• 1
    World Health Organization. World Malaria Report 2012. Geneva: WHO, 2012.
  • 2
    World Health Organization. Guidelines for the treatment of malaria, 2nd edn. Geneva: WHO, 2010.
  • 3
    Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR. Epidemiology of drug-resistant malaria. Lancet Infect Dis 2002; 2: 209218.
  • 4
    Mita T, Tanabe K. Evolution of Plasmodium falciparum drug resistance: implications for the development and containment of artemisinin resistance. Jpn J Infect Dis 2012; 65: 465475.
  • 5
    Djimdé A, Doumbo O, Cortese J et al. A molecular marker for chloroquine-resistant falciparum malaria. New Engl J Med 2001; 344: 257263.
  • 6
    Wongsrichanalai C, Meshnick SR. Declining artesunate–mefloquine efficacy against falciparum malaria on the Cambodia–Thailand border. Emerg Infect Dis 2008; 14: 716719.
  • 7
    Denis MB, Tsuyuoka R, Lim P et al. Efficacy of artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in northwest Cambodia. Trop Med Int Health 2006; 11: 18001807.
  • 8
    Rogers WO, Sem R, Tero T et al. Failure of artesunate–mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia. Malaria J 2009; 8: 10.
  • 9
    White N. Delaying antimalarial drug resistance with combination chemotherapy. Parassitologia 1999; 41: 301308.
  • 10
    WHO Global Malaria Programme. Update on artemisinin resistance—April 2012. 2012. Available from:
  • 11
    WHO Global Malaria Programme. The status of drug-resistant malaria along the Thailand–Myanmar border. Revised 9 May 2012. 2012. Available from:
  • 12
    Dondorp AM, Nosten F, Yi P et al. Artemisinin resistance in Plasmodium falciparum malaria. New Engl J Med 2009; 361: 455467.
  • 13
    Phyo AP, Nkhoma S, Stepniewska K et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet 2012; 379: 19601966.
  • 14
    Bustos MD, Wongsrichanalai C, Delacollette C, Burkholder B. Chapter 5 Monitoring antimalarial drug efficacy in the Greater Mekong Subregion: an overview of in vivo results from 2008 to 2010. In: Mekong Malaria III Monograph, Towards Malaria Elimination in the Greater Mekong Sub-region. Southeast Asian J Trop Med Public Health 2013; 44 (suppl 1): 201230.
  • 15
    Tran TH, Nguyen TT-N, Nguyen HP et al. In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam. Malaria J 2012; 11: 355.
  • 16
    Amaratunga C, Sreng S, Suon S et al. Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. Lancet Infect Dis 2012; 12: 851858.
  • 17
    Dondorp AM, Yeung S, White L et al. Artemisinin resistance: current status and scenarios for containment. Nat Rev Microbiol 2010; 8: 272280.
  • 18
    Fairhurst RM, Nayyar GML, Breman JG et al. Artemisinin-resistant malaria: research challenges, opportunities, and public health implications. Am J Trop Med Hyg 2012; 87: 231241.
  • 19
    Stepniewska K, Ashley E, Lee SJ et al. In vivo parasitological measures of artemisinin susceptibility. J Infect Dis 2010; 201: 570579.
  • 20
    Flegg JA, Guerin PJ, White NJ, Stepniewska K. Standardizing the measurement of parasite clearance in falciparum malaria: the parasite clearance estimator. Malaria J 2011; 10: 339.
  • 21
    Xiao S, Yao J, Utzinger J, Cai Y, Chollet J, Tanner M. Selection and reversal of Plasmodium berghei resistance in the mouse model following repeated high doses of artemether. Parasitol Res 2004; 92: 215219.
  • 22
    Witkowski B, Khim N, Chim P et al. Reduced artemisinin susceptibility of Plasmodium falciparum ring stages in Western Cambodia. Antimicrob Agents Chemother 2013; 57: 914923.
