Buckner F S, Wilson A J, White T C, Van Voorhis W C
Department of Medicine, Infectious Diseases, University of Washington, Seattle, Washington 98195-7185, USA.
Antimicrob Agents Chemother. 1998 Dec;42(12):3245-50. doi: 10.1128/AAC.42.12.3245.
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.
克氏锥虫是一种原生动物寄生虫，可引发恰加斯病，这是一种常累及心脏和胃肠系统且往往致命的疾病。据估计，拉丁美洲有1600万至1800万人以及美国有5万至10万人感染了这种病原体。由于现有药物存在毒性且疗效有限，克氏锥虫感染的治疗选择并不理想。已发现唑类抗菌剂通过抑制麦角固醇合成具有抗锥虫活性。三唑类药物伊曲康唑最近显示，在慢性感染患者中可产生53%的寄生虫学治愈率（W. Apt等人，《美国热带医学与卫生杂志》59:133 - 138，1998年），这一结果可能会促使更多地使用这类药物来治疗克氏锥虫感染。在本文报道的实验中，通过在氟康唑存在的情况下将哺乳动物阶段的寄生虫连续传代4个月，在体外诱导出对唑类的耐药性。这些寄生虫对其他唑类药物酮康唑、咪康唑和伊曲康唑具有交叉耐药性。它们对苯硝唑和两性霉素B仍敏感。在无氟康唑的情况下，体外连续传代2个多月，唑类耐药表型保持稳定。此外，这些寄生虫在接受酮康唑治疗的小鼠中具有抗性。克氏锥虫在体外对唑类耐药性的快速产生表明，患者体内可能会出现对唑类药物的耐药性，这可能会阻碍克氏锥虫感染治疗所取得的进展。
