Antimalarial Drug Resistance: Clinical Perspectives

  • Bruno PradinesEmail author


Despite efforts to discover new antiplasmodial drugs and to accomplish effective implementation of therapeutic combinations for malaria treatment by health systems, P. falciparum fits permanently and develops resistance, including to artemisinin-based combination therapy (ACT). Some mutations allow the parasite to survive in the presence of antimalarial drugs and to become resistant. Thus, other factors favoring the emergence of resistance include the following: (1) misuse of antimalarial drugs by infected people (abusive self-medication, poor compliance) leading to incomplete treatment; (2) unavailability of effective drugs or inadequate deployment of drugs as monotherapies; (3) sub-dosed or counterfeit consumption that allows parasites to survive at suboptimal concentrations of antimalarial drugs and to be selected for their ability to resist; (4) the pharmacokinetics and pharmacodynamics of the antimalarial drugs; and (5) the immunity profile of the community and the individual. Updated epidemiologic data on resistance and the molecular mechanisms involved are presented for each antimalarial drug used. The strategies for delaying the emergence and spread are also presented. The roles of heterogeneous biting and transmission in the establishment and spread of resistance in a population are very important. The role of asymptomatic P. falciparum parasites is also important in the evolution of antimalarial drug resistance. Several strategies are considered for controlling the emergence and spread of resistance to antimalarial drugs, such as interruption of asymptomatic carriage with mass drug administration, improvement of surveillance, development of new diagnostics and vaccines, and discovery of new drugs.


Antiplasmodial Monotherapy Plasmodium falciparum Artemisinin-based therapy (ACT) Chloroquine Point mutations Quinine Hyperparasitemia Amodiaquine Prophylaxis Mefloquine 


  1. 1.
    WHO (2013) World Malaria report 2013. Geneva: World Health Organization; 2013.Google Scholar
  2. 2.
    Hayward R, Saliba KJ, Kirk K. Pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum. Mol Microbiol. 2005;55:1285–95.PubMedCrossRefGoogle Scholar
  3. 3.
    Noranate N, Durand R, Tall A, et al. Rapid dissemination of Plasmodium falciparum drug resistance despite strictly controlled antimalarial use. PLoS One. 2007;2:139.CrossRefGoogle Scholar
  4. 4.
    Trape JF, Pison G, Preziosi MP, et al. Impact of chloroquine resistance on malaria mortality. C R Acad Sci. 1998;321:689–97.CrossRefGoogle Scholar
  5. 5.
    Trape JF. The public health impact of chloroquine resistance in Africa. Am J Trop Med Hyg. 2001;64(1–2 Suppl):12–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Fidock DA, Nomura T, Talley AK, et al. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell. 2000;6:861–71.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Djimdé A, Doumbo OK, Cortese JF, et al. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med. 2001;344:257–63.PubMedCrossRefGoogle Scholar
  8. 8.
    Nagesha HS, Casey GJ, Rieckmann H, et al. New haplotypes of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene among chloroquine-resistant parasite isolates. Am J Trop Med Hyg. 2003;68:398–402.PubMedGoogle Scholar
  9. 9.
    Johnson DJ, Fidock DA, Mungthin M, et al. Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Mol Cell. 2004;15:867–77.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Picot S, Olliaro P, de Monbrison F, et al. A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria. Malar J. 2009;8:89.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Baro NK, Callaghan PS, Roepe PD. Function of resistance conferring Plasmodium falciparum chloroquine resistance transporter isoforms. Biochemistry. 2013;52:4242–9.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Basco LK, Ringwald P. Molecular epidemiology of malaria in Yaoundé, Cameroon. III. Analysis of chloroquine resistance and point mutations in the multidrug resistance 1 (pfmdr 1) gene of Plasmodium falciparum. Am J Trop Med Hyg. 1998;59:577–81.PubMedCrossRefGoogle Scholar
  13. 13.
    Duraisingh MT, Drakeley CJ, Muller O, et al. Evidence for selection for the tyrosine-86 allele of the pfmdr 1 gene of Plasmodium falciparum by chloroquine and amodiaquine. Parasitology. 1997;114:205–11.PubMedCrossRefGoogle Scholar
  14. 14.
