title: In vivo efficacy and pharmacokinetics of AC98-6446, a novel cyclic glycopeptide, in experimental infection models.
abstract: AC98-6446 is a novel semisynthetic derivative of a natural product related to the mannopeptimycins produced by Streptomyces hygroscopicus. Naturally occurring esterified mannopeptimycins exhibited excellent in vitro activity but only moderate in vivo efficacy against staphylococcal infection. The in vivo efficacy and pharmacokinetics of AC98-6446 were investigated in murine acute lethal, bacterial thigh and rat endocarditis infections. Pharmacokinetics were performed in mice, rats, monkeys, and dogs. Acute lethal infections were performed with several gram-positive isolates: Staphylococcus aureus (methicillin-susceptible and methicillin-resistant staphylococci), vancomycin-resistant Enterococcus faecalis, and penicillin-susceptible and -resistant Streptococcus pneumoniae. The 50% effective dose for all isolates tested ranged from 0.05 to 0.39 mg/kg of body weight after intravenous (i.v.) administration. Vancomycin was more than fivefold less efficacious against all of these same infections. Results of the thigh infection with S. aureus showed a static dose for AC98-6446 of 0.4 mg/kg by i.v. administration. Reduction of counts in the thigh of >2 log(10) CFU were achieved with doses of 1 mg/kg. i.v. administration of 3 mg/kg twice a day for 3 days resulted in a >3 log(10) reduction in bacterial counts of vancomycin-susceptible and -resistant E. faecalis in a rat endocarditis model. Pharmacokinetics of AC98-6446 showed an increase in exposure (area under the concentration-time curve) from mouse to dog species. The i.v. half-life (t(1/2)) increased threefold between rodents and the higher species dosed. Efficacy of AC98-6446 has been demonstrated in several models of infection with resistant gram-positive pathogens. This glycopeptide exhibited bactericidal activity in these models, resulting in efficacy at low doses with reduction in bacterial load.
authors.affiliation: Infectious Disease Section. Discovery Analytical Chemistry, Wyeth Research, Pearl River, New York 10965, USA. williamweiss@cumbre.biz
authors.forename: William J
authors.initials: WJ
authors.lastname: Weiss
authors.forename: Timothy
authors.initials: T
authors.lastname: Murphy
authors.forename: Eileen
authors.initials: E
authors.lastname: Lenoy
authors.forename: Mairead
authors.initials: M
authors.lastname: Young
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D001424:Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D015169:Colony Count, Microbial; D004285:Dogs; D004697:Endocarditis, Bacterial / Q000382:microbiology; D005260:Female; D006020:Glycopeptides / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006207:Half-Life; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013848:Thigh / Q000382:microbiology; D014640:Vancomycin / Q000627:therapeutic use
chemical_list: C483958:AC98-6446; D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D014640:Vancomycin