Activity of LY333328 combined with gentamicin in vitro and in rabbit experimental endocarditis due to vancomycin-susceptible or -resistant Enterococcus faecalis

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 glycopeptid e-resistant transconjugants, BM4316 (VanA) and BM4275 (VanB), MICs of LY333 328 and gentamicin were 2 and 16 mug/ml, respectively, for the three strain s. In vitro, LY333328 alone was bactericidal at 24 h against JH2-2 at a con centration of 2 mug/ml and against BM4316 and BM4275 at a concentration of 30 mug/ml. The combination of LY333328 and gentamicin (4 mug/ml) was synerg istic and bactericidal after 24 h of incubation against the three strains a t LY333328 concentrations of 2 mug/ml for JH2-2 and 8 mug/ml for BM4275 and BM4316. The combination of LY333328 and gentamicin was the only regimen de monstrating in vitro bactericidal activity against BM4316, In vivo, intrave nous treatment with LY333328 alone, providing peak and trough serum levels of 83.3 +/- 1.3 and 3.8 +/- 0.2 mug/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 mug/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 agai nst VanA-type strains.