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Induction of resistance to azole drugs in Trypanosoma cruzi
F S Buckner1, A J Wilson, T C White
1Department of Medicine, Infectious Diseases, University of Washington, Seattle, Washington 98195-7185, USA. fbuckner@u.washington.edu
Insights
Drug resistance to azoles in Trypanosoma cruzi (the parasite causing Chagas' disease) can develop rapidly in vitro. This acquired resistance may hinder the effectiveness of azole drugs for treating Chagas' disease patients.
Area of Science:
- * Infectious Diseases
- * Parasitology
- * Antimicrobial Resistance
Background:
- * Chagas' disease, caused by Trypanosoma cruzi, affects millions globally and has limited treatment options.
- * Azole antifungals show promise against T. cruzi by inhibiting ergosterol synthesis.
- * Itraconazole demonstrated a 53% cure rate in patients with chronic T. cruzi infections.
Purpose of the Study:
- * To investigate the potential for developing azole resistance in Trypanosoma cruzi.
- * To assess the stability and cross-resistance patterns of azole-resistant T. cruzi strains.
- * To evaluate the in vivo efficacy of azole treatment in the presence of induced resistance.
Main Methods:
- * Induction of azole resistance in vitro through serial passage of mammalian-stage T. cruzi with fluconazole.
- * Testing cross-resistance to other azoles (ketoconazole, miconazole, itraconazole) and non-azole drugs (benznidazole, amphotericin B).
- * Assessing the stability of the resistant phenotype during prolonged in vitro culture without the selective drug.
- * Evaluating treatment efficacy in a mouse model using ketoconazole.
Main Results:
- * In vitro serial passage rapidly induced stable resistance to fluconazole in T. cruzi.
- * The induced azole resistance conferred cross-resistance to ketoconazole, miconazole, and itraconazole.
- * Azole-resistant parasites remained susceptible to benznidazole and amphotericin B.
- * The resistant phenotype was stable for over two months without drug pressure.
- * Ketoconazole treatment was ineffective in mice infected with azole-resistant T. cruzi.
Conclusions:
- * Rapid in vitro development of stable azole resistance in T. cruzi is achievable.
- * Azole resistance in T. cruzi has the potential to emerge in patients, complicating treatment.
- * The findings highlight the need for careful monitoring and alternative therapeutic strategies for Chagas' disease.
Abstract:
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.