    Foote SJ, Kyle DE, Martin RK, et al. Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance. Nature. 1990;345:255–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Grobusch MP, Adagu IS, Kremsner PG, et al. Plasmodium falciparum: in vitro chloroquine susceptibility and allele-specific PCR detection of Pfmdr1 Asn86Tyr polymorphism in Lambarene, Gabon. Parasitology. 1998;116:211–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Chen N, Gao Q, Wang S, et al. No genetic bottleneck in Plasmodium falciparum wild-type Pfcrt alleles reemerging in Hainan Island, China, following high-level chloroquine resistance. Antimicrob Agents Chemother. 2008;52:345–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Yang H, Yang Y, Yang P, et al. Monitoring Plasmodium falciparum chloroquine resistance in Yunnan Province, China, 1981–2006. Acta Trop. 2008;108:44–9.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Isozumi R, Uemura H, Le DD, et al. Longitudinal survey of Plasmodium falciparum infection in Vietnam: characteristics of antimalarial resistance and their associated factors. J Clin Microbiol. 2010;48:70–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Kublin JG, Cortese JF, Njunju EM, et al. Remergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine in Malawi. J Infect Dis. 2003;187:1870–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Mita T, Kaneko A, Lum JK, et al. Recovery of chloroquine sensitivity and low prevalence of the Plasmodium falciparum chloroquine resistance transporter gene mutation K76T following the discontinuance of chloroquine use in Malawi. Am J Trop Med Hyg. 2003;68:413–5.PubMedGoogle Scholar
  21. 21.
    Laufer MK, Thesing PC, Eddington ND, et al. Return of chloroquine antimalarial efficacy in Malawi. N Engl J Med. 2006;355:1959–66.PubMedCrossRefGoogle Scholar
  22. 22.
    Wilson PE, Kazadi W, Kamwendo DD, et al. Prevalence of pfcrt mutations in Congolese and Malawian Plasmodium falciparum isolates as determined by a new Taqman assay. Acta Trop. 2005;93:97–106.PubMedCrossRefGoogle Scholar
  23. 23.
    Nkhoma S, Molyneux M, Ward S. In vitro antimalarial susceptibility profile and prcrt/pfmdr-1 genotypes of Plasmodium falciparum field isolates from Malawi. Am J Trop Med Hyg. 2007;76:1107–12.PubMedGoogle Scholar
  24. 24.
    Mwai L, Ochong E, Abdirahman A, et al. Chloroquine resistance before and after its withdrawal in Kenya. Malar J. 2009;8:106.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Gharbi M, Flegg JA, Hubert V, et al. Longitudinal study assessing the return of chloroquine susceptibility of Plasmodium falciparum in isolates from travellers returning from West and Central Africa, 2000–2011. Malar J. 2013;12:35.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Mekonnen SK, Aseffa A, Berhe N, et al. Return of chloroquine-sensitive Plasmodium falciparum parasites and emergence of chloroquine-resistant Plasmodium vivax in Ethiopia. Malar J. 2014;13:244.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Wurtz N, Fall B, Pascual A, et al. Prevalence of molecular markers of Plasmodium falciparum drug resistance in Dakar, Senegal. Malar J. 2012;11:197.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Ndiaye M, Faye B, Tine R, et al. Assessment of the molecular marker of Plasmodium falciparum chloroquine resistance (Pfcrt) in Senegal after several years of chloroquine withdrawal. Am J Trop Med Hyg. 2012;87:640–5.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Trape JF, Tall A, Sokhna C, et al. The rise and fall of malaria in a west African rural community, Dielmo, Senegal, from 1990 to 2012: a 22 year longitudinal study. Lancet Infect Dis. 2014;14:476–88.PubMedCrossRefGoogle Scholar
  30. 30.
    Van Tyne D, Dieye B, Valim C, et al. Changes in drug sensitivity and anti-malarial drug resistance mutations over time among Plasmodium falciparum parasites in Senegal. Malar J. 2013;12:441.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Ly O, Gueye PE, Deme AB, et al. Evolution of the pfcrt T76 and pfmdr1 Y86 markers and chloroquine susceptibility 8 years after cessation of chloroquine use in Pikine, Senegal. Parasitol Res. 2012;111:1541–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Fall B, Camara C, Fall M, et al. Plasmodium falciparum susceptibility to standard and potential anti-malarial drugs in Dakar, Senegal, during the 2013-2014 malaria season. Malar J. 2015;14:60.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Mita T, Kaneko A, Lum JK, et al. Expansion of wild type allele rather than back mutation in pfcrt explains the recent recovery of chloroquine sensitivity of Plasmodium falciparum in Malawi. Mol Biochem Parasitol. 2004;135:159–63.PubMedCrossRefGoogle Scholar
  34. 34.
