title: In vitro and in vivo activities of SCH 56592 (posaconazole), a new triazole antifungal agent, against Aspergillus and Candida.
abstract: SCH 56592 (posaconazole), a new triazole antifungal agent, was tested in vitro, and its activity was compared to that of itraconazole against 39 Aspergillus strains and to that of fluconazole against 275 Candida and 9 Cryptococcus strains. The SCH 56592 MICs for Aspergillus ranged from </=0.002 to 0.5 microg/ml, and those of itraconazole ranged from </=0.008 to 1 microg/ml. The SCH 56592 MICs for Candida and Cryptococcus strains ranged from </=0. 004 to 16 microg/ml, and those of fluconazole ranged from </=0.062 to >64 microg/ml. SCH 56592 showed excellent activity against Aspergillus fumigatus and Aspergillus flavus in a pulmonary mouse infection model. When administered therapeutically, the 50% protective doses (PD(50)s) of SCH 56592 ranged from 3.6 to 29.9 mg/kg of body weight, while the PD(50)s of SCH 56592 administered prophylactically ranged from 0.9 to 9.0 mg/kg; itraconazole administered prophylactically was ineffective (PD(50)s, >75 mg/kg). SCH 56592 was also very efficacious against fluconazole-susceptible, -susceptible dose-dependent, or -resistant Candida albicans strains in immunocompetent or immunocompromised mouse models of systemic infection. The PD(50)s of SCH 56592 administered therapeutically ranged from 0.04 to 15.6 mg/kg, while the PD(50)s of SCH 56592 administered prophylactically ranged from 1.5 to 19.4 mg/kg. SCH 56592 has excellent potential for therapy against serious Aspergillus or Candida infections.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, New Jersey 07033-1300, USA. anthony.cacciapuoti@spcorp.com
authors.forename: A
authors.initials: A
authors.lastname: Cacciapuoti
authors.forename: D
authors.initials: D
authors.lastname: Loebenberg
authors.forename: E
authors.initials: E
authors.lastname: Corcoran
authors.forename: F
authors.initials: F
authors.lastname: Menzel
authors.forename: E L
authors.initials: EL
authors.lastname: Moss
authors.forename: C
authors.initials: C
authors.lastname: Norris
authors.forename: M
authors.initials: M
authors.lastname: Michalski
authors.forename: K
authors.initials: K
authors.lastname: Raynor
authors.forename: J
authors.initials: J
authors.lastname: Halpern
authors.forename: C
authors.initials: C
authors.lastname: Mendrick
authors.forename: B
authors.initials: B
authors.lastname: Arnold
authors.forename: B
authors.initials: B
authors.lastname: Antonacci
authors.forename: R
authors.initials: R
authors.lastname: Parmegiani
authors.forename: T
authors.initials: T
authors.lastname: Yarosh-Tomaine
authors.forename: G H
authors.initials: GH
authors.lastname: Miller
authors.forename: R S
authors.initials: RS
authors.lastname: Hare
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D001230:Aspergillus / Q000187:drug effects*; D002175:Candida / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D004195:Disease Models, Animal; D008172:Lung Diseases, Fungal / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole