EMERGENCE OF AZOLE DRUG-RESISTANCE IN CANDIDA SPECIES FROM HIV-INFECTED PATIENTS RECEIVING PROLONGED FLUCONAZOLE THERAPY FOR ORAL CANDIDOSIS

We examined the effect of different fluconazole treatment regimens on the emergence of azole drug resistance among Candida species recovered from the mouths of 54 HIV-infected individuals. Patients were assigned to one of three treatment groups depending on their history of oral candidosis and fluconazole use. Mouthwashes obtained at regular intervals were cultured and isolates identified using standard methods. Antifungal broth micro-dilution tests were performed to determine IC(30)s of fluconazole and ketoconazole. Sixty-four Candida albicans isolates from 20 patients with no evidence of oral candidosis who had not received fluconazole all had IC(30)s of less than or equal to 4 mg/L. Thirty-four (83%) of 41 C. albicans isolates from ten patients receiving intermittent, short-term fluconazole treatment for oral candidosis had IC(30)s of less than or equal to 4 mg/L, but only two isolates (5%) had IC(30)s greater than or equal to 64 mg/L. In contrast, 26 (40%) of 65 C. albicans isolates from 15 patients given long-term fluconazole (50-200 mg/day or 150 mg/week) were classified as resistant having IC(30)s of fluconazole of greater than or equal to 64 mg/L. Ten of these 26 fluconazole-resistant isolates were susceptible to ketoconazole with IC(30)s of less than or equal to 4 mg/L suggesting azole drug cross-resistance is not inevitable. Tests on multiple colonies from individual isolation plates showed that it was not unusual to obtain differing IC30 values, indicating that a sweep inoculum is essential if resistance is to be detected. Nine (60%) of the 15 patients given long-term fluconazole harboured isolates of C. albicans that were resistant to fluconazole at some time during the study period. All had low CD4 counts and were approaching the final stage of their illness. Three patients on long-term treatment had resistant organisms at the outset of the study; in the remainder, resistant strains emerged during the study period. In six of the nine cases, emergence of resistance in vitro correlated with persistent clinical signs of oral infection. Thirty-six isolates of Candida species other than C. albicans were also recovered from patients receiving long-term fluconazole and 29 (81%) of these had IC(30)s of greater than or equal to 64 mg/L. Our experience with C. albicans in patients with HIV infection, suggests that the long-term azole drug use may be an important factor in the development of fluconazole resistance as such resistance was rare and transient in patients on intermittent short-term treatment.