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), alone and in combination with gentamicin, against one vancomycin-susceptible and two vancomycin-resistant Enterococcus faecium strains were studied with a multiple-dose, in vitro pharmacodynamic model (PDM). Dose-range data for the PDM studies were obtained from static time-kill curve studies. In PDM experiments conducted over 48 h, peak LY concentrations of 0.1x and 1x the MIC every 24 h and peak gentamicin concentrations of 18 micrograms/ml every 24 h (Gq24 h) and 6 micrograms/ml every 8 h (Gq8 h) were studied alone and in the four possible LY-gentamicin combinations. Compared to either antibiotic alone, LY-gentamicin combination regimens produced significantly higher apparent killing rates (KRs) calculated during the initial 2 h postdosing. The mean KRs for LY or gentamicin alone versus those for the LY-gentamicin combination regimens were 0.35 +/- 0.55 log10 CFU/ml/h (95% confidence interval [CI95%], 0 to 0.70) and 1.46 +/- 0.71 log10 CFU/ml/h (CI95%, 1.01 to 1.91), respectively (P < 0.0001). Bacterial killing at 48 h (BK48), which was calculated 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 BK48S were -0.69 +/- 0.44 log10 CFU/ml (CI95%, -0.41 to -0.97) and 3.72 +/- 2.28 log10 CFU/ml (CI95%, 2.28 to 5.17) for LY or gentamicin alone versus LY-gentamicin combination regimens, respectively (P < 0.0001). 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 percent (10 of 12) of the LY-gentamicin combination regimens also demonstrated synergy. No significant differences between the pharmacodynamics of LY-gentamicin combination regimens containing Gq24 h versus those containing Gq8h were detected.
Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada. zelenits@ms.umanitoba.ca
S A
SA
Zelenitsky
B
B
Booker
N
N
Laing
J A
JA
Karlowsky
D J
DJ
Hoban
G G
GG
Zhanel
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D016984:Enterococcus faecium / Q000187:drug effects*; D005839:Gentamicins / Q000494:pharmacology*; D006020:Glycopeptides; D000077427:Lipoglycopeptides; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D013997:Time Factors; D014640:Vancomycin / Q000494:pharmacology* / Q000031:analogs & derivatives
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D006020:Glycopeptides; D000077427:Lipoglycopeptides; D014640:Vancomycin; C100708:oritavancin