Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure

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 w...

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Bibliographic Details
Published in:Emerging infectious diseases 2015-10, Vol.21 (10), p.1733-1741
Main Authors: Ménard, Sandie, Ben Haddou, Tanila, Ramadani, Arba Pramundita, Ariey, Frédéric, Iriart, Xavier, Beghain, Johann, Bouchier, Christiane, Witkowski, Benoit, Berry, Antoine, Mercereau-Puijalon, Odile, Benoit-Vical, Françoise
Format: Article
Language:English
Subjects:
Antimalarials
Antimalarials - therapeutic use
artemisinin
Artemisinins - therapeutic use
Asia, Southeastern
atovaquone
by Extended Artemisinin Pressure
Chemical Sciences
Coordination chemistry
drug pressure
Drug resistance
Drug Tolerance - immunology
Health aspects
Humans
Induction of Multidrug Tolerance in
Malaria
Malaria - drug therapy
Malaria, Falciparum - drug therapy
Malaria, Falciparum - parasitology
multidrug tolerance
parasites
Plasmodium falciparum
Plasmodium falciparum - drug effects
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Summary: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.
ISSN:1080-6040
1080-6059
DOI:10.3201/eid2110.150682