    Ariey F, Fandeur T, Durand R, et al. Invasion of Africa by a single pfcrt allele of South East Asian type. Malar J. 2006;5:34.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Laufer MK, Takala-Harrison S, Dzinjamala FK, et al. Return of chloroquine-susceptible falciparum malaria in Malawi was a reexpansion of diverse susceptible parasites. J Infect Dis. 2010;202:801–8.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    White NJ. The assessment of antimalarial drug efficacy. Trends Parasitol. 2002;18:458–64.PubMedCrossRefGoogle Scholar
  37. 37.
    Rieckmann KH, Davis DR, Hutton DC. Plasmodium vivax resistance to chloroquine? Lancet. 1989;2:1183–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Baird JK, Basri H, Purnomo, et al. Resistance to chloroquine by Plasmodium vivax in Irian Jaya, Indonesia. Am J Top Med Hyg. 1991;44:547–52.Google Scholar
  39. 39.
    Sumawinata IW, Bernadeta, Leksana B, et al. Very high risk of therapeutic failure with chloroquine for uncomplicated Plasmodium falciparum and Plasmodium vivax in Indonesian Papua. Am J Trop Med Hyg. 2003;68:416–20.Google Scholar
  40. 40.
    Ratcliff A, Siswantoro H, Kenangalem E, et al. Therapeutic response of multidrug-resistant Plasmodium falciparum and P. vivax to chloroquine and sulfadoxine-pyrimethamine in southern Papua Indonesia. Trans R Soc Trop Med Hyg. 2007;101:351–9.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Karunajeewa HA, Mueller I, Senn M, et al. A trial of combination antimalarial therapies in children from Papua New Guinea. N Engl J Med. 2008;359:2545–57.PubMedCrossRefGoogle Scholar
  42. 42.
    Baird JK. Resistance to therapies for infection by Plasmodium vivax. Clin Microbiol Rev. 2009;22:508–34.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Baird JK, Leksana B, Masbar S, et al. Diagnosis of resistance to chloroquine by Plasmodium vivax: timing of recurrence and whole blood chloroquine levels. Am J Trop Med Hyg. 1997;56:621–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Singh RK. Emergence of chloroquine-resistant vivax malaria in south Bihar (India). Trans R Soc Trop Med Hyg. 2000;94:327.PubMedCrossRefGoogle Scholar
  45. 45.
    Price RN, von Seidlein L, Valecha N, et al. Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. Lancet Infect Dis. 2014;14:982–91.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Arias AE, Corredor A. Low response of Colombian strains of Plasmodium vivax to classical antimalarial therapy. Trop Med Parasitol. 1989;40:21–3.PubMedGoogle Scholar
  47. 47.
    Garavelli PL, Corti E. Chloroquine resistance in Plasmodium vivax: the first case in Brazil. Trans R Soc Trop Med Hyg. 1992;86:128.PubMedCrossRefGoogle Scholar
  48. 48.
    Phillips EJ, Keystone JS, Kain KC. Failure of combined chloroquine and high-dose primaquine therapy for Plasmodium vivax malaria acquired in Guyana, South America. Clin Infect Dis. 1996;23:1171–3.PubMedCrossRefGoogle Scholar
  49. 49.
    Soto J, Toledo J, Gutierrez P, et al. Plasmodium vivax clinically resistant to chloroquine in Colombia. Am J Trop Med Hyg. 2001;65:90–3.PubMedCrossRefGoogle Scholar
  50. 50.
    Ruebush 2nd TK, Zegarra J, Cairo J, et al. Chloroquine-resistant Plasmodium vivax malaria in Peru. Am J Trop Med Hyg. 2003;69:548–52.PubMedGoogle Scholar
  51. 51.
    de Santana Filho FS, Arcanjo AR, Chehuan YM, et al. Chloroquine-resistant Plasmodium vivax, Brazilian Amazon. Emerg Infect Dis. 2007;13:1125–6.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Marques MM, Costa MR, Santana Filho FS, et al. Plasmodium vivax chloroquine resistance and anemia in the western Brazilian Amazon. Antimicrob Agents Chemother. 2014;58:342–7.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Ketema T, Getahun K, Bacha K. Therapeutic efficacy of chloroquine for treatment of Plasmodium vivax malaria cases in Halaba district, South Ethiopia. Parasit Vectors. 2011;4:46.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Teka H, Petros B, Yamuah L, et al. Chloroquine-resistant Plasmodium vivax malaria in Debre Zeit, Ethiopia. Malar J. 2008;7:220.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Ketema T, Bacha K, Birhanu T, et al. Chloroquine-resistant Plasmodium vivax malaria in Serbo town, Jimma zone, south-west Ethiopia. Malar J. 2009;8:177.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Yohannes AM, Teklehaimanot A, Bergqvist Y, et al. Confirmed vivax resistance to chloroquine and effectiveness of artemether-lumefantrine for the treatment of vivax malaria in Ethiopia. Am J Trop Med Hyg. 2011;84:137–40.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Hwang J, Alemayehu BH, Reithinger R, et al. In vivo efficacy of artemether-lumefantrine and chloroquine against Plasmodium vivax: a randomized open label trial in central Ethiopia. PLoS One. 2013;8:63433.CrossRefGoogle Scholar
  58. 58.
