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Translated to infectious disease control, this evolutionary uncertainty means that when multiple types of drug resistance are present we do not know whether recombination will act more strongly to (1) bring together single-resistant genotypes into multi-drug resistant (MDR) genotypes, or (2) break apart MDR genotypes into single-resistant genotypes. In this paper, we introduce a new version of an established and validated individual-based malaria transmission model where we have added 25 drug-resistance related loci, individual mosquito bites, and mosquitoes feeding on multiple hosts in a single meal (interrupted feeds) allowing for recombination events of different <jats:italic><jats:italic>Plasmodium falciparum<\/jats:italic><\/jats:italic> genotypes from different hosts. Recombination among <jats:italic><jats:italic>P. falciparum<\/jats:italic><\/jats:italic> genotypes in this model occurs from two sources of variation, multi-clonal infections in single hosts and interrupted feeds on multiple hosts, and we show that 80% to 97% of MDR recombinant falciparum genotypes are projected to occur from single uninterrupted bites on hosts with multi-clonal infections (for malaria prevalence\u2009&gt;\u20095%). Increases in the model\u2019s interrupted feeding rate slowly increase the number of recombination events occurring from interrupted feeds. A comparison of drug-resistance management strategies with this new model shows that, over a 15-year timeframe, triple artemisinin-combination therapies (ACT) strategies show the largest reductions in treatment failures and the longest delays until artemisinin resistance reaches a critical 1% threshold. Multiple first-line therapies (MFT) are second best under these criteria, and ACT cycling approaches are third best. When compared to cycling strategies, MFT strategies generate a greater diversity of recombinant genotypes but fewer recombination events generating MDR and slower emergence of these recombinant MDR genotypes.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013401","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T17:27:33Z","timestamp":1756142853000},"page":"e1013401","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effects of recombination on multi-drug resistance evolution in Plasmodium falciparum malaria"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3046-8547","authenticated-orcid":true,"given":"Kien Trung","family":"Tran","sequence":"first","affiliation":[]},{"given":"Tran Dang","family":"Nguyen","sequence":"additional","affiliation":[]},{"given":"Daniel B.","family":"Weissman","sequence":"additional","affiliation":[]},{"given":"Eric Zhewen","family":"Li","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9605-0154","authenticated-orcid":true,"given":"Sachel","family":"Mok","sequence":"additional","affiliation":[]},{"given":"Jennifer L.","family":"Small-Saunders","sequence":"additional","affiliation":[]},{"given":"Teun","family":"Bousema","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8757-483X","authenticated-orcid":true,"given":"Robert J.","family":"Zupko","sequence":"additional","affiliation":[]},{"given":"Thu Nguyen-Anh","family":"Tran","sequence":"additional","affiliation":[]},{"given":"Maciej F.","family":"Boni","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"pcbi.1013401.ref001","volume-title":"World Malaria Report 2023","author":"WHO","year":"2023","edition":"1"},{"issue":"11","key":"pcbi.1013401.ref002","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1038\/s41591-023-02551-w","article-title":"Modeling policy interventions for slowing the spread of artemisinin-resistant pfkelch R561H mutations in Rwanda","volume":"29","author":"RJ Zupko","year":"2023","journal-title":"Nat Med"},{"key":"pcbi.1013401.ref003","doi-asserted-by":"crossref","unstructured":"Watson OJ, Muchiri S, Ward A, Meier-Sherling C, Asua V, Katairo T, et al. 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