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Antimicrobial Agents and Chemotherapy, February 1999, p. 322-328, Vol. 43, No. 2
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Comparison of a New Triazole Antifungal Agent, Schering 56592, with Itraconazole and Amphotericin B for Treatment of Histoplasmosis in Immunocompetent Mice

Patricia Connolly,1,2 Joe Wheat,1,2,3,4,* Carol Schnizlein-Bick,1 Michelle Durkin,1,2 Steve Kohler,2,4 Melinda Smedema,1,2 Janet Goldberg,1,2 Edward Brizendine,1 and David Loebenberg5

Department of Medicine1 and Department of Pathology and Laboratory Medicine,3 Indiana University School of Medicine, Department of Veterans' Affairs Hospital,4 and Histoplasmosis Reference Laboratory,2 Indianapolis, Indiana, and Schering-Plough Research Institute, Kenilworth, New Jersey5

Received 10 July 1998/Returned for modification 18 August 1998/Accepted 11 November 1998

A murine model of intratracheally induced histoplasmosis was used to evaluate a new triazole antifungal agent, Schering (SCH) 56592, for treatment of histoplasmosis. MICs were determined for SCH 56592, amphotericin B, and itraconazole by testing yeast-phase isolates from 20 patients by a macrobroth dilution method. The MICs at which 90% of the isolates are inhibited were for 0.019 µg/ml for SCH 56592, 0.5 µg/ml for amphotericin B, and <= 0.019 µg/ml for itraconazole. Survival studies were done on groups of 10 B6C3F1 mice with a lethal inoculum of 105. All mice receiving 5, 1, or 0.25 mg of SCH 56592 per kg of body weight per day, 2.5 mg of 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 itraconazole/kg/day survived to day 29. Fungal burden studies done in similar groups of mice with a sublethal inoculum of 104 showed a reduction in CFUs and Histoplasma antigen levels in lung and spleen tissue in animals treated with 2 mg of amphotericin B/kg qod, 1 mg of SCH 56592/kg/day, and 75 mg of itraconazole/kg/day, but not in those treated with lower doses of the study drugs (0.2 mg of amphotericin B/kg qod, 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 µg/ml at 3 h and 0.35 µg/ml at 24 h); SCH 56592, 1 mg/kg/day (0.54 µg/ml at 3 h and none detected at 24 h); itraconazole, 75 mg/kg/day (22.53 µg/ml at 3 h and none detected at 24 h); itraconazole, 10 mg/kg/day (1.33 µg/ml at 3 h and none detected at 24 h). Confirmatory results were obtained by high-pressure liquid chromatography assay. These studies show SCH 56592 to be a promising candidate for studies of treatment of histoplasmosis in humans.

* Corresponding author. Mailing address: Histoplasmosis Reference Laboratory, 1001 W. Tenth St., OPW 430, Indianapolis, IN 46202. Phone: (317) 630-6262. Fax: (317) 630-7522. E-mail: lwheat{at}iupui.edu.

Antimicrobial Agents and Chemotherapy, February 1999, p. 322-328, Vol. 43, No. 2
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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