    Suwanarusk R, Russell B, Chavchich M, et al. Chloroquine resistant Plasmodium vivax: in vitro characterisation and association with molecular polymorphisms. PLoS One. 2007;2:1089.CrossRefGoogle Scholar
  59. 59.
    Suwanarusk R, Chavchich M, Russell B, et al. Amplification of pvmdr1 associated with multidrug-resistant Plasmodium vivax. J Infect Dis. 2008;198:1558–64.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Barnadas C, Ratsimbasoa A, Tichit M, et al. Plasmodium vivax resistance to chloroquine in Madagascar: clinical efficacy and polymorphisms in pvmdr1 and pvcrt-o genes. Antimicrob Agents Chemother. 2008;52:4233–40.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Orjuela-Sánchez P, de Santana Filho FS, Machado-Lima A, et al. Analysis of single-nucleotide polymorphisms in the crt-o and mdr1 genes of Plasmodium vivax among chloroquine-resistant isolates from the Brazilian Amazon region. Antimicrob Agents Chemother. 2009;53:3561–4.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    WHO. Guidelines for the treatment of malaria. 2nd ed. Geneva: World Health Organization; 2010.Google Scholar
  63. 63.
    Dondorp A, Nosten F, Stepniewska K, et al. South-East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group: Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005;366:717–35.PubMedCrossRefGoogle Scholar
  64. 64.
    Dondorp AM, Fanello CI, Hendriksen ICE, et al. AQUAMAT group: Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010;376:1647–57.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Chongsuphajaisiddhi T, Sabchareon A, Attanath P. Treatment of quinine resistant falciparum malaria in Thai children. Southeast Asian J Trop Med Public Health. 1983;14:357–62.PubMedGoogle Scholar
  66. 66.
    Pukrittayakamee S, Supanaranond W, Looareesuwan S, et al. Quinine in severe falciparum malaria: evidence of declining efficacy in Thailand. Trans R Soc Trop Med Hyg. 1994;88:324–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Harinasuta T, Bunnag D, Lasserre R. Quinine resistant falciparum malaria treated with mefloquine. Southeast Asian J Trop Med Public Health. 1990;21:552–7.PubMedGoogle Scholar
  68. 68.
    Zalis MG, Pang L, Silveira MS, et al. Characterization of Plasmodium falciparum isolated from the Amazon region of Brazil: evidence for quinine resistance. Am J Trop Med Hyg. 1998;58:630–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Jelinek T, Schelbert P, Loscher T, et al. Quinine resistant falciparum malaria acquired in east Africa. Trop Med Parasitol. 1995;46:38–40.PubMedGoogle Scholar
  70. 70.
    Couto M. Les injections endo-veineuses du bleu de méthylène dans le paludisme. Bull Soc Path Ex. 1908;1:292–5.Google Scholar
  71. 71.
    Neiva A. Formação de raça do hematozoario do impaludismo rezistente à quinine. Mem Instit Oswaldo Cruz. 1910;2:131–40.CrossRefGoogle Scholar
  72. 72.
    Demar M, Carme B. Plasmodium falciparum in vivo resistance to quinine: description of two RIII responses in French Guiana. Am J Trop Med Hyg. 2004;70:125–7.PubMedGoogle Scholar
  73. 73.
    Bertaux L, Kraemer P, Taudon N, et al. Quinine-resistant malaria in traveler returning from French Guiana, 2010. Emerg Infect Dis. 2011;17:943–5.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Pradines B, Pistone T, Ezzedine K. Quinine-resistant malaria in traveler returning from Senegal, 2007. Emerg Infect Dis. 2010;16:546–8.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Palmieri F, Petrosillo N, Paglia MG, et al. Genetic confirmation of quinine-resistant Plasmodium falciparum malaria followed by post-malaria neurological syndrome in a traveler from Mozambique. J Clin Microbiol. 2004;42:5424–6.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Gachot B, Houze S, Le Bras J, et al. Possible prognostic significance of a brief rise in parasitaemia following quinine treatment of severe Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg. 1996;90:388–90.PubMedCrossRefGoogle Scholar
  77. 77.
