Activities of D0870, a novel triazole, against Candida lusitaniae and Trichosporon beigelii in experimental murine infections.

Candida lusitaniae and Trichosporon beigelii may cause life-threatening infections in the immunocompromisedhostandmayberesistanttoamphotericinB.Weassessedtheactivitiesofanewtriazole,D0870,against one T. beigelii and four C. lusitaniae strains, in comparison with those of fluconazole and amphotericin B. Immunosuppressed CF1 mice, intravenously infected with each fungal strain, received 3 days of therapy with oral D0870 (5 or 25 mg/kg of body weight daily),fluconazole (5 to 50 mg/kg daily), or parenteral amphotericin B (1 or 2 mg/kg daily). Survival was significantly prolonged and kidney fungus titers were reduced in mice treated with D0870 compared with untreated mice (P #0.05). Treatment with D0870 was significantly more effective than that with amphotericin B orfluconazole in animals infected with two of theC. lusitaniaestrains and equally effective for the remaining two C. lusitaniae strains and the T. beigelii strain. Fluconazole and amphotericin B failed to improve the survival of mice infected with one and twoC. lusitaniaestrains, respectively. D0870 was active against all the organisms tested, including those resistant tofluconazole and amphotericin B. Candida lusitaniae and Trichosporon beigelii can cause lifethreatening hematogenous infections in patients with hematologic malignancies (1, 5, 13, 14). Both agents are frequently resistant to amphotericin B, and management of infections caused by these organisms may be difficult (16, 22). We tested the in vitro and in vivo antifungal activities of D0870, a new orally administered bis-triazole, in comparison with those of fluconazole and amphotericin B against one T. beigelii strain and four C. lusitaniae strains. D0870 is the mycologically active R-enatiomer of ICI195,739, which shows promise as a potent broad-spectrum antifungal agent (7‐12, 17‐21, 23) and in a recent clinical pilot study proved safe and effective for the treatment for AIDS patients with oropharyngeal candidiasis unresponsive tofluconazole (6). Animals.Four-week-old CF1 male mice (average weight, 25 g; Harlan-Sprague Breeding Laboratories, Indianapolis, Ind.) were used. Animal studies were performed in accordance with the guidelines of the Animal Welfare Act and the National Institutes of Health for the care and use of laboratory animals. Organisms.OneC.lusitaniaestrain(CL5W31)knowntobe resistant to amphotericin B and one T. beigelii isolate (TCM 756) were kindly provided by W. G. Merz (Johns Hopkins Medical Institutions, Baltimore, Md.) and M. G. Rinaldi (The University of Texas Health Science Center, San Antonio, Tex.), respectively. Three additionalC. lusitaniaeisolates (CL 1706, CL 2819, and CL 524) were recovered from the blood of patients cared for at The University of Texas M. D. Anderson Cancer Center, Houston, Tex. All isolates were maintained in water stock and subcultured on Sabouraud’s dextrose agar (SDA) plates. Inocula of C. lusitaniae for in vitro and in vivo studies were prepared by suspending yeast cells in sterile 0.9% NaCl and adjusting the mixture to 5% spectrophotometric transmission (Spectronic 20; Bausch & Lomb, Rochester, N.Y.). Inocula for theT. beigeliiexperiments were prepared as follows. Twenty-four hours after incubation at 358 C, 5m l of 0.9% NaCl was added to the SDA plates. A bent glass rod was gentlyusedtodislodgethecoloniesofT.beigeliifromtheplate