  • 23
    Klonis N, Xie SC, McCaw JM et al. Altered temporal response of malaria parasites determines differential sensitivity to artemisinin. Proc Natl Acad Sci USA 2013. 110: 51575162. Available from:
  • 24
    Anderson TJC, Nair S, Nkhoma S et al. High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia. J Infect Dis 2010; 201:13261330.
  • 25
    Cheeseman IH, Miller BA, Nair S et al. A major genome region underlying artemisinin resistance in malaria. Science 2012; 336: 7982.
  • 26
    Su X, Kirkman LA, Fujioka H, Wellems TE. Complex polymorphisms in an approximately 330 kDa protein are linked to chloroquine-resistant P. falciparum in Southeast Asia and Africa. Cell 1997; 91: 593603.
  • 27
    Gardner M, Shallom S, Carlton J et al. Sequence of Plasmodium falciparum chromosomes 2, 10, 11 and 14. Nature 2002; 419: 531534.
  • 28
    Volkman S, Sabeti P, DeCaprio D et al. A genome-wide map of diversity in Plasmodium falciparum. Nat Genet 2007; 39: 113119.
  • 29
    Mu J, Myers RA, Jiang H et al. Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs. Nat Genet 2010; 42: 268271.
  • 30
    Manske M, Miotto O, Campino S et al. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing. Nature 2012; 487: 375379.
  • 31
    Tan JC, Miller BA, Tan A et al. An optimized microarray platform for assaying genomic variation in Plasmodium falciparum field populations. Genome Biol 2011; 12: R35.
  • 32
    Anderson T, Nkhoma S, Ecker A, Fidock D. How can we identify parasite genes that underlie antimalarial drug resistance? Pharmacogenomics 2011; 12: 5985.
  • 33
    Takala-Harrison S, Clark TG, Jacob CG et al. Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia. Proc Natl Acad Sci USA 2013; 110: 240245.
  • 34
    Miotto O, Almagro-Garcia J, Manske M et al. Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia. Nat Genet 2013; 45: 648655.
  • 35
    Pearce RJ, Pota H, Evehe M-S et al. Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria. PLoS Med 2009; 6: e1000055.
  • 36
    Nkhoma S, Molyneux M, Ward S. Molecular surveillance for drug-resistant Plasmodium falciparum malaria in Malawi. Acta Trop 2007; 102: 138142.
  • 37
    Ecker A, Lehane A, Clain J, Fidock DA. PfCRT and its role in antimalarial drug resistance. Trends Parasitol 2012; 28: 504514.
  • 38
    Jambou R, Legrand E, Niang M et al. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet 2005; 366: 19601963.
  • 39
    Imwong M, Dondorp AM, Nosten F et al. Exploring the contribution of candidate genes to artemisinin resistance in Plasmodium falciparum. Antimicrob Agents Chemother 2010; 54: 28862892.
  • 40
    Adhin MR, Labadie-Bracho M, Vreden SG. Status of potential PfATP6 molecular markers for artemisinin resistance in Suriname. Malaria J 2012; 11: 322.
  • 41
    Veiga M, Ferreira P, Jörnhagen L et al. Novel polymorphisms in Plasmodium falciparum ABC transporter genes are associated with major ACT antimalarial drug resistance. PLoS ONE 2011; 6: e20212.
  • 42
    Malmberg M, Ferreira PE, Tarning J et al. Plasmodium falciparum drug resistance phenotype as assessed by patient antimalarial drug levels and its association with pfmdr1 polymorphisms. J Infect Dis 2013; 207: 842847.
  • 43
    Lim P, Wongsrichanalai C, Chim P et al. Decreased in vitro susceptibility of Plasmodium falciparum isolates to artesunate, mefloquine, chloroquine, and quinine in Cambodia from 2001 to 2007. Antimicrob Agents Chemother 2010; 54: 21352142.
