title: 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.
authors.affiliation: Institute for Clinical Pharmacodynamics, Inc, Latham, New York, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
authors.forename: William A
authors.initials: WA
authors.lastname: Craig
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006224:Cricetinae; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006020:Glycopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D000077427:Lipoglycopeptides; D051379:Mice; D011817:Rabbits; D051381:Rats; D014640:Vancomycin / Q000031:analogs & derivatives
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D000077427:Lipoglycopeptides; C100708:oritavancin; D014640:Vancomycin