Comparison of a new triazole, posaconazole, with itraconazole and amphotericin B for treatment of histoplasmosis following pulmonary challenge in immunocompromised mice

A murine model of intratracheally induced histoplasmosis in immunocompromis ed B6C3F(1) mice was used to evaluate a new triazole antifungal agent, posa conazole. This compound was previously shown to be comparable to amphoteric in B and superior to itraconazole for the treatment of histoplasmosis in im munocompetent mice. The current study used mice that were depleted of T lym phocytes by intraperitoneal injection of anti-CD4 and anti-CD8 monoclonal a ntibodies beginning 2 days before infection and continuing at 5-day interva ls until completion of the study. Groups of B6C3F(1) mice that were deplete d of CD4 and CD8 T cells were infected with an inoculum of 10(4) Histoplasm a capsulatum yeasts. All mice receiving posaconazole at 1 or 0.1 mg/kg of b ody weight/day, amphotericin B at 2 mg/kg every other day (qod), or itracon azole at 75 mg/kg/day survived to day 29. Only 60% of mice receiving itraco nazole at 10 mg/kg/day and none receiving amphotericin B at 0.2 mg/kg qod s urvived to that date. Fungal burdens were determined at day 14 of infection , 1 day after discontinuation of therapy. Quantitative colony counts and Hi stoplasma antigen levels in lung and spleen tissues declined following trea tment 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 amphoterici n B at 0.2 mg/kg god or itraconazole at 10 mg/kg/day. Posaconazole at 0.1 m g/kg/day reduced fungal colony counts and antigen levels in spleens but not in lungs. This study shows posaconazole activity for the treatment of hist oplasmosis in immunosuppressed animals.