Comparative efficacies of amphotericin B, triazoles, and combination of both as experimental therapy for murine trichosporonosis.

We assessed the activities of amphotericin B deoxycholate, liposomal amphotericin B, fluconazole, and SCH 39304 against 10 strains of Trichosporon beigelii in mice with hematogenous infections. Cyclophosphamide-immunosuppressed CF1 male mice were challenged intravenously with a lethal inoculum of T. beigelii (5 x 10(6) conidia per mouse) and were assigned to different treatment groups or were left untreated. Amphotericin B deoxycholate (1 mg/kg of body weight and liposomal amphotericin B (1, 5, and 10 mg/kg) were given parenterally once daily. Escalating doses (5, 10, and 20 mg/kg/day) of fluconazole and SCH 39304 were tested. We also compared the activity of amphotericin B deoxycholate plus fluconazole (1 and 10 mg/kg/day, respectively) with that of each agent alone. Fluconazole significantly prolonged the survival of mice infected with each of the 10 strains tested. Amphotericin B deoxycholate achieved various responses, improving the outcomes in mice infected with seven of the strains. Liposomal amphotericin B was not more effective than amphotericin B deoxycholate against the two strains tested. Both fluconazole and SCH 39304 reduced the kidney fungal counts in a dose-dependent pattern, with SCH 39304 being more active than fluconazole against one of the two strains tested. The activity of the combination of amphotericin B deoxycholate plus fluconazole appeared to be superior to that of either agent alone, especially in reducing the kidney fungal burden. Fluconazole is more active than amphotericin B deoxycholate against experimental murine trichosporonosis.

Azole therapy for trichosporonosis: clinical evaluation of eight patients, experimental therapy for murine infection, and review.

We studied the in vivo antifungal activity of azoles in humans and in a murine model of disseminated trichosporonosis. Eight patients infected with Trichosporon species were treated with fluconazole, SCH 39304, or miconazole for 2-26 weeks. Four patients had fungemia, two patients had disseminated trichosporonosis, and one patient each had soft-tissue infection and cystitis. Response of trichosporonosis to azoles was seen in all eight patients, although one patient died with disseminated aspergillosis while still receiving SCH 39304. A literature review indicated that responses to ketoconazole or miconazole were noted in four patients with trichosporonosis. In the experimental infection, amphotericin B, SCH 39304, and fluconazole were effective in prolonging survival and reducing fungal counts in the kidneys of mice infected with a clinical strain of Trichosporon beigelii. Fluconazole but not amphotericin B prolonged survival of mice infected with a clinical strain of Trichosporon capitatum. We conclude that azoles represent effective therapy for infection with Trichosporon species.

A novel murine model of disseminated trichosporonosis.

Serious infections caused by Trichosporon beigelii have been noted with increasing frequency in immuno-compromised patients. Progress in understanding the pathogenesis of this emerging infection has been limited by the lack of an animal model. We developed a CF1 mouse intravenous inoculation model of disseminated trichosporonosis to evaluate the pathogenicity of T. beigelii in transiently immunosuppressed mice. Four inocula (1 x 10(6), 1 x 10(7), 2 x 10(7), and 4 x 10(7) CFU per animal) of one clinical strain of T. beigelii 3001 were tested. Mice in groups of 10 were each injected with a single intravenous dose of one inoculum. Mortality correlated with inoculum size, as survival time was significantly shorter in mice injected with 4 x 10(7) or 2 x 10(7) CFU than in mice that received 1 x 10(7) or 1 x 10(6) CFU (P less than 0.01). Necrotizing abscesses with conidial and hyphal elements and neutrophil and macrophage infiltration were observed in all major organs examined. Resistance to infection was markedly lowered by immunosuppression with either cyclophosphamide or cortisone acetate, with a significantly shorter survival time and a greater fungal burden per organ in immunosuppressed animals than in normal animals (P less than 0.01). Nine additional strains were inoculated intravenously with around 5 x 10(6) CFU. Injection of each of these strains caused 100% mortality, in a pattern similar to that observed with strain 3001.