FLUCONAZOLE VERSUS CANDIDA-ALBICANS - A COMPLEX RELATIONSHIP

A murine model of systemic candidiasis was used to assess the virulenc e of serial Candida albicans strains for which fluconazole MICs sere i ncreasing. Serial isolates from five patients with 17 episodes of orop haryngeal candidiasis were evaluated. The MICs for these isolates exhi bited at least an eightfold progressive increase from susceptible (MIC < 8 mu g/ml; range, 0.25 to 4 mu g/ml) to resistant (MIC greater than or equal to 16 mu g/ml; range, 16 to greater than or equal to 128 mu g/ml). Virulence of the serial isolates from three of five patients sh owed a more than fivefold progressive decrease in the dose accounting for 50% mortality and was associated with development of fluconazole r esistance. Low doses of fluconazole prolonged survival of mice infecte d with susceptible yeasts but failed to prolong survival following cha llenge with a resistant strain. In addition, a decreased burden of ren al infection was noted in mice challenged with two of the three resist ant strains. This was consistent with reduced virulence. Fluconazole d id not further decrease the level of infection. In the isolates with a decrease in virulence, two exhibited overexpression of CDR, which enc odes an ABC drug efflux pump. In contrast, serial isolates from the re maining two patients with the development of resistance did not demons trate a change in virulence and fluconazole remained effective in prol onging survival, although significantly higher doses of fluconazole we re required for efficacy, Resistant isolates from both of these patien ts exhibited overexpression of MDR, This study demonstrates that decre ased virulence of serial C. albicans isolates is associated with incre asing fluconazole MICs in some cases but not in others and shows that these low-virulence strains may not consistently cause infection.