EXPERIMENTAL ANTIFUNGAL CHEMOTHERAPY IN GRANULOCYTOPENIC ANIMAL-MODELS OF DISSEMINATED CANDIDIASIS - APPROACHES TO UNDERSTANDING INVESTIGATIONAL ANTIFUNGAL COMPOUNDS FOR PATIENTS WITH NEOPLASTIC DISEASES

Disseminated candidiasis is the most common life-threatening invasive fungal infection in granulocytopenic patients. A review of recent approaches to pre-clinical laboratory investigation of promising antifungal compounds, which may have potential utility in granulocytopenic patients is presented. A particularly useful strategy is the study of persistently granulocytopenic rabbit models of acute, subacute, and chronic forms of disseminated candidiasis. When the antifungal triazoles (fluconazole, itraconazole, and SCH 39304 [SCH 42427]) were each evaluated for use as preventive, early treatment, or delayed treatment in the different models, the triazoles were consistently more active when used for preventive and early treatment than for delayed treatment. These triazoles were as active as amphotericin B plus flucytosine (AB + FC) when used for early treatment but were less active than AB + FC when used for delayed treatment. Several lipid formulations of amphotericin B demonstrate reduced nephrotoxicity at higher safely achievable dosages in comparison to those of deoxycholate amphotericin B in several models of disseminated candidiasis. When administered to follow non-linear saturable Michaelis-Menten-type plasma pharmacokinetics, the antifungal activity of the echinocandin compound cilofungin was significantly augmented. Thoughtfully designed and carefully conducted laboratory investigations in appropriate animal models of disseminated candidiasis can provide a scientific foundation and guide for development of clinical protocols investigating new approaches to prevention and treatment of invasive candidiasis in granulocytopenic patients.