Rojas Ricardo, Valderrama Liliana, Valderrama Mabel, Varona Maria X, Ouellette Marc, Saravia Nancy G
Centro Internacional de Entrenamiento e Investigaciones Medicas, Cali, Colombia, and Centre Hospitalier Universitaire Laval, Quebec, Canada.
J Infect Dis. 2006 May 15;193(10):1375-83. doi: 10.1086/503371. Epub 2006 Apr 7.
Failure of antimonial therapy has been increasingly reported in anthroponotic visceral leishmaniasis and in cutaneous disease. The role of drug resistance in treatment failure has been difficult to ascertain because therapeutic response is multifactorial, and the efficacy of antimonial drugs depends on an effective immune response. In this study, we sought to determine whether standard treatment selects for resistant organisms and whether drug resistance contributes to treatment failure.
We evaluated the susceptibility to antimony of 19 strains isolated before treatment with meglumine antimoniate and 21 strains isolated at treatment failure from 20 patients. The 50% effective dose (ED50) of antimony in the form of additive-free meglumine antimoniate was determined for intracellular amastigotes in human promonocytic U-937 cells.
Before treatment, 16% of strains (3/19) showed primary resistance (ED50 of >128 microg Sb/mL), whereas 84% (16/19) were susceptible (ED50 of <20 microg Sb/mL). However, 88% of susceptible strains (14/16) had ED90 values of >128 microg Sb/mL. At treatment failure, 40% of strains (8/20) were resistant. Secondary resistance was documented in 4 patients.
Primary and secondary resistance to antimony can contribute to treatment failure in American cutaneous leishmaniasis. Selection for resistance to antimony occurs during standard treatment with antimonial drugs, and primary resistance to antimony supports the plausibility of anthroponotic transmission.
在人源内脏利什曼病和皮肤疾病中，越来越多的报告称锑剂治疗失败。由于治疗反应是多因素的，且锑剂的疗效取决于有效的免疫反应，因此耐药性在治疗失败中所起的作用难以确定。在本研究中，我们试图确定标准治疗是否会选择出耐药菌株，以及耐药性是否会导致治疗失败。
我们评估了20例患者在接受葡甲胺锑酸盐治疗前分离出的19株菌株和治疗失败时分离出的21株菌株对锑的敏感性。测定了人原单核细胞U-937细胞内无添加剂的葡甲胺锑酸盐形式的锑的50%有效剂量（ED50）。
治疗前，16%的菌株（3/19）显示出原发性耐药（ED50>128μg Sb/mL），而84%（16/19）是敏感的（ED50<20μg Sb/mL）。然而，88%的敏感菌株（14/16）的ED90值>128μg Sb/mL。治疗失败时，40%的菌株（8/20）耐药。4例患者出现继发性耐药。
对锑的原发性和继发性耐药可导致美洲皮肤利什曼病治疗失败。在用锑剂进行标准治疗期间会出现对锑的耐药性选择，而对锑的原发性耐药支持了人传人的合理性。
