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Antimicrobial Agents and Chemotherapy, March 1999, p. 592-597, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Synergy of an Investigational Glycopeptide, LY333328, with Once-Daily Gentamicin against Vancomycin-Resistant Enterococcus faecium in a Multiple-Dose, In Vitro Pharmacodynamic Model

S. A. Zelenitsky,1,2,* B. Booker,1 N. Laing,3 J. A. Karlowsky,1,2,3 D. J. Hoban,2,3 and G. G. Zhanel1,2,3

Faculty of Pharmacy1 and Faculty of Medicine,2 University of Manitoba, and Department of Clinical Microbiology, Health Sciences Centre,3 Winnipeg, Manitoba, Canada

Received 10 April 1998/Returned for modification 24 August 1998/Accepted 9 December 1998

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 0.1× and 1× the MIC every 24 h and peak gentamicin concentrations of 18 µg/ml every 24 h (Gq24h) and 6 µg/ml every 8 h (Gq8h) 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 Gq24h versus those containing Gq8h were detected.

* Corresponding author. Mailing address: Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2. Phone: (204) 474-8414. Fax: (204) 474-7616. E-mail: zelenits{at}ms.umanitoba.ca.

Antimicrobial Agents and Chemotherapy, March 1999, p. 592-597, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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