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Antimicrobial Agents and Chemotherapy, December 1998, p. 3245-3250, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Induction of Resistance to Azole Drugs in Trypanosoma cruzi

Frederick S. Buckner,1,* Aaron J. Wilson,1 Theodore C. White,2,3 and Wesley C. Van Voorhis1,3

Department of Medicine, Infectious Diseases, University of Washington, Seattle, Washington 98195-71851; Seattle Biomedical Research Institute, Seattle, Washington 981092; and Department of Pathobiology, University of Washington, Seattle, Washington 981953

Received 11 May 1998/Returned for modification 21 July 1998/Accepted 28 September 1998

Trypanosoma cruzi is the protozoan parasite that causes Chagas' disease, a frequently fatal illness affecting the heart and gastrointestinal systems. An estimated 16 million to 18 million people in Latin America and 50,000 to 100,000 people in the United States are infected with this pathogen. Treatment options for T. cruzi infections are suboptimal due to the toxicities and limited effectiveness of the available drugs. Azole antimicrobial agents have been discovered to have antitrypanosomal activity by inhibition of ergosterol synthesis. The triazole itraconazole was recently shown to produce a parasitologic cure rate of 53% in chronically infected patients (W. Apt et al., Am. J. Trop. Med. Hyg. 59:133-138, 1998), a result which may lead to more use of this family of drugs for the treatment of T. cruzi infections. In the experiments reported on here, resistance to azoles was induced in vitro by serial passage of mammalian-stage parasites in the presence of fluconazole for 4 months. These parasites were cross resistant to the other azoles, ketoconazole, miconazole, and itraconazole. They remained susceptible to benznidazole and amphotericin B. The azole-resistant phenotype was stable for more than 2 months of in vitro serial passage without fluconazole. In addition, the parasites resisted treatment in mice receiving ketoconazole. The rapid development of azole resistance in T. cruzi in vitro suggests that resistance to azole drugs has the potential to occur in patients and may pose an impediment to the progress being made in the treatment of T. cruzi infection.

* Corresponding author. Mailing address: Infectious Diseases, University of Washington, Box 357185, Seattle, WA, 98195-7185. Phone: (206) 543-7902. Fax: (206) 685-8681. E-mail: fbuckner{at}u.washington.edu.

Antimicrobial Agents and Chemotherapy, December 1998, p. 3245-3250, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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