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

Abstract

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 104showed 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.

Salvage treatment of histoplasmosis with posaconazole

“…27,28 This paper describes the use of posaconazole oral suspension (800 mg/day, in divided doses) as salvage treatment in 6 patients with histoplasmosis.…”

“…Posaconazole is an extended-spectrum triazole antifungal agent with excellent in vitro activity against clinical isolates of H. capsulatum (minimum fungicidal concentration [MFC] 0.5e2.0 mg/mL) 26,27 and activity in murine models of intratracheally induced histoplasmosis. 27,28 This paper describes the use of posaconazole oral suspension (800 mg/day, in divided doses) as salvage treatment in 6 patients with histoplasmosis.…”

A case of disseminated histoplasmosis successfully treated with the investigational drug posaconazole

“…Furthermore, posaconazole was more than 10 times as effective as itraconazole at reducing fungal burdens in the lung and spleen. 13 In our patient, symptoms resolved after 1 month of posaconazole therapy. Serum concentrations of inflammatory markers normalised, and lymphadenopathy resolved.…”

“…Its potent in vitro activity against H. capsulatum 12 was confirmed in murine models, in which posaconazole demonstrated greater efficacy than itraconazole. 13,14 We describe a case of disseminated histoplasmosis in a well-travelled elderly man, who responded to posaconazole after clinical failure of initial itraconazole therapy.…”

“…Third, posaconazole has demonstrated more potent activity in histoplasmosis than itraconazole or amphotericin B in mouse models of H. capsulatum infection 13,14. In CD4-and CD8-depleted mice challenged with lethal intratracheal inoculations of H. capsulatum, low doses of posaconazole (1.0 mg/kg daily and 0.1 mg/kg daily) were as effective as high doses of itraconazole (75 mg/kg daily) or amphotericin B (2 mg/kg every other day)…”