    White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother. 1997;41:1413–22.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Edwards G, Krishna S. Pharmacokinetic and pharmacodynamic issues in the treatment of parasitic infections. Eur J Clin Microbiol Infect Dis. 2004;23:233–42.PubMedCrossRefGoogle Scholar
  79. 79.
    Parola P, Pradines B, Simon F, et al. Antimalarial drug susceptibility and point mutations associated with resistance in 248 Plasmodium falciparum isolates imported from Comoros to Marseille. Am J Trop Med Hyg. 2007;77:431–7.PubMedGoogle Scholar
  80. 80.
    Briolant S, Pelleau S, Bogreau H, et al. In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger (pfnhe-1) gene: the absence of association in clinical isolates from the Republic of Congo. Malar J. 2011;10:37.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Pradines B, Tall A, Parzy D, et al. In vitro activity of pyronaridine and amodiaquine against African isolates (Senegal) of Plasmodium falciparum in comparison with standard antimalarial agents. J Antimicrob Chemother. 1998;42:333–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Fall B, Diawara S, Sow K, Baret E, et al. Ex vivo susceptibility of Plasmodium isolates from Dakar, Senegal, to seven standard anti-malarial drugs. Malar J. 2011;10:310.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Baliraine FN, Nsobya SL, Achan J, et al. Limited ability of Plasmodium falciparum pfcrt, pfmdr1, and pfnhe1 polymorphims to predict quinine in vitro sensitivity or clinical effectiveness in Uganda. Antimicrob Agents Chemother. 2011;55:615–22.PubMedCrossRefGoogle Scholar
  84. 84.
    Ferdig MT, Cooper RA, Mu J, et al. Dissecting the loci of low-level quinine resistance in malaria parasites. Mol Microbiol. 2004;52:985–97.PubMedCrossRefGoogle Scholar
  85. 85.
    Pascual A, Fall B, Wurtz N, et al. In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger transporter (Pfnhe-1) gene in 393 isolates from Dakar, Senegal. Malar J. 2013;12:189.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Andriantsoanirina V, Khim N, Ratsimbasoa A, et al. Plasmodium falciparum Na+/H+ exchanger (pfnhe-1) genetic polymorphism in Indian Ocean malaria-endemic areas. Am J Trop Med Hyg. 2013;88:37–42.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Sinou V, Le Quang H, Pelleau S, et al. Polymorphism of Plasmodium falciparum Na(+)/H(+) exchanger is indicative of a low in vitro quinine susceptibility in isolates from Viet Nam. Malar J. 2011;10:164.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Meng H, Zhang R, Yang H, et al. In vitro sensitivity of Plasmodium falciparum clinical isolates from the China-Myanmar border area to quinine and association with polymorphism in the Na+/H+ exchanger. Antimicrob Agents Chemother. 2010;54:4306–13.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Vinayak S, Tauqeer Alam M, Upadhyay M, et al. Extensive genetic diversity in the Plasmodium falciparum Na+/H+ exchanger 1 transporter protein implicated in quinine resistance. Antimicrob Agents Chemother. 2007;51:4508–11.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Henry M, Briolant S, Zettor A, et al. Plasmodium falciparum Na+/H+ exchanger 1 transporter is involved in reduced susceptibility to quinine. Antimicrob Agents Chemother. 2009;53:1926–30.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Pelleau S, Bertaux L, Briolant S, et al. Differential association of Plasmodium falciparum Na+/H+ exchanger polymorphism and quinine responses in field- and culture-adapted isolates of Plasmodium falciparum. Antimicrob Agents Chemother. 2011;55:5834–41.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Okombo J, Kiara SM, Rono J, et al. In vitro activities of quinine and other antimalarials and pfnhe polymorphisms in Plasmodium isolates from Kenya. Antimicrob Agents Chemother. 2010;54:3302–7.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Andriantsoanirina V, Menard D, Rabearimanana S, et al. Association of microsatellite variations of Plasmodium falciparum Na+/H+ exchanger (Pfnhe-1) gene with reduced in vitro susceptibility to quinine: lack of confirmation in clinical isolates from Africa. Am J Trop Med Hyg. 2010;82:782–7.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Poyomtip T, Suwandittakul N, Sitthichot N, et al. Polymorphisms of the pfmdr1 but not the pfnhe-1 gene is associated with in vitro quinine sensitivity in Thai isolates of Plasmodium falciparum. Malar J. 2012;11:7.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Reed MB, Saliba KJ, Caruana SR, et al. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature. 2000;403:906–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Sidhu AB, Valderramos SG, Fidock DA. pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum. Mol Microbiol. 2005;57:913–26.PubMedCrossRefGoogle Scholar
  97. 97.
