In vitro and in vivo activities of SCH 56592 (posaconazole), a new triazole antifungal agent, against Aspergillus and Candida.
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.
Cacciapuoti
A
A
Schering-Plough Research Institute, Kenilworth, New Jersey 07033-1300, USA. anthony.cacciapuoti@spcorp.com
Loebenberg
D
D
Corcoran
E
E
Menzel
F
F
Moss
E L
EL
Norris
C
C
Michalski
M
M
Raynor
K
K
Halpern
J
J
Mendrick
C
C
Arnold
B
B
Antonacci
B
B
Parmegiani
R
R
Yarosh-Tomaine
T
T
Miller
G H
GH
Hare
R S
RS
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
D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole