{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T13:31:27Z","timestamp":1769607087838,"version":"3.49.0"},"reference-count":34,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T00:00:00Z","timestamp":1643587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ginsberg Foundation","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/100009720","name":"Katz foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100009720","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Malaria is a prevalent parasitic disease that is estimated to kill between one and two million people\u2014mostly children\u2014every year. Here, we query PubMed for malaria drug resistance and plot the yearly citations of 14 common antimalarials. Remarkably, most antimalarial drugs display cyclic resistance patterns, rising and falling over four decades. The antimalarial drugs that exhibit cyclic resistance are quinine, chloroquine, mefloquine, amodiaquine, artesunate, artemether, sulfadoxine, doxycycline, halofantrine, piperaquine, pyrimethamine, atovaquone, artemisinin, and dihydroartemisinin. Exceptionally, the resistance of the two latter drugs can also correlate with a linear rise. Our predicted antimalarial drug resistance is consistent with clinical data reported by the Worldwide Antimalarial Resistance Network (WWARN) and validates our methodology. Notably, the cyclical resistance suggests that most antimalarial drugs are sustainable in the end. Furthermore, cyclic resistance is clinically relevant and discourages routine monotherapy, in particular, while resistance is on the rise. Finally, cyclic resistance encourages the combination of antimalarial drugs at distinct phases of resistance.<\/jats:p>","DOI":"10.3390\/jcm11030781","type":"journal-article","created":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T09:59:21Z","timestamp":1643709561000},"page":"781","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Resistance to Antimalarial Monotherapy Is Cyclic"],"prefix":"10.3390","volume":"11","author":[{"given":"Rachel","family":"Weitzman","sequence":"first","affiliation":[{"name":"Bioinformatic Department, Jerusalem College of Technology, Jerusalem 9372115, Israel"},{"name":"Drug Discovery Lab, Azrieli Faculty of Medicine, Bar Ilan University, Safed 1311502, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6563-5216","authenticated-orcid":false,"given":"Ortal","family":"Calfon-Peretz","sequence":"additional","affiliation":[{"name":"Bioinformatic Department, Jerusalem College of Technology, Jerusalem 9372115, Israel"},{"name":"Drug Discovery Lab, Azrieli Faculty of Medicine, Bar Ilan University, Safed 1311502, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6951-956X","authenticated-orcid":false,"given":"Trishna","family":"Saha","sequence":"additional","affiliation":[{"name":"Drug Discovery Lab, Azrieli Faculty of Medicine, Bar Ilan University, Safed 1311502, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naamah","family":"Bloch","sequence":"additional","affiliation":[{"name":"Drug Discovery Lab, Azrieli Faculty of Medicine, Bar Ilan University, Safed 1311502, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Ben Zaken","sequence":"additional","affiliation":[{"name":"Drug Discovery Lab, Azrieli Faculty of Medicine, Bar Ilan University, Safed 1311502, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avi","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Jerusalem College of Technology, Jerusalem 9372115, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6897-9580","authenticated-orcid":false,"given":"Moshe","family":"Amitay","sequence":"additional","affiliation":[{"name":"Bioinformatic Department, Jerusalem College of Technology, Jerusalem 9372115, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7436-3515","authenticated-orcid":false,"given":"Abraham O.","family":"Samson","sequence":"additional","affiliation":[{"name":"Drug Discovery Lab, Azrieli Faculty of Medicine, Bar Ilan University, Safed 1311502, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1172\/JCI21682","article-title":"Antimalarial drug resistance","volume":"113","author":"White","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1086\/512743","article-title":"Combination Therapy for Malaria: Mission Accomplished?","volume":"44","author":"Plowe","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1056\/NEJMoa0808859","article-title":"Artemisinin Resistance in Plasmodium falciparum Malaria","volume":"361","author":"Dondorp","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1475-2875-6-119","article-title":"World Antimalarial Resistance Network I: Clinical efficacy of antimalarial drugs","volume":"6","author":"Price","year":"2007","journal-title":"Malar. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"a025619","DOI":"10.1101\/cshperspect.a025619","article-title":"Antimalarial Drug Resistance: A Threat to Malaria Elimination","volume":"7","author":"Menard","year":"2017","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ijpddr.2021.04.002","article-title":"The molecular basis of antimalarial drug resistance in Plasmodium vivax","volume":"16","author":"Buyon","year":"2021","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/nrmicro2239","article-title":"Artemisinin-based combination therapies: A vital tool in efforts to eliminate malaria","volume":"7","author":"Eastman","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1007\/s00436-006-0313-x","article-title":"Hemozoin Biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors","volume":"100","author":"Hempelmann","year":"2006","journal-title":"Parasitol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.actatropica.2015.04.007","article-title":"How genomics is contributing to the fight against artemisinin-resistant malaria parasites","volume":"148","author":"Cravo","year":"2015","journal-title":"Acta Trop."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1345\/aph.1M732","article-title":"Intravenous Artesunate for the Treatment of Severe Malaria","volume":"44","author":"Hess","year":"2010","journal-title":"Ann. Pharmacother."},{"key":"ref_11","first-page":"4","article-title":"Mode of action of artemether lumefantrine (COARTEM): The sole, fixed, oral ADCC and its role in combatting multidrug resistance","volume":"32","author":"Warhurst","year":"2001","journal-title":"Southeast Asian J. Trop. Med. Public Health"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nmicrobiol.2017.3","article-title":"LoaP is a broadly conserved antiterminator protein that regulates antibiotic gene clusters in Bacillus amyloliquefaciens","volume":"2","author":"Goodson","year":"2017","journal-title":"Nat. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12936-015-0980-0","article-title":"Tetracyclines in malaria","volume":"14","author":"Gaillard","year":"2015","journal-title":"Malar. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1186\/1475-2875-13-152","article-title":"High levels of sulphadoxine-pyrimethamine resistance Pfdhfr-Pfdhps quintuple mutations: A cross sectional survey of six regions in Tanzania","volume":"13","author":"Matondo","year":"2014","journal-title":"Malar. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1093\/jac\/dks504","article-title":"Antimalarial pharmacology and therapeutics of atovaquone","volume":"68","author":"Nixon","year":"2013","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"eaau3174","DOI":"10.1126\/scitranslmed.aau3174","article-title":"Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay","volume":"11","author":"Dziekan","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.jgar.2016.09.003","article-title":"Global antibiotic resistance is mostly periodic","volume":"7","author":"Dabour","year":"2016","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yayan, J., Ghebremedhin, B., and Rasche, K. (2015). Antibiotic Resistance of Pseudomonas aeruginosa in Pneumonia at a Single University Hospital Center in Germany over a 10-Year Period. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0139836"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.diagmicrobio.2009.08.020","article-title":"Summary trends for the Meropenem Yearly Susceptibility Test Information Collection Program: A 10-year experience in the United States (1999\u20132008)","volume":"65","author":"Rhomberg","year":"2009","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Asbell, P.A., and Sanfilippo, C.M. (2017). Antibiotic Resistance Trends Among Ocular Pathogens in the US\u2014Cumulative Results from the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) Surveillance Study. US Ophthalmic Rev., 10.","DOI":"10.17925\/USOR.2017.10.01.35"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/msb.2009.98","article-title":"A side effect resource to capture phenotypic effects of drugs","volume":"6","author":"Kuhn","year":"2010","journal-title":"Mol. Syst. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ymeth.2014.11.020","article-title":"DISEASES: Text mining and data integration of disease\u2013gene associations","volume":"74","author":"Tsafou","year":"2015","journal-title":"Methods"},{"key":"ref_23","first-page":"i","article-title":"Mekong malaria. Malaria, multi-drug resistance and economic development in the greater Mekong subregion of Southeast Asia","volume":"30","author":"Singhasivanon","year":"1999","journal-title":"Southeast Asian J. Trop. Med. Public Health"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/1475-2875-10-116","article-title":"Patterns of chloroquine use and resistance in sub-Saharan Africa: A systematic review of household survey and molecular data","volume":"10","author":"Frosch","year":"2011","journal-title":"Malar. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1056\/NEJMp1901233","article-title":"A Temporizing Solution to \u201cArtemisinin Resistance\u201d","volume":"380","author":"Wang","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11672","DOI":"10.1073\/pnas.1507142112","article-title":"Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt","volume":"112","author":"Pelleau","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Carrara, V., Lwin, K.M., Phyo, A.P., Ashley, E., Wiladphaingern, J., Sriprawat, K., Rijken, M., Boel, M., Mcgready, R., and Proux, S. (2013). Malaria Burden and Artemisinin Resistance in the Mobile and Migrant Population on the Thai\u2013Myanmar Border, 1999\u20132011: An Observational Study. PLoS Med., 10.","DOI":"10.1371\/journal.pmed.1001398"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"White, L.J., Flegg, J.A., Phyo, A.P., Wiladpai-Ngern, J.H., Bethell, D., Plowe, C., Anderson, T., Nkhoma, S., Nair, S., and Tripura, R. (2015). Defining the In Vivo Phenotype of Artemisinin-Resistant Falciparum Malaria: A Modelling Approach. PLoS Med., 12.","DOI":"10.1371\/journal.pmed.1001823"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"692","DOI":"10.4269\/ajtmh.17-0763","article-title":"Impacts of Antimalarial Drugs on Plasmodium falciparum Drug Resistance Markers, Western Kenya, 2003\u20132015","volume":"98","author":"Umukoro","year":"2018","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"91","DOI":"10.2165\/00003088-200847020-00002","article-title":"Clinical Pharmacology of Artemisinin-Based Combination Therapies","volume":"47","author":"Aweeka","year":"2008","journal-title":"Clin. Pharmacokinet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/S0140-6736(20)30552-3","article-title":"Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: A multicentre, open-label, randomised clinical trial","volume":"395","author":"Tripura","year":"2020","journal-title":"Lancet"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Alven, S., and Aderibigbe, B. (2019). Combination Therapy Strategies for the Treatment of Malaria. Molecules, 24.","DOI":"10.3390\/molecules24193601"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12936-020-03446-8","article-title":"Global estimation of anti-malarial drug effectiveness for the treatment of uncomplicated Plasmodium falciparum malaria 1991\u20132019","volume":"19","author":"Rathmes","year":"2020","journal-title":"Malar. J."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Dutta, S., Biswas, A., and Ahrens, J. (2019). Multivariate Pointwise Information-Driven Data Sampling and Visualization. Entropy, 21.","DOI":"10.3390\/e21070699"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/3\/781\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:12:02Z","timestamp":1760134322000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/3\/781"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,31]]},"references-count":34,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["jcm11030781"],"URL":"https:\/\/doi.org\/10.3390\/jcm11030781","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,31]]}}}