sm-8668 and Mycoses

The first oral agents for treatment of mycoses included potassium iodide, griseofulvin and flucytosine. While each is still used in specific indications, the advent of ketoconazole in the late 1980s radically expanded the spectrum and efficacy of oral antifungals. Ketoconazole was the first drug sufficiently potent and benign to permit use for both superficial and deep fungal infections. Ketoconazole quickly proved highly effective in many systemic and cutaneous infections, but it was soon appreciated that high doses caused impairment of testosterone and ultimately cortisol synthesis. Dose-dependent nausea and vomiting also became apparent, as did the necessity for very high doses for treatment of fungal meningitis. Hepatic cellular toxicity was also noticed, particularly after prolonged treatment at high doses. Just as these limitations became apparent, Janssen, Pfizer and, most recently, Schering brought forth the triazole antifungals. These differ markedly in pharmacokinetics and fungal spectrum, requiring careful consideration of the appropriate drug. In addition to the above, terbinafine has been recently developed for dermatophytes, particularly refractory onychomycoses.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Humans; Itraconazole; Ketoconazole; Mycoses; Naphthalenes; Terbinafine; Triazoles

For more than two decades, amphotericin B has been the single broad-spectrum agent for the treatment of systemic mycoses. Amphotericin B is not always effective, must be given parenterally, and is associated with a host of adverse reactions. Despite amphotericin B toxicity, until recently the systemic mycoses did not rate enough attention to prompt a search for new alternatives. However, three recent events have overcome this inertia: the gradually increasing use of potent immunosuppressive agents and broad-spectrum antibacterial drugs; the discovery of the relatively nontoxic azole classes of antifungal drugs in the 1980s and the rapid emergence of AIDS, with its severe accompanying opportunistic fungal infections. In just ten years we have seen the emergence of second-generation imidazole and third-generation triazole antifungal drugs and, most recently, entirely new classes of agents. It is remarkable that so many alternatives are becoming available just at the time when new antifungal drugs have become a major need. This discussion will concentrate on the new antifungal drugs of the past ten years, with the exception of developments in the polyenes and flucytosine, which are covered elsewhere.

Topics: Aminoglycosides; Anti-Bacterial Agents; Antifungal Agents; Azoles; Echinocandins; Fluconazole; Fungi; Humans; Itraconazole; Ketoconazole; Mycoses; Peptides; Peptides, Cyclic; Triazoles

Topics: Animals; Antifungal Agents; Azoles; Fluconazole; Humans; Itraconazole; Ketoconazole; Microbial Sensitivity Tests; Mycoses; Triazoles

Fungal infections are the most common infectious cause of death among patients with hematologic malignancies. Conventional antifungal agents have limited activity and a narrow therapeutic index. In an open-label study we assessed the activity of an oral triazole, SCH 39304, in the treatment of refractory life-threatening mold infections in 50 patients with cancer, most of whom had previously received amphotericin B and/or fluconazole. SCH 39304 was given at a daily dose of 200-400 mg for a median of 8 weeks. The overall rate of response was 79% among 34 evaluable patients, with a complete response in 22 instances and a partial response in 5. Some patients responded despite persistent, profound immunosuppression. Three patients developed relapses, and two developed fungal superinfections. SCH 39304 was well tolerated. We conclude that oral triazoles such as SCH 39304 may represent effective and safe treatment of mold infections in immunosuppressed patients, at least after standard antifungal chemotherapy. Unfortunately, the carcinogenic potential of SCH 39304 in animals has precluded its development. Our hope is that analogues with similar efficacy but without carcinogenic potential can be developed.

Topics: Administration, Oral; Adult; Aged; Antifungal Agents; Female; Humans; Leukemia; Male; Middle Aged; Mycoses; Neoplasms; Opportunistic Infections; Prospective Studies; Triazoles

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.

Topics: Adult; Aged; Amphotericin B; Animals; Antifungal Agents; Child, Preschool; Disease Models, Animal; Female; Fluconazole; Humans; Immunocompromised Host; Male; Mice; Miconazole; Middle Aged; Mycoses; Triazoles; Trichosporon