    Ekland EH, Fidock DA. Advances in understanding the genetic basis of antimalarial drug resistance. Curr Opin Microbiol. 2007;10:363–70.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Patel JC, Dalal SD. Treatment of malaria with a single dose of amodiaquin (Camoquin). Indian J Malariol. 1954;8:71–6.PubMedGoogle Scholar
  99. 99.
    Powell RD, Brewer GJ, Alving AS. Studies on a strain of chloroquine-resistant Plasmodium falciparumfrom Colombia, South America. Am J Trop Med Hyg. 1963;12:509–12.PubMedCrossRefGoogle Scholar
  100. 100.
    Young MD. Failure of chloroquine and amodiaquine to suppress Plasmodium falciparum. Trans R Soc Trop Med Hyg. 1962;56:252–6.PubMedCrossRefGoogle Scholar
  101. 101.
    Olliaro P, Nevill C, LeBras J, et al. Systematic review of amodiaquine treatment in uncomplicated malaria. Lancet. 1996;348:1196–201.PubMedCrossRefGoogle Scholar
  102. 102.
    Muller O, Van Hensbroek MB, Jaffar S, et al. A randomized trial of chloroquine, amodiaquine, and pyrimethamine/sulfadoxine in Gambian children with uncomplicated malaria. Trop Med Int Health. 1996;1:124–32.PubMedCrossRefGoogle Scholar
  103. 103.
    Brasseur P, Agnamey P, Ekobo AS, et al. Sensitivity of Plasmodium falciparum to amodiaquine and chloroquine in central Africa: a comparative study in vivo and in vitro. Trans R Soc Trop Med Hyg. 1995;89:528–30.PubMedCrossRefGoogle Scholar
  104. 104.
    Brasseur P, Guiguemde R, Diallo S, et al. Amodiaquine remains effective for treating uncomplicated malaria in west and central Africa. Trans R Soc Trop Med Hyg. 1999;93:645–50.PubMedCrossRefGoogle Scholar
  105. 105.
    Mandi G, Mockenhaupt FP, Coulibaly B, et al. Efficacy of amodiaquine in the treatment of uncomplicated falciparum malaria in young children of rural north-western Burkina Faso. Malar J. 2008;7:58.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Mbacham WF, Evehe MS, Netongo PM, et al. Efficacy of amodiaquine, sulphadoxine-pyrimethamine and their combination for the treatment of uncomplicated Plasmodium falciparum malaria in children in Cameroon at the time of policy change to artemisinin-based combination therapy. Malar J. 2010;9:34.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Stivanello E, Cavailler P, Cassano F, et al. Efficacy of chloroquine, sulphadoxine-pyrimethamine and amodiaquine for treatment of uncomplicated Plasmodium falciparum malaria in Kajo Keji county, Sudan. Trop Med Int Health. 2004;9:975–80.PubMedCrossRefGoogle Scholar
  108. 108.
    Checchi F, Balkan S, Vonhm BT, et al. Efficacy of amodiaquine for uncomplicated Plasmodium falciparum malaria in Harper, Liberia. Trans R Soc Trop Med Hyg. 2002;96:670–3.PubMedCrossRefGoogle Scholar
  109. 109.
    Nsimba B, Guiyedi V, Mabika-Mamfoumbi M, et al. Sulphadoxine/pyrimethamine versus amodiaquine for treating uncomplicated childhood malaria in Gabon: a randomized trial to guide national policy. Malar J. 2008;7:31.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Sá JM, Twu O, Hayton K, et al. Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine. Proc Natl Acad Sci U S A. 2009;106:18883–9.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Basco LK, Ringwald P. Molecular epidemiology of malaria in Cameroon. X. Evaluation of Pfmdr1 mutations as genetic markers for resistance to amino alcohols and artemisinin derivatives. Am J Trop Med Hyg. 2002;66:667–71.PubMedCrossRefGoogle Scholar
  112. 112.
    Tinto H, Ouédraogo JB, Erhart A, et al. Relationship between the Pfcrt T76 and the Pfmdr-1 Y86 mutations in Plasmodium falciparum and in vitro/in vivo chloroquine resistance in Burkina Faso, West Africa. Infect Genet Evol. 2003;3:287–92.PubMedCrossRefGoogle Scholar
  113. 113.
