AUTHOR=Boni Maciej F. TITLE=Breaking the cycle of malaria treatment failure JOURNAL=Frontiers in Epidemiology VOLUME=Volume 2 - 2022 YEAR=2022 URL=https://www.frontiersin.org/journals/epidemiology/articles/10.3389/fepid.2022.1041896 DOI=10.3389/fepid.2022.1041896 ISSN=2674-1199 ABSTRACT=Treatment of symptomatic malaria became a routine component of the clinical and public health response to malaria after the second world war. However, all antimalarial drugs deployed against malaria eventually generated enough drug resistance that they had to be removed from use. Chloroquine, sulfadoxine-pyrimethamine, and mefloquine are well known examples of antimalarial drugs to which resistance readily evolved. Artemisinin-based combination therapies (ACTs) are currently facing the same challenge as resistance is wide spread in Southeast Asia and emerging in Africa. Here, I review some aspects of drug-resistance management in malaria that influence the strength of selective pressure on drug-resistant malaria parasites, as well as an approach we can take in the future to avoid the repeat occurrences on new drug deployment followed by high levels of drug-resistance induced treatment failure. A desirable goal of drug-resistance management is to reduce selection pressure without reducing the overall percentage of patients that are treated. This can be achieved by distributing multiple first-line therapies (MFT) simultaneously in the population, thereby keeping treatment levels high but the overall selection pressure exerted by each individual therapy low. I review the primary reasons that make MFT a preferred resistance management option in many malaria-endemic settings, and I describe two exceptions where caution and additional analyses may be warranted before deploying MFT. MFT has shown to be feasible in practice in many endemic settings. The continual improvement and increased coverage of genomic surveillance in malaria may allow countries to implement custom MFT strategies based on current drug-resistance profiles.