Activity of LY333328 Combined with Gentamicin In Vitro and in Rabbit Experimental Endocarditis Due to Vancomycin-Susceptible or -Resistant Enterococcus faecalis

Abstract

We investigated the activity of LY333328 alone and combined with gentamicin, both in vitro and in a rabbit model of experimental endocarditis, against the susceptible strain Enterococcus faecalis JH2-2 and its two glycopeptide-resistant transconjugants, BM4316 (VanA) and BM4275 (VanB). MICs of LY333328 and gentamicin were 2 and 16 g/ml, respectively, for the three strains. In vitro, LY333328 alone was bactericidal at 24 h against JH2-2 at a concentration of 2 g/ml and against BM4316 and BM4275 at a concentration of 30 g/ml. The combination of LY333328 and gentamicin (4 g/ml) was synergistic and bactericidal after 24 h of incubation against the three strains at LY333328 concentrations of 2 g/ml for JH2-2 and 8 g/ml for BM4275 and BM4316. The combination of LY333328 and gentamicin was the only regimen demonstrating in vitro bactericidal activity against BM4316. In vivo, intravenous treatment with LY333328 alone, providing peak and trough serum levels of 83.3 ؎ 1.3 and 3.8 ؎ 0.2 g/ml, respectively, was inactive against BM4316 and BM4275 and selected mutants resistant to LY333328 in half of the rabbits infected with the VanA-type strain (MICs, 8 to 20 g/ml). However, the LY333328-gentamicin combination was active against the three strains and prevented the emergence of mutants resistant to both components of the combination. We conclude that the LY333328-gentamicin combination might be of interest for the treatment of enterococcal infections, particularly against VanA-type strains.In recent years, enterococci have become significant nosocomial pathogens and now represent the second leading cause of nosocomial infections in the United States (17). A major reason for their spread in the hospital environment is their ability to resist most of the available antibiotics, including ␤-lactams, aminoglycosides, and glycopeptides, through intrinsic and/or acquired mechanisms of resistance (14, 21). Vancomycin-resistant enterococci have emerged since 1989 and have rapidly increased, being responsible for severe hospital outbreaks (4,11,21). In 1998, almost 15% of enterococci isolated in intensive care units in the United States exhibited vancomycin resistance (13). The lack of uniformly effective antimicrobial therapy for patients infected with glycopeptide-resistant enterococci has led to new therapeutic proposals.LY333328 is a semisynthetic carbohydrate-modified glycopeptide derivative that interacts directly with bacterial proteins involved in the transglycosylation step of cell wall biosynthesis. LY333328 has demonstrated excellent in vitro concentrationdependent activity against vancomycin-susceptible and -resistant enterococci (16,18,23). We previously showed that the activity of intramuscular (i.m.) LY333328 against experimental Enterococcus faecalis endocarditis was limited compared to that observed in vitro (16). This discrepancy could be explained, in part, by insufficient serum LY333328 concentrations achieved with the i.m. route. In order to investigate whether serum levels were the major factor limiting the in vi...

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“…That method used gradient high-performance liquid chromatography for the determination of vancomycin-related substances. Considering the difference in the bioanalytical methods used and the normal variability between pharmacokinetic studies, the data were considered similar overall (26).…”

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“…24,25 In brief, a polyethylene catheter (PE50, Clay Adams) was connected to a manometer and inserted into the left ventricle through the right carotid artery, under ketaminexylazine anesthesia. The ventricular location of the catheter was checked on the pressure curve ( Figure 1A).…”

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