    Wurtz N, Fall B, Pascual A, et al. Role of Pfmdr1 in in vitro Plasmodium falciparum susceptibility to chloroquine, quinine, monodesethylamodiaquine, mefloquine, lumefantrine, and dihydroartemisinin. Antimicrob Agents Chemother. 2014;58:7032–40.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Folarin OA, Bustamante C, Gbotosho GO, et al. In vitro amodiaquine resistance and its association with mutations in pfcrt and pfmdr1 genes of Plasmodium falciparum isolates from Nigeria. Acta Trop. 2011;120:224–30.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Dahlström S, Aubouy A, Maïga-Ascofaré O, et al. Plasmodium falciparum polymorphism associated with ex vivo drug susceptibility and clinical effectiveness of artemisinin-based combination therapies in Benin. Antimicrob Agents Chemother. 2014;58:1–10.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Holmgren G, Gil JP, Ferreira PM, et al. Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y. Infect Genet Evol. 2006;6:309–14.PubMedCrossRefGoogle Scholar
  117. 117.
    Danquah I, Coulibaly B, Meissner P, et al. Selection of pfmdr1 and pfcrt alleles in amodiaquine treatment failure in north-western Burkina Faso. Acta Trop. 2010;114:63–73.PubMedCrossRefGoogle Scholar
  118. 118.
    Nsobya SL, Dokomajilar C, Joloba M, et al. Resistance mediating Plasmodium falciparum pfcrt and pfmdr1 alleles after treatment with artesunate-amodiaquine in Uganda. Antimicrob Agents Chemother. 2007;51:3023–5.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Echeverry DF, Holmgren G, Murillo C, et al. Polymorphisms in the pfcrt and pfmdr1 genes of Plasmodium falciparum and in vitro susceptibility to amodiaquine and desethylamodiaquine. Am J Trop Med Hyg. 2007;77:1034–8.PubMedGoogle Scholar
  120. 120.
    Palmer KJ, Holliday SM, Brogden RN. Mefloquine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1993;45:430–75.PubMedCrossRefGoogle Scholar
  121. 121.
    Boudreau EF, Webster HK, Pavanand K, et al. Type II mefloquine resistance in Thailand. Lancet. 1982;2:1335.PubMedCrossRefGoogle Scholar
  122. 122.
    Simpson JA, Watkins ER, Price RN, et al. Mefloquine pharmacokinetic-pharmacodynamic models: implications for dosing and resistance. Antimicrob Agents Chemother. 2000;44:3414-24.Google Scholar
  123. 123.
    Price RN, Uhlemann AC, Borckman A, et al. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet. 2004;364:438–47.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Sidhu AB, Uhlemann AC, Valderramos SG, et al. Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J Infect Dis. 2006;194:528–35.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Nkhoma S, Nair S, Mukala M, et al. 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. 2009;111:78–81.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Ruetz S, Delling U, Brault M, et al. The pfmdr1 gene of Plasmodium falciparum confers cellular resistance to antimalarial drugs in yeast cells. Proc Natl Acad Sci U S A. 1996;93:9942–7.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Pillai DR, Hijar G, Montoya I, et al. Lack of prediction of mefloquine and mefloquine-artesunate treatment outcome by mutations in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene for P. falciparum malaria in Peru. Am J Trop Med Hyg. 2003;68:107–10.PubMedGoogle Scholar
  128. 128.
    Pickard AL, Wongsrichanalai C, Purfield A, et al. Resistance to anti-malarials in Southeast Asia and genetic polymorphisms in pfmdr1. Antimicrob Agents Chemother. 2003;47:2418–23.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Khim N, Bouchier C, Ekala MT, et al. Countrywide survey shows very high prevalence of Plasmodium falciparum multilocus resistance genotypes in Cambodia. Antimicrob Agents Chemother. 2005;49:3147–52.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Price RN, Cassar C, Brockman A, et al. The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the Western border of Thailand. Antimicrob Agents Chemother. 1999;43:2943–9.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Duraisingh MT, Jones P, Sambou I, et al. The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin. Mol Biochem Parasitol. 2000;108:13–23.PubMedCrossRefGoogle Scholar
  132. 132.
    Duraisingh MT, Roper C, Walliker D, Warhurst DC. Increased sensitivity to the antimalarials mefloquine and artemisinin is conferred by mutations in the pfmdr1 gene of Plasmodium falciparum. Mol Microbiol. 2000;36:955–61.PubMedCrossRefGoogle Scholar
  133. 133.
