In Vivo Activity of Oritavancin in Animal Infection Models and Rationale for a New Dosing Regimen in Humans

Abstract

Oritavancin is a novel glycopeptide antibiotic with concentration-dependent killing of Gram-positive cocci and pharmacokinetics characterized by extensive tissue distribution and a long terminal half-life. Its development was hindered by a 16- to 32-fold underestimation of activity against staphylococci and enterococci because of oritavancin's sticking to vials and tubes. Dose-fractionation studies in animal models suggested the peak concentration was the major index for efficacy. Once-daily intravenous administration of oritavancin was effective in methicillin-resistant Staphylococcus aureus (MRSA) endocarditis, penicillin-susceptible and cephalosporin-resistant pneumococcal meningitis in rabbits, staphylococcal and enterococcal central venous catheter infections in rats, and 24-hour postprophylaxis of inhaled anthrax in mice. Orally administered oritavancin was more effective than vancomycin in Clostridium difficile infection in hamsters. Pharmacodynamics suggested that a single dose of oritavancin at 1200 mg would be efficacious in humans. Simulation of this dose in neutropenic mice was highly effective in methicillin-sensitive S. aureus and MRSA thigh and bacteremia infections and pneumococcal lung infections.