Kofoed Poul-Erik, Alfrangis Michael, Poulsen Anja, Rodrigues Amabelia, Gjedde Susanne Borum, Rønn Anita, Rombo Lars
Projecto de Saúde de Bandim, Guinea-Bissau.
Trop Med Int Health. 2004 Jan;9(1):171-7. doi: 10.1046/j.1365-3156.2003.01164.x.
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.
抗叶酸药物磺胺多辛和乙胺嘧啶用于治疗非洲地区对氯喹耐药的恶性疟原虫。对乙胺嘧啶的耐药性与二氢叶酸还原酶（dhfr）基因突变有关，而对磺胺多辛的耐药性与二氢蝶酸合酶（dhps）基因突变有关。人们担心使用抗叶酸药物甲氧苄啶和磺胺甲恶唑治疗其他传染病会导致这些基因发生突变的疟原虫被筛选出来。在几内亚比绍，含磺胺类药物和甲氧苄啶的药物被广泛使用，我们决定评估从患有急性疟疾的儿童中分离出的恶性疟原虫中dhfr和dhps基因的突变率，并评估从同一患者中分离出的大肠杆菌对甲氧苄啶/磺胺甲恶唑的耐药模式。从比绍班迪姆健康中心的100名有疟疾症状的儿童中采集了用于聚合酶链反应（PCR）的厚血膜和血样。此外，从这些儿童中采集粪便样本并培养大肠杆菌。在培养的大肠杆菌中，67%对磺胺类药物和甲氧苄啶均耐药，4%仅对磺胺类药物耐药，3%仅对甲氧苄啶耐药，而26%对两种药物均完全敏感。97份血样成功进行了PCR。其中，41%在dhfr基因（第51、59和108位密码子）有三重突变，15%在dhps基因的第437位密码子有三重突变加一个突变。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，但在个体儿童中并无关联。由于磺胺多辛-乙胺嘧啶在几内亚比绍仅作为氯喹耐药疟疾的二线治疗药物使用了几年，令人担忧的是，编码对这些药物耐药性的寄生虫基因中突变率很高。因此，只要广泛使用抗叶酸药物，限制磺胺多辛-乙胺嘧啶用于治疗氯喹耐药疟疾可能不足以防止寄生虫产生耐药性。
