TY - JOUR AU - Ménard, Sandie AU - Ben Haddou, Tanila AU - Ramadani, Arba Pramundita AU - Ariey, Frédéric AU - Iriart, Xavier AU - Beghain, Johann AU - Bouchier, Christiane AU - Witkowski, Benoit AU - Berry, Antoine AU - Mercereau-Puijalon, Odile AU - Benoit-Vical, Françoise T1 - Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure T2 - Emerging Infectious Disease journal PY - 2015 VL - 21 IS - 10 SP - 1733 SN - 1080-6059 AB - Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated whether long-lasting artemisinin pressure selects a novel multidrug-tolerance profile. Although 50% inhibitory concentrations for 10 antimalarial drugs tested were unchanged, drug-tolerant parasites showed higher recrudescence rates for endoperoxides, quinolones, and an antifolate, including partner drugs of recommended combination therapies, but remained susceptible to atovaquone. Moreover, the age range of intraerythrocytic stages able to resist artemisinin was extended to older ring forms and trophozoites. Multidrug tolerance results from drug-induced quiescence, which enables parasites to survive exposure to unrelated antimalarial drugs that inhibit a variety of metabolic pathways. This novel resistance pattern should be urgently monitored in the field because this pattern is not detected by current assays and represents a major threat to antimalarial drug policy. KW - artemisinin KW - Plasmodium falciparum KW - parasites KW - multidrug tolerance KW - drug pressure KW - atovaquone KW - quinolone KW - antifolate KW - malaria KW - Southeast Asia KW - antimicrobial resistance DO - 10.3201/eid2110.150682 UR - https://wwwnc.cdc.gov/eid/article/21/10/15-0682_article ER - End of Reference