Activities of LY333328 and Vancomycin Administered Alone or in Combination with Gentamicin against Three Strains of Vancomycin-Intermediate Staphylococcus aureus in an In Vitro Pharmacodynamic Infection Model

Staphylococcus aureus with intermediate glycopeptide susceptibility (glycopeptide-intermediate S. aureus [GISA]) has been isolated from patients with apparent therapy failures. We studied the killing activity of vancomycin over 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 ({"type":"entrez-nucleotide","attrs":{"text":"LY333328","term_id":"1257359838","term_text":"LY333328"}}LY333328) at a simulated 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 of {"type":"entrez-nucleotide","attrs":{"text":"LY333328","term_id":"1257359838","term_text":"LY333328"}}LY333328 were administered over the 48-h study period. The vancomycin and {"type":"entrez-nucleotide","attrs":{"text":"LY333328","term_id":"1257359838","term_text":"LY333328"}}LY333328 MICs and minimal bactericidal concentrations (MBCs) for the three GISA strains (strains 14379, 992, and Mu50) were 8 and 8 μg/ml and 1 and 2 μg/ml, respectively, for GISA 14379, 6 and 6 μg/ml and 1 and 1 μg/ml, respectively, for GISA 992, and 8 and 12 μg/ml and 2 and 8 μg/ml, respectively, for GISA Mu50. Vancomycin and {"type":"entrez-nucleotide","attrs":{"text":"LY333328","term_id":"1257359838","term_text":"LY333328"}}LY333328 MICs and MBCs were 0.75 and 1.0 μg/ml and 1 and 1 μg/ml, respectively for a vancomycin-susceptible comparator strain (methicillin-resistant S. aureus [MRSA] 494). The addition of albumin to the growth medium increased the {"type":"entrez-nucleotide","attrs":{"text":"LY333328","term_id":"1257359838","term_text":"LY333328"}}LY333328 MICs and MBCs approximately 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 bactericidal at the dose of 1.5 g every 12 h against all strains; bactericidal activity occurred against the GISA strains at 8- to 10-fold lower ratios of the peak concentration to the MIC and the area under the concentration-time curve from time zero to 24 h (AUC0–24) to the MIC compared to those for the vancomycin-sensitive control strain. Overall, vancomycin activity was significantly correlated with the AUC0–24 (R2 = 0.79; P < 0.001) by multiple stepwise regression analyses. The addition of gentamicin did not significantly affect killing activity against any strain. {"type":"entrez-nucleotide","attrs":{"text":"LY333328","term_id":"1257359838","term_text":"LY333328"}}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 {"type":"entrez-nucleotide","attrs":{"text":"LY333328","term_id":"1257359838","term_text":"LY333328"}}LY333328 also prevented regrowth over the 48-h experiments for all strains tested. Higher doses of vancomycin (1.5 g every 12 h) and {"type":"entrez-nucleotide","attrs":{"text":"LY333328","term_id":"1257359838","term_text":"LY333328"}}LY333328 (5 mg/kg every 24 h) may represent potential treatment options for infections caused by GISA strains.