CLINICALLY SIGNIFICANT AZOLE CROSS-RESISTANCE IN CANDIDA ISOLATES FROM HIV-POSITIVE PATIENTS WITH ORAL CANDIDOSIS

Objectives: To determine the proportion of fluconazole-resistant Candi da albicans isolates that have clinically significant cross-resistance to itraconazole or ketoconazole, that is sufficient to result in fail ure of these agents at their standard doses (200 and 400 mg daily for 7 days, respectively). Methods: Seven hundred C. albicans isolates fro m HIV-positive patients with oral candidosis underwent susceptibility testing using a relative growth method, for which cut-off values corre sponding to clinical drug failure have been established. Results: A to tal of 431 isolates were fully azole-susceptible and three main resist ance patterns were detected: isolates resistant to fluconazole alone ( n = 100); isolates resistant to fluconazole and ketoconazole but susce ptible to itraconazole (n = 94); and isolates resistant to all three d rugs (n = 50). No isolates were consistently resistant to ketoconazole without being fluconazole-resistant, and no itraconazole resistance w as detected without ketoconazole resistance. Resistance to fluconazole alone was more common in specimens obtained soon after first clinical fluconazole failure, whereas specimens from patients with a longer hi story of fluconazole-unresponsive candidosis were more likely to be in fected with cross-resistant isolates. Median days of prior azole expos ure and cumulative fluconazole dose were significantly less for those with isolates resistant to fluconazole alone than for those with ketoc onazole cross-resistant isolates, who had received less azole therapy and smaller cumulative fluconazole doses than those with isolates cros s-resistant to all three drugs (although not statistically significant ). After the diagnosis of fluconazole-unresponsive candidosis, increas ing cumulative doses of itraconazole solution were associated with inc reasing likelihood of cross-resistance. Conclusions: Clinically signif icant cross-resistance to other azoles may occur in fluconazole-resist ant isolates of C. albicans, although initially most isolates are not cross-resistant and the detection of cross-resistant isolates is assoc iated with a history of greater prior azole exposure. Patients who hav e been treated for fluconazole-resistant candidosis for longer and wit h greater cumulative doses of itraconazole solution tend to become inf ected with increasingly cross-resistant isolates of C. albicans.