Institut Pasteur, Université Paris Cité, CNRS UMR3528, Unité de Microbiologie Structurale, F-75015 Paris, France.
Institut Pasteur, Pasteur International Unit, Pasteur International Network, Malaria Translational Research Unit, Phnom Penh, Cambodia and Paris, France.
J Antimicrob Chemother. 2023 Feb 1;78(2):411-417. doi: 10.1093/jac/dkac403.
In early 2016, in Preah Vihear, Northern Cambodia, artesunate/mefloquine was used to cope with dihydroartemisinin/piperaquine-resistant Plasmodium falciparum parasites. Following this policy, P. falciparum strains harbouring molecular markers associated with artemisinin, piperaquine and mefloquine resistance have emerged. However, the lack of a viable alternative led Cambodia to adopt artesunate/mefloquine countrywide, raising concerns about a surge of triple-resistant P. falciparum strains.
To assess the prevalence of triple-resistant parasites after artesunate/mefloquine implementation countrywide in Cambodia and to characterize their phenotype.
For this multicentric study, 846 samples were collected from 2016 to 2019. Genotyping of molecular markers associated with artemisinin, piperaquine and mefloquine resistance was coupled with phenotypic analyses.
Only four triple-resistant P. falciparum isolates (0.47%) were identified during the study period. These parasites combined the pfk13 polymorphism with pfmdr1 amplification, pfpm2 amplification and/or pfcrt mutations. They showed significantly higher tolerance to artemisinin, piperaquine and mefloquine and also to the mefloquine and piperaquine combination.
The use of artesunate/mefloquine countrywide in Cambodia has not led to a massive increase of triple-resistant P. falciparum parasites. However, these parasites circulate in the population, and exhibit clear resistance to piperaquine, mefloquine and their combination in vitro. This study demonstrates that P. falciparum can adapt to more complex drug associations, which should be considered in future therapeutic designs.
2016 年初，在柬埔寨北部的柏威夏，青蒿琥酯/甲氟喹被用于应对对二氢青蒿素/哌喹耐药的恶性疟原虫。按照这一政策，出现了携带与青蒿素、哌喹和甲氟喹耐药相关的分子标记的恶性疟原虫株。然而，由于缺乏可行的替代药物，柬埔寨在全国范围内采用了青蒿琥酯/甲氟喹，这引发了对三耐药恶性疟原虫株激增的担忧。
评估柬埔寨在全国范围内实施青蒿琥酯/甲氟喹后三耐药寄生虫的流行情况，并对其表型进行特征描述。
在这项多中心研究中，于 2016 年至 2019 年期间采集了 846 个样本。对与青蒿素、哌喹和甲氟喹耐药相关的分子标记进行基因分型，并结合表型分析。
在研究期间，仅鉴定出 4 株三耐药恶性疟原虫分离株（0.47%）。这些寄生虫同时携带 pfk13 多态性、pfmdr1 扩增、pfpm2 扩增和/或 pfcrt 突变。它们对青蒿素、哌喹和甲氟喹表现出显著更高的耐受性，对甲氟喹和哌喹的联合用药也表现出更高的耐受性。
柬埔寨在全国范围内使用青蒿琥酯/甲氟喹并未导致大量三耐药恶性疟原虫寄生虫的出现。然而，这些寄生虫在人群中循环，并在体外表现出对哌喹、甲氟喹及其联合用药的明显耐药性。本研究表明，恶性疟原虫能够适应更复杂的药物联合，这在未来的治疗设计中应加以考虑。
