VARIATION IN FLUCONAZOLE EFFICACY FOR CANDIDA-ALBICANS STRAINS SEQUENTIALLY ISOLATED FROM ORAL CAVITIES OF PATIENTS WITH AIDS IN AN EXPERIMENTAL MURINE CANDIDIASIS MODEL

Four strains of Candida albicans, isolated from two patients with AIDS who had undergone prolonged fluconazole therapy for oral candidiasis, were studied in a model of disseminated murine candidiasis. Pre- and posttreatment isolates from each patient were genetically related, and the fluconazole MICs for the strains had increased significantly, fro m 0.25 to 32 mu g/ml for the strains isolated from patient 1 and from 1.0 to 16 mu g/ml for the strains isolated from patient 2. Mice were i nfected intravenously and were treated orally with fluconazole. For su rvival studies, mice were treated from day 1 to day 10 postinfection a nd were observed through day 30. The fluconazole dosages were as follo ws: 0.25, 0.5, 1.0, and 5.0 mg/kg of body weight twice a day. For tiss ue burden studies, two groups of mice (each group received fluconazole at 0.25 or 5.0 mg/kg) were treated from day 1 to day 7 and were sacri ficed 1 day later for quantitative tissue cultures of the spleen and b oth kidneys. For pretreatment isolates from both patients, all flucona zole dosing regimens were effective at prolonging survival compared wi th the survival of the control groups. For posttreatment isolates, onl y fluconazole at 5.0 mg/kg was effective at prolonging survival. Both fluconazole dosing regimens used in the tissue burden studies signific antly reduced the counts of the pretreatment isolate from patient 1 in the spleen and kidney, while fluconazole at 5.0 mg/kg was effective a t reducing the counts of the posttreatment isolate, For both isolates from patient 2, only fluconazole at 5.0 mg/kg was effective at reducin g the counts in the spleen and kidney. The study indicates that C. alb icans mutation to resistance to fluconazole may play a critical role i n fluconazole-refractory oral candidiasis in AIDS patients.