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Lumefantrine attenuates Plasmodium falciparum artemisinin resistance during the early ring stage.

ABSTRACT: Emerging artemisinin resistance in Plasmodium falciparum malaria has the potential to become a global public health crisis. In Southeast Asia, this phenomenon clinically manifests in the form of delayed parasite clearance following artemisinin treatment. Reduced artemisinin susceptibility is limited to the early ring stage window, which is sufficient to allow parasites to survive the short half-life of artemisinin exposure. A screen of known clinically-implemented antimalarial drugs was performed to identify a drug capable of enhancing the killing activity of artemisinins during this critical resistance window. As a result, lumefantrine was found to increase the killing activity of artemisinin against an artemisinin-resistant clinical isolate harboring the C580Y kelch13 mutation. Isobologram analysis revealed synergism during the early ring stage resistance window, when lumefantrine was combined with artemether, an artemisinin derivative clinically partnered with lumefantrine. These findings suggest that lumefantrine should be clinically explored as a partner drug in artemisinin-based combination therapies to control emerging artemisinin resistance.

SUBMITTER: Kumpornsin K

PROVIDER: S-EPMC8528645 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Lumefantrine attenuates Plasmodium falciparum artemisinin resistance during the early ring stage.

Kümpornsin Krittikorn K Loesbanluechai Duangkamon D de Cozar Cristina C Kotanan Namfon N Chotivanich Kesinee K White Nicholas J NJ Wilairat Prapon P Gomez-Lorenzo Maria G MG Gamo Francisco Javier FJ Sanz Laura Maria LM Lee Marcus C S MCS Chookajorn Thanat T

International journal for parasitology. Drugs and drug resistance 20211002

Emerging artemisinin resistance in Plasmodium falciparum malaria has the potential to become a global public health crisis. In Southeast Asia, this phenomenon clinically manifests in the form of delayed parasite clearance following artemisinin treatment. Reduced artemisinin susceptibility is limited to the early ring stage window, which is sufficient to allow parasites to survive the short half-life of artemisinin exposure. A screen of known clinically-implemented antimalarial drugs was performe ...[more]

PMID: 34673330

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Project description:BackgroundArtemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance.MethodsIn two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.ResultsWe studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups.ConclusionsP. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)

Dataset Information

Lumefantrine attenuates Plasmodium falciparum artemisinin resistance during the early ring stage.

Publications

Lumefantrine attenuates Plasmodium falciparum artemisinin resistance during the early ring stage.

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