Antagonism of azole activity against Candida albicans following induction of multidrug resistance genes by selected antimicrobial agents

Antifungal azoles (e.g., fluconazole) are widely used for prophylaxis or tr eatment of Candida albicans infections in immunocompromised individuals, su ch as those with AIDS. These individuals are frequently treated with a vari ety of additional antimicrobial agents. Potential interactions between thre e azoles and 16 unrelated drugs (antiviral, antibacterial, antifungal, and antiprotozoal agents) were examined in vitro. Two compounds, tested at conc entrations achievable in serum, demonstrated an antagonistic effect on azol e activity against C. albicans, At fluconazole concentrations two to four t imes the 50% inhibitory concentration, C. albicans growth (relative to trea tment with fluconazole alone) increased 3- to IS-fold in the presence of al bendazole (2 mu g/ml) or sulfadiazine (50 mu g/ml). Antagonism (3- to 78-fo ld) of ketoconazole and itraconazole activity by these compounds was also o bserved. Since azole resistance has been correlated with overexpression of genes encoding efflux proteins, we hypothesized that antagonism results fro m drug-induced overexpression of these same genes. Indeed, brief incubation of C. albicans with albendazole or sulfadiazine resulted in a 3-to->10-fol d increase in RNAs encoding multidrug transporter Cdr1p or Cdr2p. Zidovudin e, trimethoprim, and isoniazid, which were not antagonistic with azoles, di d not induce these RNAs, Fluphenazine, a known substrate for Cdr1p and Cdr2 p, strongly induced their RNAs and, consistent with our hypothesis, strongl y antagonized azole activity. Finally, antagonism was shown to require a fu nctional Cdr1p. The possibility that atole activity against C. albicans is antagonized in vivo as well as in vitro in the presence of albendazole and sulfadiazine warrants investigation. Drug-induced overexpression of efflux proteins represents a new and potentially general mechanism for drug antago nism.