and 0.25/0.5 μg/ml, respectively. Our experience with daptomycin in an in vitro infection model has shown significant kill against the two GISA strains (Mu-50 and 992) ( P < 0.03). We also noted that kill was related to a total dose effect for 992, in which simulated daptomycin in vivo dosages of 6 mg/kg q24h and 3 mg/kg q12h produced similar kill and 4 mg/kg q24h resulted in significant regrowth ( P ≤ 0.05). Combination therapy with arbekacin resulted in synergistic activity against Mu-50. Daptomycin area under the concentration-time curve/MIC and C max /MIC ranges for GISA isolates were 80 to 116 and 6 to 12, respectively, and ranges for MRSA-67 were 320 to 461 and 24 to 48, respectively, and appeared to have an association with kill (i.e., decreased CFU/milliliter) at 24 and 48 h. Therefore, these experiments suggest that daptomycin alone or in combination could provide an alternative for the treatment of GISA.