Therapeutic effect of the triazole Bay R 3783 in mouse models of coccidioidomycosis, blastomycosis, and histoplasmosis

Abstract

A new triazole, Bay R 3783, was compared with ketoconazole, itraconazole, and fluconazole, which were given via the alimentary tract at three dosages, and amphotericin B, which was given at 1 mg/kg intraperitoneally, in murine models of the systemic mycoses coccidioidomycosis, histoplasmosis, and blastomycosis. In a pulmonary coccidioidomycosis model, Bay R 3783, fluconazole, and itraconazole were essentially equally efficacious and more active than ketoconazole in protecting mice against death; but they were inferior to amphotericin B. In a short-term organ load experiment, Bay R 3783 and amphotericin B were equally effective and were more effective than the other drugs in reducing the amount of Coccidioides immitis in the lungs. Against meningocerebral coccidioidomycosis, Bay R 3783, itraconazole, and fluconazole at 25 mg/kg and amphotericin B prevented death only during therapy, with mortalities ensuing shortly thereafter. In mice with systemic histoplasmosis, Bay R 3783 and itraconazole at 25 mg/kg and amphotericin B prevented death in all mice through a 44-day observation period. Clearance of Histoplasma capsulatum from organs was similar in mice treated with Bay R 3783 and itraconazole; this clearance was greater than that in mice treated with ketoconazole and fluconazole but less than that in mice treated with amphotericin B. In mice with systemic blastomycosis, Bay R 3783 at 25 mg/kg yielded 90% survivors at 60 days, which was greater than that achieved with amphotericin B (60%) or itraconazole (30%). Clearance of Blastomyces dermatitidis from the lungs was greatest with Bay R 3783, followed by that with amphotericin B, itraconazole, fluconazole, and ketoconazole, in that order. Therefore, Bay R 3783 showed effectiveness comparable to or exceeding those of itraconazole and fluconazole and exceeding that of ketoconazole against these systemic mycoses in mice.The chemotherapy of systemic infections caused by dimorphic fungi has relied on amphotericin B for three decades, and in recent years this polyene has been supplemented or supplanted by flucytosine and by the antifungal azoles. Whereas miconazole has found some utility by the parenteral, particularly intrathecal and intraventricular, routes (15), other azoles (ketoconazole, itraconazole, and fluconazole) have the advantage of being effective even when given by the oral route. The newer triazoles itraconazole and fluconazole additionally appear to have the advantages of less toxicity and apparently greater potency than ketoconazole against some systemic pathogens and greater activity than ketoconazole against meningocerebral infections (1-5, 12, 13, 16, 17).Previous in vitro studies with Bay R 3783 and several other azoles against Coccidioides immitis (7) and fluconazole and ketoconazole against Histoplasma capsulatum (14) demonstrated the activity of this class of drug against the dimorphic fungal pathogens. This lead to the present study, in which Bay R 3783 (Fig. 1)

Comparison of Itraconazole and Fluconazole Treatments in a Murine Model of Coccidioidal Meningitis

“…This model differs from those reported previously (7,15,27) in the method of central nervous system (CNS) infection and the form of the organism used for infection. The model mimics the disease in humans and appears to be appropriate for the testing of therapy.…”

“…For the analysis of the fungal burdens in the surviving animals, a value of 8 log 10 CFU/g was given to missing datum points (due to the death of the animal) (21,27). Horizontal lines, median log 10 of numbers of CFU/g tissue; * , P Ͻ 0.001 versus the results for the control; †, P Ͻ 0.05 for the results for ICZ versus the results for FCZ at 25 mg/kg; ‡, P Ͻ 0.005 for the results for ICZ versus the results for FCZ at 25 mg/kg.…”

In Vitro Antifungal Activity of Micafungin (FK463) against Dimorphic Fungi: Comparison of Yeast-Like and Mycelial Forms

“…Kobayashi et al reported that, in a mouse model, FLC was more effective against histoplasmosis caused by a highly FLC-resistant strain (MIC for the Y form, Ͼ1,000 g/ml) than against that caused by a susceptible strain (MIC for the Y form, 0.78 g/ml) (13). Pappagianis et al demonstrated that three azole drugs had comparable efficacies against a murine pulmonary infection by C. immitis for which the MICs (for either spherules or endospores) of the three drugs were considerably different (0.25, 1.0, and Ͼ64 g/ml) and concluded that the results of the in vitro susceptibility tests for this fungus were not predictive of therapeutic outcome (23). In addition, notwithstanding that the Y forms of H. capsulatum and B. dermatitidis showed relatively high susceptibility to FLC in this study (Candida isolates for which the MIC of FLC is 8 g/ml or lower are categorized as susceptible), FLC is described as having poor clinical efficacy against histoplasmosis and blastomycosis (15).…”

Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models

“…Mice were infected intracerebrally according to a previously published model (20,21) for the CNS studies. Briefly, anesthetized mice were inoculated through the calvarium with a target dose of 90 spores in 30 l of saline.…”