No abstract

We describe a patient with recurrent episodes of oropharyngeal candidiasis who required progressively higher doses of fluconazole to control and infection. The patient was treated for 14 infections over a 2-year period with doses of fluconazole that ranged from 100 to 800 mg per day. Clinical response, two methods of in vitro susceptibility testing, and molecular epidemiologic techniques were evaluated for 12 of the 14 episodes. Ultimately, the patient became unresponsive clinically to a dose of 800 mg of fluconazole per day. In vitro susceptibility testing of isolates obtained during these successive episodes of infection revealed the development of resistance to fluconazole, and molecular epidemiologic techniques confirmed the persistence of the same Candida albicans strain throughout all 12 episodes.

Neither fluconazole nor itraconazole showed statistically superior efficacy in nonmeningeal coccidioidomycosis, although there is a trend toward slightly greater efficacy with itraconazole at the doses studied.

Oral candidiasis is one of the earliest and most frequent complications of a failing immune system in HIV-infected individuals. For several years, oral candidiasis has been treated effectively with azole drugs, the one most frequently used is fluconazole. Unfortunately, extensive use of the drug for treatment and prophylaxis has led to treatment failure in an increasing number of patients. In most of these cases, strains of C. albicans isolated from the infection are less susceptible to fluconazole. The development of azole resistance in strains of C. albicans has been studied biochemically and more recently with molecular techniques. One excellent example of the development of azole resistance in C. albicans has been documented in a series of 17 C. albicans isolates from a single patient over a 2-year period. During this time, the patient experienced 14 episodes of oral candidiasis and was treated with increasing doses of fluconazole. Molecular and biochemical analyses confirms that the isolates are the same strain of C. albicans and that the resistance in these isolates is stable over 600 generations, suggesting that the changes in this strain are genetic in nature. In addition, the development of resistance is correlated with the identification of a substrain or variant of the original strain, as identified by restriction fragment length polymorphism (RFLP) analysis with the moderately repetitive probe, Ca3. The analysis of this series of isolates demonstrates that azole drug resistance is associated with several small genetic changes, each of which contributes to the overall resistance of the strain. Clearly, continual use of azole drugs by a patient can select for genetic changes that render oral candidiasis refractory to treatment.