Synergy of an investigational glycopeptide, LY333328, with once-daily gentamicin against vancomycin-resistant Enterococcus faecium in a multiple-dose, in vitro pharmacodynamic model

The pharmacodynamics of an investigational glycopeptide, LY333328 (LY), alo ne and in combination with gentamicin, against one vancomycin-susceptible a nd two vancomycin-resistant Enterococcus faecium strains were studied with a multiple-dose, in vitro pharmacodynamic model (PDM), Dose-range data for the PDM studies mere obtained from static time-kill curve studies, In PDM e xperiments conducted over 48 h, peak LY concentrations of 0.1X and 1x the M IC every 24 h and peak gentamicin concentrations of 18 mu g/ml every 24 h ( Gq24h) and 6 mu g/ml every 8 h (Gq8h) were studied atone and in the four po ssible LY-gentamicin combinations, Compared to either antibiotic alone, LY- gentamicin combination regimens produced significantly higher apparent kill ing rates (KRs) calculated during the initial 2 h postdosing, The mean KRs for LY or gentamicin alone versus those fur the LY-gentamicin combination r egimens were 0.35 +/- 0.55 log(10) CFU/ml/h (95% confidence interval [CI95% ], 0 to 0.70) and 1.46 +/- 0.71 log(10) CFU/ml/h (CI95%, 1.01 to 1.91), res pectively (P < 0.0001). Bacterial killing at 48 h (BK48), which was calcula ted by subtracting the bacterial counts at 48 h from the initial inoculum, with a negative value indicating net growth, was also significantly greater . The mean BK(48)s were -0.69 +/- 0.44 log(10) CFU/ml (CI95%, -0.41 to -0.9 7) and 3.72 +/- 2.28 log(10) CFU/ml (CI95%, 2.28 to 5.17) for LY or gentami cin alone versus LY-gentamicin combination regimens, respectively (P < 0.00 01). None of the 12 regimens with LY or gentamicin alone but 75% (9 of 12) of the LY-gentamicin combination regimens were bactericidal. Eighty-three p ercent: (10 of 12) of the LY-gentamicin combination regimens also demonstra ted synergy. No significant differences between the pharmacodynamics of LY- gentamicin combination regimens containing Gq24h versus those containing Gq 8h were detected.