sm-8668 and saperconazole

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

The in vitro activity of saperconazole against eight candidal species (81 strains) was determined and compared with fluconazole, Sch 39304 and amphotericin B. Using brain heart infusion broth with an inoculum of 10(4) CFU/ml, the MIC ranges (micrograms/ml) of saperconazole were: less than or equal to 0.015- greater than 32 for Candida albicans, less than or equal to 0.015-16 for C. tropicalis, less than or equal to 0.015-32 for C. glabrata, less than or equal to 0.015-32 for C. parapsilosis, less than or equal to 0.015-0.12 for C. guilliermondii and less than or equal to 0.015-0.06 for C. krusei. Saperconazole was the most active agent tested against Candida species. Saperconazole and 5-fluorocytosine combinations showed synergistic interactions against Candida species, and no antagonistic interaction was demonstrated. In a rat vaginal candidiasis infection model, saperconazole and fluconazole were equipotent producing 75-100% cures at levels of 0.016-0.25%, respectively, when dosed intravaginally. After single oral dosing, saperconazole was 5-fold more potent than fluconazole with an ED50 value of 0.53 mg/kg. These data demonstrate that saperconazole is effective in a rat vaginal candidiasis infection either with a single oral dose or by intravaginal treatment.

Topics: Amphotericin B; Antifungal Agents; Azoles; Candida; Drug Synergism; Fluconazole; Microbial Sensitivity Tests; Species Specificity; Triazoles