Comparison of a new triazole antifungal agent, Schering 56592, with itraconazole and amphotericin B for treatment of histoplasmosis in immunocompetent mice

A murine model of intratracheally induced histoplasmosis was used to evalua te a new triazole antifungal agent, Schering (SCH) 56592, for treatment of histoplasmosis, MICs were determined for SCH 56592, amphotericin B, and itr aconazole by testing yeast-phase isolates from 20 patients by a macrobroth dilution method. The MICs at which 90% of the isolates are inhibited were f or 0.019 mu g/ml for SCH 56592, 0.5 mu g/ml for amphotericin B, and less th an or equal to 0.019 mu g/ml for itraconazole. Survival studies were done o n groups of 10 B6C3F(1) mice with a lethal inoculum of 10(5), All mice rece iving 5, 1, or 0.25 mg of SCH 56592 per kg of body weight per day, 2.5 mg o f amphotericin B per kg every other day (qod), or 75 mg of itraconazole per kg per day survived to day 29, Only 44% of mice receiving 5 mg of itracona zole/kg/day survived to day 29, Fungal burden studies done in similar group s of mice with a sublethal inoculum of 10(4) showed a reduction in CFUs and Histoplasma antigen levels in lung and spleen tissue in animals treated wi th 2 mg of amphotericin B/kg qod, 1 mg of SCH 56592/kg/day, and 75 mg of it raconazole/kg/day, but not in those treated with lower doses of the study d rugs (0.2 mg of amphotericin B/kg god, 0.1 mg of SCH 56592/kg/day, or 10 mg of itraconazole/kg/day), Serum drug concentrations were measured 3 and 24 h after the last dose in mice (groups of five to seven mice), each treated for 7 days with SCH 56592 (10 and 1 mg/kg/day) and itraconazole (75 and 10 mg/kg/day). Mean levels measured by bioassay were as follows: SCH 56592, 10 mg/kg/day (2.15 mu g/ml at 3 h and 0.35 mu g/ml at 24 h); SCH 56592, 1 mg/ kg/day (0.54 mu g/ml at 3 h and none detected at 24 h); itraconazole, 75 mg /kg/day (22.53 mu g/ml at 3 h and none detected at 24 h); itraconazole, 10 mg/kg/day (1.33 mu g/ml at 3 h and none detected at 24 h), Confirmatory res ults were obtained by high-pressure liquid chromatography assay. These stud ies show SCH 56592 to be a promising candidate for studies of treatment of histoplasmosis in humans.