Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
Antimicrob Agents Chemother. 2013 Nov;57(11):5277-83. doi: 10.1128/AAC.00687-13. Epub 2013 Aug 12.
In 2008, dihydroartemisinin (DHA)-piperaquine (PPQ) became the first-line treatment for uncomplicated Plasmodium falciparum malaria in western Cambodia. Recent reports of increased treatment failure rates after DHA-PPQ therapy in this region suggest that parasite resistance to DHA, PPQ, or both is now adversely affecting treatment. While artemisinin (ART) resistance is established in western Cambodia, there is no evidence of PPQ resistance. To monitor for resistance to PPQ and other antimalarials, we measured drug susceptibilities for parasites collected in 2011 and 2012 from Pursat, Preah Vihear, and Ratanakiri, in western, northern, and eastern Cambodia, respectively. Using a SYBR green I fluorescence assay, we calculated the ex vivo 50% inhibitory concentrations (IC50s) of 310 parasites to six antimalarials: chloroquine (CQ), mefloquine (MQ), quinine (QN), PPQ, artesunate (ATS), and DHA. Geometric mean IC50s (GMIC50s) for all drugs (except PPQ) were significantly higher in Pursat and Preah Vihear than in Ratanakiri (P ≤ 0.001). An increased copy number of P. falciparum mdr1 (pfmdr1), an MQ resistance marker, was more prevalent in Pursat and Preah Vihear than in Ratanakiri and was associated with higher GMIC50s for MQ, QN, ATS, and DHA. An increased copy number of a chromosome 5 region (X5r), a candidate PPQ resistance marker, was detected in Pursat but was not associated with reduced susceptibility to PPQ. The ex vivo IC50 and pfmdr1 copy number are important tools in the surveillance of multidrug-resistant (MDR) parasites in Cambodia. While MDR P. falciparum is prevalent in western and northern Cambodia, there is no evidence for PPQ resistance, suggesting that DHA-PPQ treatment failures result mainly from ART resistance.
2008 年，双氢青蒿素（DHA）-哌喹（PPQ）成为柬埔寨西部治疗无并发症恶性疟原虫感染的一线药物。最近有报道称，该地区 DHA-PPQ 治疗后治疗失败率增加，这表明寄生虫对 DHA、PPQ 或两者的耐药性现在正在对治疗产生不利影响。虽然柬埔寨西部已经存在青蒿素（ART）耐药性，但没有证据表明存在 PPQ 耐药性。为了监测对 PPQ 和其他抗疟药物的耐药性，我们测量了分别来自柬埔寨西部 Pursat、北部 Preah Vihear 和东部 Ratanakiri 的 2011 年和 2012 年采集的寄生虫对 6 种抗疟药物的药物敏感性。使用 SYBR 绿 I 荧光测定法，我们计算了 310 个寄生虫对氯喹（CQ）、甲氟喹（MQ）、奎宁（QN）、PPQ、青蒿琥酯（ATS）和 DHA 的体外 50%抑制浓度（IC50s）。除了 PPQ 之外，所有药物的几何平均 IC50（GMIC50）在 Pursat 和 Preah Vihear 均显著高于 Ratanakiri（P≤0.001）。Pfmdr1（pfmdr1）的拷贝数增加，一个 MQ 耐药性标记，在 Pursat 和 Preah Vihear 比在 Ratanakiri 更为普遍，与 MQ、QN、ATS 和 DHA 的 GMIC50 升高有关。在 Pursat 检测到染色体 5 区域（X5r）的拷贝数增加，一个候选的 PPQ 耐药性标记，但与对 PPQ 的敏感性降低无关。体外 IC50 和 pfmdr1 拷贝数是柬埔寨监测多药耐药（MDR）寄生虫的重要工具。虽然 MDR 恶性疟原虫在柬埔寨西部和北部很普遍，但没有证据表明存在 PPQ 耐药性，这表明 DHA-PPQ 治疗失败主要是由于 ART 耐药性所致。
