Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania
Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania
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DOI：
10.1016/s0140-6736(01)06344-9
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发表时间：
2001-10-13
期刊：
影响因子：
168.9
通讯作者：
Watkins, W
中科院分区：
文献类型：
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作者：
Mutabingwa, T;Nzila, A;Watkins, W
背景：对负担得起的疟疾治疗药物氯喹和乙胺-磺胺多辛的耐药性严重阻碍了东非通过治疗控制疟疾。我们进行了一项开放的替代药物分配研究，以评估氯氯胍-氨苯砜治疗临床对乙胺磺胺多辛耐药的恶性疟疾的疗效。方法对坦桑尼亚Muheza地区医院收治的5岁以下非重度恶性疟疾患儿采用乙胺嘧啶-磺胺多辛标准方案治疗。对临床症状缓解但经乙胺磺胺多辛治疗后7天仍有寄生症状的患者进行1个月的随访。用单剂量乙胺-磺胺多辛或氯原胍-氨苯砜3天治疗方案治疗临床疟疾发作。7 d后出现寄生虫血症者给予氯丙胍-氨苯砜治疗。第一次用乙胺-磺胺多辛处理后第7天采集寄生虫DNA，寻找编码二氢叶酸还原酶（dhfr）和二氢叶酸合成酶（dhps）基因的点突变。结果360名儿童入组并接受乙胺-磺胺多辛治疗。第7天，348例患者中192例（55%）清除了寄生虫病。在其余156名感染寄生虫的儿童中，140名（90%）被随访至第28天，其中92名（66%）发展为临床疟疾。这92例患者交替使用乙胺嘧啶-磺胺多辛（46例）或氯胍-氨苯砜（46例）进行治疗。使用乙胺磺胺-磺胺多辛治疗的46例患儿中28例（61%）在第7天仍有寄生虫，而使用氯原胍-氨苯砜治疗的46例患儿中有3例（15%）仍有寄生虫。对乙胺磺胺多辛的抗性从第一次处理时的45%（156/348）上升到再处理后的61%（28/46）。在第一次乙胺-磺胺多辛处理前后和第二次乙胺-磺胺多辛和氯胍-氨苯砜处理前后收集的85株寄生虫分离物中，有83株DHFR等位基因出现三突变，并伴有多种DHPS突变。解释大多数接受乙胺-磺胺多辛治疗的患者在第7天仍处于寄生虫状态，在1个月内出现新的疟疾症状。在这种情况下，氯氯胍-氨苯砜是一种可行的治疗方法。对治疗前后寄生虫dhfr和dhps的分析支持以下观点，即非洲这一地区的乙胺嘧啶-磺胺多辛耐药性主要是由于在dhfr结构域具有三种突变的寄生虫。
Background Resistance to the affordable malaria treatments chloroquine and pyrimethamine-sulfadoxine is seriously impeding malaria control through treatment in east Africa. We did an open, alternate drug allocation study to assess the efficacy of chlorproguanil-dapsone in the treatment of falciparum malaria clinically resistant to pyrimethamine-sulfadoxine.Methods Children younger than 5 years with non-severe falciparum malaria, attending Muheza district hospital in Tanzania, were treated with the standard regimen of pyrimethamine-sulfadoxine. Patients whose clinical symptoms resolved but who remained parasitaemic 7 days after pyrimethamine-sulfadoxine were followed up for 1 month. Clinical malaria episodes were retreated with either single dose pyrimethamine-sulfadoxine or a 3-day regimen of chlorproguanil-dapsone. Those with parasitaemia after 7 days were treated with chlorproguanil-dapsone. Parasite DNA was collected on day 7 after first treatment with pyrimethamine-sulfadoxine and we looked for point mutations in the genes encoding dihydrofolate reductase (dhfr) and dyhydropteroate synthetase (dhps).Findings 360 children were enrolled and treated with pyrimethamine-sulfadoxine. On day 7, 192 (55%) of 348 had cleared parasitaemia. Of the remaining 156 parasitaemic children, 140 (90%) were followed up to day 28, and 92 (66%) of 140 developed clinical malaria. These 92 patients were alternately retreated with either pyrimethamine-sulfadoxine (46) or chlorproguanil-dapsone (46). 28 (61%) of 46 children retreated with pyrimethamine-sulfadoxine were still parasitaemic at day 7, compared with three (15%) of 46 children retreated with chlorproguanil-dapsone. Resistance to pyrimethamine-sulfadoxine increased from 45% (156/348) at the first treatment to 61% (28/46) after retreatment. 83 of 85 parasite isolates collected after the first pyrimethamine-sulfadoxine treatment, and before and after the second treatments with pyrimethamine-sulfadoxine and chlorproguanil-dapsone showed triple-mutant dhfr alleles, associated with a variety of dhps mutations.Interpretation Most patients treated with pyrimethamine-sulfadoxine, who remain parasitaemic at day 7, develop new malaria symptoms within 1 month. Chlorproguanil-dapsone was a practicable therapy under these circumstances. Analysis of parasite dhfr and dhps before and after treatment supports the view that pyrimethamine-sulfadoxine resistance in this part of Africa is primarily due to parasites with three mutations in the dhfr domain.