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Antimicrobial Agents and Chemotherapy, August 1999, p. 1968-1974, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Antagonism of Azole Activity against Candida albicans following Induction of Multidrug Resistance Genes by Selected Antimicrobial Agents

Karl W. Henry,* M. Cristina Cruz,dagger Santosh K. Katiyar, and Thomas D. Edlind

Department of Microbiology and Immunology, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania 19129

Received 6 November 1998/Returned for modification 27 January 1999/Accepted 28 May 1999

Antifungal azoles (e.g., fluconazole) are widely used for prophylaxis or treatment of Candida albicans infections in immunocompromised individuals, such as those with AIDS. These individuals are frequently treated with a variety of additional antimicrobial agents. Potential interactions between three azoles and 16 unrelated drugs (antiviral, antibacterial, antifungal, and antiprotozoal agents) were examined in vitro. Two compounds, tested at concentrations achievable in serum, demonstrated an antagonistic effect on azole activity against C. albicans. At fluconazole concentrations two to four times the 50% inhibitory concentration, C. albicans growth (relative to treatment with fluconazole alone) increased 3- to 18-fold in the presence of albendazole (2 µg/ml) or sulfadiazine (50 µg/ml). Antagonism (3- to 78-fold) of ketoconazole and itraconazole activity by these compounds was also observed. Since azole resistance has been correlated with overexpression of genes encoding efflux proteins, we hypothesized that antagonism results from drug-induced overexpression of these same genes. Indeed, brief incubation of C. albicans with albendazole or sulfadiazine resulted in a 3-to->10-fold increase in RNAs encoding multidrug transporter Cdr1p or Cdr2p. Zidovudine, trimethoprim, and isoniazid, which were not antagonistic with azoles, did not induce these RNAs. Fluphenazine, a known substrate for Cdr1p and Cdr2p, strongly induced their RNAs and, consistent with our hypothesis, strongly antagonized azole activity. Finally, antagonism was shown to require a functional Cdr1p. The possibility that azole 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 antagonism.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, MCP Hahnemann School of Medicine, 2900 Queen Ln., Philadelphia, PA 19129. Phone: (215) 991-8374. Fax: (215) 848-2271. E-mail: henryk1{at}auhs.edu.

dagger Present address: Department of Genetics, Duke University Medical Center, Durham, NC 27710.

Antimicrobial Agents and Chemotherapy, August 1999, p. 1968-1974, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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