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Our results show that the population-wide use of multiple first-line therapies (MFT) against malaria yields a better clinical outcome than using a single therapy or a cycling strategy where therapies are rotated, either on a fixed cycling schedule or when resistance levels or treatment failure become too high. MFT strategies also delay the emergence and slow the fixation of resistant strains (phenotypes), and they allow a larger fraction of the population to be treated without trading off future treatment of cases that may be untreatable because of high resistance levels. Earlier papers have noted that cycling strategies have the disadvantage of creating a less temporally variable environment than MFT strategies, making resistance evolution easier for the parasite. Here, we illustrate a second feature of parasite ecology that impairs the performance of cycling policies, namely, that cycling policies degrade the mean fitness of the parasite population more quickly than MFT policies, making it easier for new resistant types to invade and spread. The clinical benefits of using multiple first-line therapies against malaria suggest that MFT policies should play a key role in malaria elimination and control programs.<\/jats:p>","DOI":"10.1073\/pnas.0804628105","type":"journal-article","created":{"date-parts":[[2008,9,9]],"date-time":"2008-09-09T21:06:44Z","timestamp":1220994404000},"page":"14216-14221","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":140,"title":["Benefits of using multiple first-line therapies against malaria"],"prefix":"10.1073","volume":"105","author":[{"given":"Maciej F.","family":"Boni","sequence":"first","affiliation":[{"name":"Resources for the Future, Washington, DC 20036;"},{"name":"Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08544;"},{"name":"Princeton Environmental Institute, Princeton, NJ 08544; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Zoology and"},{"name":"Emerging Pathogens Institute, University of Florida, Gainesville, FL 32611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramanan","family":"Laxminarayan","sequence":"additional","affiliation":[{"name":"Resources for the Future, Washington, DC 20036;"},{"name":"Princeton Environmental Institute, Princeton, NJ 08544; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,9,16]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.17.1.235-254.2004"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.57.1.4"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)07367-X"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1155165"},{"key":"e_1_3_3_5_2","volume-title":"Saving Lives, Buying Time","year":"2004","unstructured":"Saving Lives, Buying Time (Natl Academies Press, Washington, DC, 2004)."},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-6-72"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-3156.2000.00643.x"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(86)90248-8"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-4758(00)01707-5"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2001.1036"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0035-9203(98)90745-3"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2005.72.163"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1368-7646(98)80208-2"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI21682"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.2002.2241"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0402298101"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.22.12106"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-6296(02)00034-6"},{"key":"e_1_3_3_19_2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1090\/dimacs\/071\/11","volume-title":"Disease Evolution: Concepts, Models, Data Analyses","author":"Smith DL","year":"2006","unstructured":"DL Smith, MF Boni, R Laxminarayan Disease Evolution: Concepts, Models, Data Analyses, eds Z Feng, U Dieckmann, S Levin (American Mathematical Society, Providence, RI), pp. 213\u2013237 (2006)."},{"key":"e_1_3_3_20_2","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1017\/CBO9780511525728.030","volume-title":"Adaptive Dynamics and Infectious Diseases: In Pursuit of Virulence Management","author":"Bonhoeffer S","year":"2002","unstructured":"S Bonhoeffer Adaptive Dynamics and Infectious Diseases: In Pursuit of Virulence Management, eds U Dieckmann, et al. 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