Increased prevalence of the pfdhfr/phdhps quintuple mutant and rapid emergence of pfdhps resistance mutations at codons 581 and 613 in Kisumu, Kenya.
Increased prevalence of the pfdhfr/phdhps quintuple mutant and rapid emergence of pfdhps resistance mutations at codons 581 and 613 in Kisumu, Kenya.
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DOI：
10.1186/1475-2875-9-338
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发表时间：
2010-11-24
期刊：
影响因子：
3
通讯作者：
Waters NC
中科院分区：
文献类型：
--
作者：
Spalding MD;Eyase FL;Akala HM;Bedno SA;Prigge ST;Coldren RL;Moss WJ;Waters NC
肯尼亚对疟疾的抗药性在十年内促成了两次药物政策变化：1998年，磺胺二甲嘧啶(SP)取代氯喹(CQ)成为一线抗疟疾药物；2004年，蒿甲醚(AL)取代SP成为一线抗疟疾药物。进行了两项横断面研究，以监测在将SP用作一线抗疟疾药物期间耐药分子标志物流行率的变化。基线研究是在实施战略规划后不久的1999-2000年进行的，后续研究是在向AL过渡期间的2003-2005年进行的。在基线和后续研究期间，从肯尼亚基苏木的门诊中心就诊的疟疾涂片阳性有症状患者身上采集血液。对分离株进行了SP和CQ抗性相关密码子的基因分型。在体外，对来自随访研究的分离株测定了抗叶酸和喹诺酮类药物的IC50值。含有pfdhfr N51I/C59R/S108N/pfdhps A437G/K540E五重突变与SP抗性相关的菌株的流行率从基线研究的21%上升到随访研究的53%(p<；0.001)。两项研究均未发现含有pfdhfr I164L突变的分离株。Pfdhps突变A581G和A613S/T在基线研究中缺失，但在随访研究中分别有85%和61%的分离株存在。在随访期内，436、437、540、581和613 5个pfdhps密码子突变的寄生虫占分离株的39%。从基线到随访，CQ耐药相关突变pfcrtK76T和pfmdr1N86Y分别从82%上升到97%(p=0.001)和44%上升到76%(p<；0.001)。在SP是肯尼亚第一线抗疟疾药物期间，出现了高度耐SP的寄生虫，包括具有以前在那里没有观察到的pfdhps突变的分离株。SP继续在肯尼亚被广泛使用；然而，鉴于本研究中观察到的高度耐药的基因类型，应不鼓励将其用作抗疟疾的一线药物，特别是对于对疟疾没有获得免疫力的人群。尽管努力减少CQ的使用，但pfcrt K76T流行率的增加表明，这些努力不足以缓解基苏木的CQ压力，或者药物压力来自另一个来源，如二线抗疟疾药物阿莫地喹。
Anti-malarial drug resistance in Kenya prompted two drug policy changes within a decade: sulphadoxine-pyrimethamine (SP) replaced chloroquine (CQ) as the first-line anti-malarial in 1998 and artemether-lumefantrine (AL) replaced SP in 2004. Two cross-sectional studies were conducted to monitor changes in the prevalence of molecular markers of drug resistance over the period in which SP was used as the first-line anti-malarial. The baseline study was carried out from 1999-2000, shortly after implementation of SP, and the follow-up study occurred from 2003-2005, during the transition to AL. Blood was collected from malaria smear-positive, symptomatic patients presenting to outpatient centers in Kisumu, Kenya, during the baseline and follow-up studies. Isolates were genotyped at codons associated with SP and CQ resistance. In vitro IC50 values for antifolates and quinolones were determined for isolates from the follow-up study. The prevalence of isolates containing the pfdhfr N51I/C59R/S108N/pfdhps A437G/K540E quintuple mutant associated with SP-resistance rose from 21% in the baseline study to 53% in the follow-up study (p < 0.001). Isolates containing the pfdhfr I164L mutation were absent from both studies. The pfdhps mutations A581G and A613S/T were absent from the baseline study but were present in 85% and 61%, respectively, of isolates from the follow-up study. At follow-up, parasites with mutations at five pfdhps codons, 436, 437, 540, 581, and 613, accounted for 39% of isolates. The CQ resistance-associated mutations pfcrt K76T and pfmdr1 N86Y rose from 82% to 97% (p = 0.001) and 44% to 76% (p < 0.001), respectively, from baseline to follow-up. During the period in which SP was the first-line anti-malarial in Kenya, highly SP-resistant parasites emerged, including isolates harboring pfdhps mutations not previously observed there. SP continues to be widely used in Kenya; however, given the highly resistant genotypes observed in this study, its use as a first-line anti-malarial should be discouraged, particularly for populations without acquired immunity to malaria. The increase in the pfcrt K76T prevalence, despite efforts to reduce CQ use, suggests that either these efforts are not adequate to alleviate CQ pressure in Kisumu, or that drug pressure is derived from another source, such as the second-line anti-malarial amodiaquine.
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