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

• Published in: Antimicrobial agents and chemotherapy Vol. 43; no. 3; pp. 592 - 597
• Main Authors: ZELENITSKY, S. A, BOOKER, B, LAING, N, KARLOWSKY, J. A, HOBAN, D. J, ZHANEL, G. G
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.03.1999
• Subjects: Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Drug Resistance, Microbial; Drug Synergism; Enterococcus faecium; Enterococcus faecium - drug effects; Gentamicins - pharmacology; Glycopeptides; Medical sciences; Microbial Sensitivity Tests; Models, Biological; Pharmacology; Pharmacology. Drug treatments; Time Factors; Vancomycin - pharmacology; Drug combination; Peptides; Gentamicin; Vancomycin; In vitro; Synergism; Biological activity; Multiple dose; Streptococcaceae; Enterococcus faecium; Antibiotic; Microorganism resistance; Glycopeptide; Aminoglycoside; Minimum inhibitory concentration; Bacteria; Micrococcales; Drug interaction; Antibacterial agent
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.43.3.592

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.