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Antimicrobial Agents and Chemotherapy, October 2000, p. 2604-2608, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Comparison of a New Triazole, Posaconazole, with Itraconazole and Amphotericin B for Treatment of Histoplasmosis following Pulmonary Challenge in Immunocompromised Mice

Patricia Connolly,1,2,* L. Joseph 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 22 December 1999/Returned for modification 9 April 2000/Accepted 22 June 2000

A murine model of intratracheally induced histoplasmosis in immunocompromised B6C3F1 mice was used to evaluate a new triazole antifungal agent, posaconazole. This compound was previously shown to be comparable to amphotericin B and superior to itraconazole for the treatment of histoplasmosis in immunocompetent mice. The current study used mice that were depleted of T lymphocytes by intraperitoneal injection of anti-CD4 and anti-CD8 monoclonal antibodies beginning 2 days before infection and continuing at 5-day intervals until completion of the study. Groups of B6C3F1 mice that were depleted of CD4 and CD8 T cells were infected with an inoculum of 104 Histoplasma capsulatum yeasts. All mice receiving posaconazole at 1 or 0.1 mg/kg of body weight/day, amphotericin B at 2 mg/kg every other day (qod), or itraconazole at 75 mg/kg/day survived to day 29. Only 60% of mice receiving itraconazole at 10 mg/kg/day and none receiving amphotericin B at 0.2 mg/kg qod survived to that date. Fungal burdens were determined at day 14 of infection, 1 day after discontinuation of therapy. Quantitative colony counts and Histoplasma antigen levels in lung and spleen tissues declined following treatment with amphotericin B at 2 mg/kg qod, posaconazole at 5 and 1 mg/kg/day, and itraconazole at 75 mg/kg/day but not in mice treated with amphotericin B at 0.2 mg/kg qod or itraconazole at 10 mg/kg/day. Posaconazole at 0.1 mg/kg/day reduced fungal colony counts and antigen levels in spleens but not in lungs. This study shows posaconazole activity for the treatment of histoplasmosis in immunosuppressed animals.

* 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: paconnol{at}iupui.edu.

Antimicrobial Agents and Chemotherapy, October 2000, p. 2604-2608, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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