Genetic markers of resistance to pyrimethamine and sulfonamides in Plasmodium falciparum parasites compared with the resistance patterns in isolates of Escherichia coli from the same children in Guinea-Bissau
Genetic markers of resistance to pyrimethamine and sulfonamides in Plasmodium falciparum parasites compared with the resistance patterns in isolates of Escherichia coli from the same children in Guinea-Bissau
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DOI：
10.1046/j.1365-3156.2003.01164.x
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发表时间：
2004-01-01
影响因子：
3.3
通讯作者：
Rombo, L
中科院分区：
文献类型：
--
作者：
Kofoed, PE;Alfrangis, M;Rombo, L
抗叶酸药物磺胺嘧啶和乙胺嘧啶在非洲被用于治疗对氯喹有抗药性的恶性疟原虫。对乙胺嘧啶的耐药性与dhfr基因的点突变有关，对磺胺嘧啶的耐药性与dhps基因的突变有关。令人关切的是，使用抗叶酸剂甲氧苄啶和磺胺甲恶唑治疗其他传染病将导致选择这些基因发生突变的疟疾寄生虫。在几内亚比绍，磺胺类药物和含甲氧苄啶的药物已被广泛使用，我们决定评估从急性疟疾儿童中分离的恶性疟原虫中dhfr和dhps基因突变的流行率，并评估从同一患者中分离的大肠杆菌对甲氧苄啶/磺胺甲恶唑的耐药模式。从比绍Bandim保健中心就诊的100名症状与疟疾相符的儿童身上采集了厚膜和血样，用于聚合酶链反应。此外，从同一儿童收集粪便样品并培养E。杆菌培养的E.对磺胺类药物和甲氧苄啶均耐药的占67%，对磺胺类药物单独耐药的占4%，对甲氧苄啶单独耐药的占3%，对两种药物完全敏感的占26%。对97份血样成功进行了PCR检测。其中，41%的人在dhfr基因（密码子51，59和108）有三重突变，15%的人在dhps基因中有三重突变加上密码子437突变。只有45%携带野生型dhfr基因。因此，细菌耐药性和寄生虫基因突变都很常见，但在个别儿童中并不相关。由于磺胺嘧啶-乙胺嘧啶几年来仅在几内亚比绍用作抗氯喹疟疾的二线治疗，令人担忧的是，寄生虫基因中编码对这些药物产生抗药性的突变发生率很高。因此，只要广泛使用抗叶酸药物，限制使用磺胺嘧啶-乙胺嘧啶治疗氯喹耐药性疟疾可能不足以防止寄生虫产生耐药性。
The antifolate drugs sulphadoxine and pyrimethamine are used for treatment of chloroquine-resistant Plasmodium falciparum in Africa. Resistance to pyrimethamine has been associated with point mutations in the dhfr-gene and resistance to sulphadoxine with mutations in the dhps-gene. There is concern that the use of the antifolates trimethoprim and sulphamethoxazole for treatment of other infectious diseases will result in the selection of malaria parasites with mutations in these genes. In Guinea-Bissau, where sulfonamide and trimethoprim-containing drugs have been used extensively, we decided to assess the prevalence of mutations in the dhfr-and dhps-gene in P. falciparum isolated from children suffering from acute malaria and to assess the resistance patterns to trimethoprim/ sulphamethoxazole in Escherichia coli isolated from the same patients. A thick film and a blood sample for polymerase chain reaction (PCR) were obtained from 100 children attending the Bandim Health Centre in Bissau with symptoms compatible with malaria. Furthermore, a stool sample was collected from the same children and cultured for E. coli. Of the cultured E. coli, 67% were resistant both to sulfonamides and trimethoprim, 4% to sulfonamides alone, 3% to trimethoprim alone while 26% were fully sensitive to both drugs. PCR was successfully performed in 97 blood samples. Of these, 41% had triple mutations at the dhfr-gene (at codons 51, 59 and 108), and 15% had triple mutations plus mutation at codon 437 in the dhps-gene. Only 45% harboured the wild-type dhfr-gene. Thus both bacterial resistance and mutations in the parasitic genes were common, but not linked in the individual child. As sulphadoxine-pyrimethamine has only been used as a second line treatment for chloroquine resistant malaria in Guinea-Bissau for a few years, it is worrying to find a high prevalence of mutations in the parasitic genes coding for resistance to these drugs. Therefore, restricting the use of sulphadoxine-pyrimethamine for the treatment of chloroquine resistant malaria might not be sufficient to prevent the development of resistance in the parasites as long as antifolate drugs are used extensively.