Escalating Plasmodium falciparum antifolate drug resistance mutations in Macha, rural Zambia
Escalating Plasmodium falciparum antifolate drug resistance mutations in Macha, rural Zambia
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DOI：
10.1186/1475-2875-7-87
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发表时间：
2008-05-21
期刊：
影响因子：
3
通讯作者：
Mharakurwa, Sungano
中科院分区：
文献类型：
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作者：
Mkulama, Mtawa A. P.;Chishimba, Sandra;Mharakurwa, Sungano
背景资料：在赞比亚，治疗无并发症疟疾的第一线疗法是青蒿素综合疗法，目前使用的是蒿甲醚-苯芴醇。然而，抗叶酸方案，磺胺嘧啶-乙胺嘧啶（SP），仍然是治疗体重低于5公斤的儿童和孕妇的选择。SP也是怀孕期间间歇性预防治疗的首选药物，并在ACT缺货期间用作备用治疗。目前的研究评估了恶性疟原虫点突变与抗叶酸药物耐药性的Macha.Methods周围地区的状态：从附近的Macha的2,780居民的代表性样本进行了筛选疟疾显微镜。同时，将血液收集到滤纸上并干燥，用于随后的恶性疟原虫DNA分析。来自188个采用巢式PCR和等位基因特异性限制性内切酶消化法，对95例恶性疟原虫感染者的一个简单随机子集（6.8%）厚膜阳性个体进行DHFR和DHPS抗叶酸剂耐药突变基因分型。恶性疟原虫现场样本显示抗叶酸剂耐药突变的高流行率，包括DHFR三重（Asn-108 + Arg-59 + Ile-51）突变（41.3%）和DHPS双重（Gly-437 + Glu-540）突变（16%）。在4个（6.5%）样品中发现五重（HFR三重+ DHPS双重）突变体。与1988年以来的历次调查相比，变异寄生虫的数量急剧上升。然而，瓦尔-16和Thr-108突变，共同赋予环胍的耐药性，在人类感染中均未检测到。Leu-164突变与乙胺嘧啶和环胍的高度耐药相关，作为Asn-108，Arg-59和（或）Ile- 51的多重突变体，也不存在。建议继续监测，以确保在广泛的耐药性造成严重的公共卫生损失之前及时修订政策。
Background: In Zambia the first-line treatment for uncomplicated malaria is artemisinin combination therapy (ACT), with artemether- lumefantrine currently being used. However, the antifolate regimen, sulphadoxine-pyrimethamine (SP), remains the treatment of choice in children weighing less than 5 kg and also in expectant mothers. SP is also the choice drug for intermittent preventive therapy in pregnancy and serves as stand-by treatment during ACT stock outs. The current study assessed the status of Plasmodium falciparum point mutations associated with antifolate drug resistance in the area around Macha.Methods: A representative sample of 2,780 residents from the vicinity of Macha was screened for malaria by microscopy. At the same time, blood was collected onto filter paper and dried for subsequent P. falciparum DNA analysis. From 188 (6.8%) individuals that were thick film-positive, a simple random sub-set of 95 P. falciparum infections were genotyped for DHFR and DHPS antifolate resistance mutations, using nested PCR and allele-specific restriction enzyme digestion.Results: Plasmodium falciparum field samples exhibited a high prevalence of antifolate resistance mutations, including the DHFR triple (Asn-108 + Arg-59 + Ile-51) mutant (41.3%) and DHPS double (Gly-437 + Glu-540) mutant (16%). The quintuple (HFR triple + DHPS double) mutant was found in 4 (6.5%) of the samples. Levels of mutated parasites showed a dramatic escalation, relative to previous surveys since 1988. However, neither of the Val-16 and Thr-108 mutations, which jointly confer resistance to cycloguanil, was detectable among the human infections. The Leu-164 mutation, associated with high grade resistance to both pyrimethamine and cycloguanil, as a multiple mutant with Asn-108, Arg-59 and (or) Ile- 51, was also absent.Conclusion: This study points to escalating levels of P. falciparum antifolate resistance in the vicinity of Macha. Continued monitoring is recommended to ensure timely policy revisions before widespread resistance exacts a serious public health toll.