Activities of the triazole D0870 in vitro and against murine blastomycosis.
The novel triazole D0870 was tested for in vitro activity, as well as in vivo in a murine model of pulmonary blastomycosis. In vitro, D0870 had inhibitory and fungicidal activity against Blastomyces dermatitidis (MIC = 0.048 microgram/ml; minimal fungicidal concentration = 0.097 microgram/ml). In vivo, D0870 was approximately 100-fold more active than fluconazole on the basis of milligrams per kilogram of body weight given once daily (QD) against blastomycosis. D0870 doses of both 1 or 10 mg/kg given QD and 10 or 100 mg/kg given every other day prolonged survival (P < 0.001) over fluconazole (100 mg/kg given QD). A D0870 dosage of 1 mg/kg QD was equivalent to fluconazole given at 100 mg/kg in reduction of lung burdens of B. dermatitidis, and D0870 administered at 10 mg/kg QD and 10 or 100 mg/kg every other day caused greater reduction (P < 0.001). However, D0870 at 100 mg/kg given QD was lethally toxic, whereas fluconazole at 100 mg/kg was not. These results indicate that D0870 is an effective therapy for murine blastomycosis and should be further tested.
Department of Medicine, Santa Clara Valley Medical Center, California.
K V
KV
Clemons
L H
LH
Hanson
D A
DA
Stevens
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D001758:Blastomyces / Q000187:drug effects*; D001759:Blastomycosis / Q000188:drug therapy* / Q000382:microbiology; D015725:Fluconazole / Q000494:pharmacology; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D014230:Triazoles / Q000494:pharmacology*
D000935:Antifungal Agents; D014230:Triazoles; C058219:ICI 195739; D015725:Fluconazole