Principal role of dihydropteroate synthase mutations in mediating resistance to sulfadoxine-pyrimethamine in single-drug and combination therapy of uncomplicated malaria in Uganda
Principal role of dihydropteroate synthase mutations in mediating resistance to sulfadoxine-pyrimethamine in single-drug and combination therapy of uncomplicated malaria in Uganda
复制标题
DOI：
10.4269/ajtmh.2004.71.758
复制
发表时间：
2004-12-01
影响因子：
3.3
通讯作者：
Rosenthal, PJ
中科院分区：
文献类型：
--
作者：
Dorsey, G;Dokomajilar, C;Rosenthal, PJ
抗疟药对磺胺嘧啶-乙胺嘧啶（SP）的耐药性是由二氢叶酸还原酶（dhfr）和二氢蝶酸合酶（dhps）基因突变介导的。然而，不同突变的相对重要性尚未完全了解，也没有研究过联合治疗。在乌干达的坎帕拉，对812名接受无并发症疟疾治疗的患者的样本进行了检测，以确定是否存在非洲常见的突变。dhps Glu-540突变是治疗失败的最强独立预测因子。dhfr Arg-59突变仅在存在dhps Glu-540突变的情况下预测治疗失败。联合治疗方案与SP单药治疗相比，在SP中加入氯喹并不能提高疗效，加入青蒿琥酯仅降低了dhfr Arg-59和dhps Glu-540突变感染的治疗失败风险，加入阿莫地喹降低了所有dhfr/dhps突变模式的治疗失败风险。dhps Glu-540突变发挥了主要作用，dhfr Arg-59突变在介导对SP单独和组合的抗性中起次要作用。
Antimalarial resistance to sulfadoxine-pyrimethamine (SP) is mediated by mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes. However, the relative importance of different mutations is incompletely understood and has not been studied with combination therapy. Samples from 812 patients treated for uncomplicated malaria in Kampala, Uganda were tested for the presence of mutations commonly found in Africa. The dhps Glu-540 mutation was the strongest independent predictor of treatment failure. The dhfr Arg-59 mutation was only predictive of treatment failure in the presence of the dhps Glu-540 mutation. Comparing combination regimens with SP monotherapy, the addition of chloroquine to SP did not improve efficacy, the addition of artesunate lowered the risk of treatment failure only for infections with both the dhfr Arg-59 and dhps Glu-540 mutations, and the addition of amodiaquine lowered this risk for all dhfr/dhps mutation patterns. The dhps Glu-540 mutation played a principal role and the dhfr Arg-59 mutation a secondary role in mediating resistance to SP alone and in combination.