Assessment by time-kill methodology of the synergistic effects of oritavancin in combination with other antimicrobial agents against Staphylococcus aureus

Abstract

Oritavancin is a semisynthetic lipoglycopeptide in clinical development for serious gram-positive infections. This study describes the synergistic activity of oritavancin in combination with gentamicin, linezolid, moxifloxacin, or rifampin in time-kill studies against methicillin-susceptible, vancomycin-intermediate, and vancomycin-resistant Staphylococcus aureus.

FIG. 1.

Time-kill curves of synergistic combinations of oritavancin with gentamicin, linezolid, moxifloxacin, or rifampin against MSSA, VISA and VRSA. Exponential-phase MSSA ATCC 29213, VISA NRS402, or VRSA VRS5 was diluted in CAMHB containing 0.002% polysorbate-80 and challenged with the test agents at the indicated concentrations. The single-agent drug concentrations were maintained during combination testing with oritavancin. Viability was enumerated at the indicated time points by serial dilution plating. Each point represents the mean of duplicate determinations. Whereas experiments were performed in triplicate, the time-kill curves presented here are from a single experiment. The limit of detection (200 CFU/ml) is indicated by the dashed lines. (A) Oritavancin combinations versus MSSA ATCC 29213. Note that the points for oritavancin plus rifampin overlap those for oritavancin plus gentamicin at 6 and 24 h. *, growth control; ○, 0.031 μg/ml oritavancin; □, 0.25 μg/ml gentamicin; ⋄, 0.063 μg/ml moxifloxacin; ▿, 0.008 μg/ml rifampin; ▪, oritavancin plus gentamicin; ⧫, oritavancin plus moxifloxacin; ▾, oritavancin plus rifampin. (B and C) Oritavancin combinations versus VISA NRS402. *, growth control; ○, 0.50 μg/ml oritavancin; □, 0.13 μg/ml gentamicin; ▵, 0.25 μg/ml linezolid; ▪, oritavancin plus gentamicin; ▴, oritavancin plus linezolid. (D) Oritavancin combinations versus VRSA VRS5. *, growth control; ○, 0.13 μg/ml oritavancin; □, 0.25 μg/ml gentamicin; ▵, 1 μg/ml linezolid; ▿, 0.002 μg/ml rifampin; ▪, oritavancin plus gentamicin; ▴, oritavancin plus linezolid; ▾, oritavancin plus rifampin.