  • 44
    Hao M, Jia D, Li Q et al. In vitro sensitivities of Plasmodium falciparum isolates from the China–Myanmar border to piperaquine and association with polymorphisms in candidate genes. Antimicrob Agents Chemother 2013; 57: 17231729.
  • 45
    Price RN, Uhlemann A-C, Brockman A et al. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 2004; 364: 438447.
  • 46
    Alker AP, Lim P, Sem R et al. Pfmdr1 and in vivo resistance to artesunate–mefloquine in falciparum malaria on the Cambodian–Thai border. Am J Trop Med Hyg 2007; 76: 641647.
  • 47
    Shah NK, Alker AP, Sem R et al. Molecular surveillance for multidrug-resistant Plasmodium falciparum, Cambodia. Emerg Infect Dis 2008; 14: 16371640.
  • 48
    Vinayak S, Alam MT, Sem R et al. Multiple genetic backgrounds of the amplified Plasmodium falciparum multidrug resistance (pfmdr1) gene and selective sweep of 184F mutation in Cambodia. J Infect Dis 2011; 201: 15511560.
  • 49
    Nkhoma S, Nair S, Mukakaa M, Molyneux ME, Ward SA, Anderson TJC. Parasites bearing a single copy of the multi-drug resistance gene (pfmdr-1) with wild-type SNPs predominate amongst Plasmodium falciparum isolates from Malawi. Acta Trop 2010; 111: 7881.
  • 50
    Baliraine FN, Rosenthal PJ. Prolonged selection of pfmdr1 polymorphisms after treatment of falciparum malaria with artemether–lumefantrine in Uganda. J Infect Dis 2011; 204: 11201124.
  • 51
    Dokomajilar C, Nsobya SL, Greenhouse B, Rosenthal PJ, Dorsey G. Selection of Plasmodium falciparum pfmdr1 alleles following therapy with artemether–lumefantrine in an area of Uganda where malaria is highly endemic. Antimicrob Agents Chemother 2006; 50: 18931895.
  • 52
    Gadalla NB, Adam I, Elzaki S-E et al. Increased pfmdr1 copy number and sequence polymorphisms in Plasmodium falciparum isolates from Sudanese malaria patients treated with artemether–lumefantrine. Antimicrob Agents Chemother 2011; 55: 54085411.
  • 53
    Happi CT, Gbotosho GO, Folarin OA et al. Selection of Plasmodium falciparum multidrug resistance gene 1 alleles in asexual stages and gametocytes by artemether–lumefantrine in Nigerian children with uncomplicated falciparum malaria. Antimicrob Agents Chemother 2009; 53: 888895.
  • 54
    Humphreys GS, Merinopoulos I, Ahmed J et al. Amodiaquine and artemether–lumefantrine select distinct alleles of the Plasmodium falciparum mdr1 gene in Tanzanian children treated for uncomplicated malaria. Antimicrob Agents Chemother 2007; 51: 991997.
  • 55
    Kamugisha E, Bujila I, Lahdo M, Minde M, Kongola G, Naiwumbwe H. Large differences in prevalence of pfcrt and pfmdr1 mutations between Mwanza, Tanzania and Iganga, Uganda—a reflection of differences in policies regarding withdrawal of chloroquine? Acta Trop 2012; 121: 45.
  • 56
    Lim P, Alker AP, Khim N et al. Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia. Malaria J 2009; 8: 11.
  • 57
    Sisowath C, Petersen I, Veiga MI et al. In vivo selection of Plasmodium falciparum parasites carrying the chloroquine-susceptible pfcrt K76 allele after treatment with artemether–lumefantrine in Africa. J Infect Dis 2009; 199: 750757.
  • 58
    World Health Organization. Containment of malaria multi-drug resistance on the Cambodia–Thailand border. Report of an informal consultation, Phnom Penh, 29–30 January 2007. Geneva: WHO; 2007.
  • 59
    Talisuna AO, Karema C, Ogutu B et al. Mitigating the threat of artemisinin resistance in Africa: improvement of drug-resistance surveillance and response systems. Lancet Infect Dis 2012; 12: 888896.
