Activities of LY333328 and vancomycin administered alone or in combinationwith gentamicin against three strains of vancomycin-intermediate Staphylococcus aureus in an in vitro pharmacodynamic infection model

Staphylococcus aureus with intermediate glycopeptide susceptibility (glycop eptide-intermediate S. aureus [GISA]) has been isolated from patients with apparent therapy failures. We studied the killing activity of vancomycin ov er a range of simulated conventional doses (1 to 1.5 g every 12 h) against three of these GISA strains in an in vitro pharmacodynamic infection model. We also studied the activity of a new glycopeptide (LY333328) at a simulat ed dose of 3 mg/kg of body weight every 24 h or 5 mg/kg every 24 h, as well as the potential for vancomycin and gentamicin synergy against these GISA strains. Four doses of vancomycin with or without gentamicin or two doses o f LY333328 were administered over the 48-h study period. The vancomycin and LY333328 MICs and minimal bactericidal concentrations (MBCs) for the three GISA strains (strains 14379, 992, and Mu50) were 8 and 8 mug/ml and 1 and 2 mug/ml, respectively, for GISA 14379, 6 and 6 mug/ml and 1 and 1 mug/ml, respectively, for GISA 992, and 8 and 12 mug/ml and 2 and 8 mug/ml, respect ively, for GISA Mu50, Vancomycin and LY333328 MICs and MBCs were 0.75 and 1 .0 mug/ml and 1 and 1 mug/ml, respectively for a vancomycin-susceptible com parator strain (methicillin-resistant S. aureus [MRSA] 494), The addition o f albumin to the growth medium increased the LY333328 MICs and MBCs approxi mately 8- to 16-fold. Vancomycin was bacteriostatic against the three GISA strains at doses of 1, 1.125, and 1.25 g every 12 h, Vancomycin was bacteri cidal at the dose of 1.5 g every 12 h against all strains; bactericidal act ivity occurred against the GISA strains at 8- to 10-fold lower ratios of th e peak concentration to the MIC and the area under the concentration-time c urve from time zero to 24 h (AUC(0-24)) to the MIC compared to those for th e vancomycin-sensitive control strain, Overall, vancomycin activity was sig nificantly correlated with the AUC(0-24) (R-2 = 0.79; P < 0.001) by multipl e stepwise regression analyses. The addition of gentamicin did not signific antly affect killing activity against any strain. LY333328 was bactericidal against GISA strains 14379 and 992 and against MRSA 494 only with the 5-mg /kg/day dose simulations. The higher dose of LY333328 also prevented regrow th over the 48-h experiments for all strains tested, Higher doses of vancom ycin (1.5 g every 12 h) and LY333328 (5 mg/kg every 24 h) may represent pot ential treatment options for infections caused by GISA strains.