oritavancin and Endocarditis--Bacterial

Glycopeptides have an established role in the management of infective endocarditis, and feature in current treatment guidelines. Newer lipoglycopeptide agents (dalbavancin, telavancin and oritavancin), which are analogues of glycopeptides with structural modifications giving rise to added novel mechanisms of antimicrobial activity, are approved for the treatment of Gram-positive skin and skin structure infections, and also for nosocomial pneumonia (only telavancin has approval for the latter indication). Recent evidence has also emerged to support their use in the treatment of bone and joint infections. This article reviews the current literature on dalbavancin and telavancin in the treatment of infective endocarditis, a condition for which the role of these agents is yet to be established.

Topics: Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Endocarditis, Bacterial; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Microbial Sensitivity Tests; Middle Aged

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 microgram/ml, respectively, for the three strains. In vitro, LY333328 alone was bactericidal at 24 h against JH2-2 at a concentration of 2 microgram/ml and against BM4316 and BM4275 at a concentration of 30 microgram/ml. The combination of LY333328 and gentamicin (4 microgram/ml) was synergistic and bactericidal after 24 h of incubation against the three strains at LY333328 concentrations of 2 microgram/ml for JH2-2 and 8 microgram/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 microgram/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 microgram/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.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecalis; Female; Gentamicins; Glycopeptides; Lipoglycopeptides; Microbial Sensitivity Tests; Rabbits; Selection, Genetic; Vancomycin Resistance

The activity of LY333328 against Enterococcus faecalis JH2-2, which is susceptible to glycopeptides, and against its transconjugants E. faecalis BM4281 and BM4316, with VanB and VanA phenotypes, respectively, was investigated. LY333328 was active in vitro against the three strains, for which MICs were 2 microg/ml on agar and 0.25 microg/ml in broth. LY333328 was bactericidal in broth against E. faecalis JH2-2 and BM4281 at a concentration of 8 microg/ml and against BM4316 at a concentration of 30 microg/ml. The protein binding of LY333328 to rabbit serum was >99%, and the bactericidal activity of LY333328 in broth was reduced when it was tested in the presence of 90% rabbit serum. Autoradiographic studies performed in rabbits with enterococcal endocarditis showed that 14[C]LY333328 was distributed heterogeneously throughout cardiac vegetations. In rabbits with aortic endocarditis, a regimen of 20 mg of LY333328 per kg of body weight administered intramuscularly twice a day for 5 days after a loading dose of 40 mg/kg was active against the three strains in vivo (P < 0.01), whereas vancomycin was not active against the VanB-type strain and teicoplanin was not active against the VanA-type strain. We conclude that the activity of LY333328 is not significantly modified by acquired resistance to glycopeptides in E. faecalis either in vitro or in experimental endocarditis.

Topics: Animals; Anti-Bacterial Agents; Autoradiography; Bacterial Proteins; Blood Proteins; Carbon-Oxygen Ligases; Culture Media; Drug Resistance, Microbial; Endocarditis, Bacterial; Enterococcus faecalis; Female; Glycopeptides; Lipoglycopeptides; Microbial Sensitivity Tests; Myocardium; Protein Binding; Rabbits; Vancomycin

The in vivo efficacy of LY333328, a new glycopeptide antibiotic, was compared with that of vancomycin by using the rabbit model of left-sided methicillin-resistant Staphylococcus aureus endocarditis. Animals received LY333328 or vancomycin (25 mg/kg of body weight every 24 or 8 h, respectively) for 4 days. These drugs were equally effective in clearing bacteremia and in reducing bacterial counts in vegetations and tissues. We conclude that in this model, LY333328 was microbiologically effective and may be a therapeutic alternative to vancomycin.

Topics: Animals; Anti-Bacterial Agents; Colony Count, Microbial; Endocarditis, Bacterial; Glycopeptides; Kidney; Lipoglycopeptides; Male; Methicillin Resistance; Rabbits; Spleen; Staphylococcal Infections; Vancomycin