ici-195739 and 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.

Topics: Animals; Antifungal Agents; Blastomyces; Blastomycosis; Fluconazole; Male; Mice; Microbial Sensitivity Tests; Triazoles

ICI 195,739, a novel orally active triazole, proved 50 times as potent as ketoconazole, produced a clinical cure, and completely eradicated residual infection in a murine model of pulmonary blastomycosis. No other previously tested azole has shown similar activity. Fungicidal activity against Blastomyces dermatitidis was seen in vitro at concentrations 1/40 of those achieved in serum with protective doses.

Topics: Animals; Antifungal Agents; Blastomyces; Blastomycosis; Ketoconazole; Male; Mice; Mice, Inbred BALB C; Time Factors; Triazoles