       Document 0833
 DOCN  M9590833
 TI    Emergence of azole drug resistance in Candida species from HIV-infected
       patients receiving prolonged fluconazole therapy for oral candidosis.
 DT    9509
 AU    Johnson EM; Warnock DW; Luker J; Porter SR; Scully C; PHLS Mycology
       Reference Laboratory, Public Health Laboratory,; Bristol, UK.
 SO    J Antimicrob Chemother. 1995 Jan;35(1):103-14. Unique Identifier :
       AIDSLINE MED/95286440
 AB    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 IC30s
       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 IC30s of < or = 4 mg/L. Thirty-four (83%)
       of 41 C. albicans isolates from ten patients receiving intermittent,
       short-term fluconazole treatment for oral candidosis had IC30s of < or =
       4 mg/L, but only two isolates (5%) had IC30s > or = 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 IC30s of fluconazole of > or = 64 mg/L. Ten of these 26
       fluconazole-resistant isolates were susceptible to ketoconazole with
       IC30s of < or = 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 IC30s of > or
       = 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.
 DE    Antifungal Agents/*PHARMACOLOGY  Azoles/*PHARMACOLOGY  Candida
       albicans/*DRUG EFFECTS  Candidiasis, Oral/COMPLICATIONS/DRUG
       THERAPY/*MICROBIOLOGY  Drug Resistance, Microbial
       Fluconazole/PHARMACOLOGY/*THERAPEUTIC USE  Human  HIV
       Infections/*COMPLICATIONS  Ketoconazole/PHARMACOLOGY  Microbial
       Sensitivity Tests  Mouth/MICROBIOLOGY  Support, Non-U.S. Gov't  CLINICAL
       TRIAL  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