  • 60
    Rueangweerayut R, Phyo A, Uthaisin C et al. Pyronaridine–artesunate versus mefloquine plus artesunate for malaria. New Engl J Med 2012; 366: 12981309.
  • 61
    Poravuth Y, Socheat D, Rueangweerayut R et al. Pyronaridine–artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial. PLoS ONE 2011; 6: e14501.
  • 62
    Croft SL, Duparc S, Arbe-Barnes SJ et al. Review of pyronaridine anti-malarial properties and product characteristics. Malaria J 2012; 11: 270.
  • 63
    Korsinczky M, Chen N, Kotecka B, Saul A, Rieckmann K, Cheng Q. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob Agents Chemother 2000; 44: 21002108.
  • 64
    Kessl JJ. Cytochrome b mutations that modify the ubiquinol-binding pocket of the cytochrome bc1 complex and confer anti-malarial drug resistance in Saccharomyces cerevisiae. J Biol Chem 2005; 280: 1714217148.
  • 65
    Muehlen M, Schreiber J, Ehrhardt S et al. Short communication: prevalence of mutations associated with resistance to atovaquone and to the antifolate effect of proguanil in Plasmodium falciparum isolates from northern Ghana. Trop Med Int Health 2004; 9: 361363.
  • 66
    Vennerstrom JL, Arbe-Barnes S, Brun R et al. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 2004; 430: 900904.
  • 67
    Charman SA, Arbe-barnes S, Bathurst IC, Brun R, Campbell M, Charman WN. Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. Proc Natl Acad Sci USA 2011; 108: 44004405.
  • 68
    Anthony MP, Burrows JN, Duparc S, Moehrle JJ, Wells TNC. The global pipeline of new medicines for the control and elimination of malaria. Malaria J 2012; 11: 316.
  • 69
    Tschan S, Kremsner PG, Mordmüller B. Emerging drugs for malaria. Expert Opin Emerg Drugs 2012; 17: 319333.
  • 70
    Baird J, Surjadjaja C. Consideration of ethics in primaquine therapy against malaria transmission. Trends Parasitol 2011; 27: 1116.
  • 71
    White NJ, Qiao LG, Qi G, Luzzatto L. Rationale for recommending a lower dose of primaquine as a Plasmodium falciparum gametocytocide in populations where G6PD deficiency is common. Malaria J 2012; 11: 418.
  • 72
    Tinley KE, Loughlin AM, Jepson A, Barnett ED. Evaluation of a rapid qualitative enzyme chromatographic test for glucose-6-phosphate dehydrogenase deficiency. Am J Trop Med Hyg 2010; 82: 210214.
  • 73
    Kim S, Nguon C, Guillard B et al. Performance of the CareStart™ G6PD deficiency screening test, a point-of-care diagnostic for primaquine therapy screening. PLoS ONE 2011; 6: e28357.
  • 74
    Hsiang MS, Lin M, Dokomajilar C et al. PCR-based pooling of dried blood spots for detection of malaria parasites: optimization and application to a cohort of Ugandan children. J Clin Microbiol 2010; 48: 35393543.
  • 75
    Rogawski E, Congpuong K, Sudathip P et al. Active case detection with pooled real-time PCR to eliminate malaria in Trat province, Thailand. Am J Trop Med Hyg 2012; 86: 789791.
  • 76
    Hoyer S, Nguon S, Kim S et al. Focused Screening and Treatment (FSAT): a PCR-based strategy to detect malaria parasite carriers and contain drug resistant P. falciparum, Pailin, Cambodia. PLoS ONE 2012; 7: e45797.
  • 77
    World Health Organization. Consideration of mass drug administration for the containment of artemisinin-resistant malaria in the Greater Mekong Subregion. Report of a consensus meeting, 27–28 September 2010, Geneva, Switzerland. Geneva: WHO, 2011.