    Rojanawatsirivet C, Congpuong K, Vijaykadga S, et al. Declining mefloquine sensitivity of Plasmodium falciparum along the Thai–Myanmar border. Southeast Asian J Trop Med Public Health. 2004;35:560–5.PubMedGoogle Scholar
  134. 134.
    Preechapornkul P, Imwong M, Chotivanich K, et al. Plasmodium falciparum pfmdr1 amplification, mefloquine resistance, and parasite fitness. Antimicrob Agents Chemother. 2009;53:1509–15.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361:455–67.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Imwong M, Dondorp AM, Nosten F, et al. Exploring the contribution of candidate genes to artemisinin resistance in Plasmodium falciparum. Antimicrob Agents Chemother. 2010;54:2886–92.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Leang R, Ros S, Duong S, et al. Therapeutic efficacy of fixed dose artesunate-mefloquine for the treatment of acute, uncomplicated Plasmodium falciparum malaria in Kampong Speu, Cambodia. Malar J. 2013;12:343.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Bustos MD, Wongsrichanalai C, Delacollette C, et al. Monitoring antimalarial drug efficacy in the greater Mekong Subregion: an overview of in vivo results from 2008 to 2010. Southeast Asian J Trop Med Public Health. 2013;44:201–30.PubMedGoogle Scholar
  139. 139.
    Satimai W, Sudathip P, Vijavkadga S, et al. Artemisinin resistance containment project in Thailand. II: responses to mefloquine-artesunate combination therapy among falciparum malaria patients in provinces bordering Cambodia. Malar J. 2012;11:300.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Huong MN, Hewitt S, Davis TM, et al. Resistance of Plasmodium falciparum to antimalarial drugs in a highly endemic area of southern Viet Nam: a study in vivo and in vitro. Trans R Soc Trop Med Hyg. 2001;95:325–9.PubMedCrossRefGoogle Scholar
  141. 141.
    Trung TN, Davis TM, Hewitt S, et al. Treatment of falciparum malaria in Vietnamese children: the need for combination therapy and optimized dosage regimens. Ann Trop Paediatr. 2001;21:307–12.PubMedCrossRefGoogle Scholar
  142. 142.
    Smithuis F, Shahmanesh M, Kyaw MK, et al. Comparison of chloroquine, sulfadoxine/pyrimethamine, mefloquine and mefloquine-artesunate for the treatment of falciparum malaria in Kachin State, North Myanmar. Trop Med Int Health. 2004;9:1184–90.PubMedCrossRefGoogle Scholar
  143. 143.
    Oduola AM, Milhous WK, Salako LA, et al. Reduced in-vitro susceptibility to mefloquine in West African isolates of Plasmodium falciparum. Lancet. 1987;2:1304–5.PubMedCrossRefGoogle Scholar
  144. 144.
    Witkowski B, Iriart X, Soh PN, et al. pfmdr1 amplification associated with clinical resistance to mefloquine in West Africa: implication in artemisinin combination therapies efficacy. J Clin Microbiol. 2010;48:3797–9.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Witkowski B, Nicolau ML, Soh PN, et al. Plasmodium falciparum isolates with increased pfmdr1 copy number circulate in West Africa. Antimicrob Agents Chemother. 2010;54:3049–51.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Basco LK, Le Bras J, Rhoades Z, et al. Analysis of pfmdr1 and drug susceptibility in fresh isolates of Plasmodium falciparum from Subsaharan Africa. Mol Biochem Parasitol. 1995;74:157–66.PubMedCrossRefGoogle Scholar
  147. 147.
    Gadalla NB, Adam I, Elzaki SE, 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;55:5408–11.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Akala HM, Eyase FL, Cheruiyot AC, et al. Antimalarial drug sensitivity profile of Western Kenya Plasmodium falciparum field isolates determined by a SYBR Green I in vitro assay and molecular analysis. Am J Trop Med Hyg. 2011;85:34–41.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Holmgren G, Bjorkman A, Gil JP. Amodiaquine resistance is not related to rare findings of Pfmdr1 gene amplifications in Kenya. Trop Med Int Health. 2006;11:1808–12.PubMedCrossRefGoogle Scholar
  150. 150.
    Pascual A, Fall B, Wurtz N, et al. Plasmodium falciparum with multidrug resistance 1 gene duplications, Senegal. Emerg Infect Dis. 2013;19:814–5.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Venkatesan M, Gadalla NB, Stepniewska K, et al. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: Parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine. Am J Trop Med Hyg. 2014;91:833–43.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Duah NO, Matrevi SA, de Souza DK, et al. Increased pfmdr1 gene copy number and the decline in pfcrt and pfmdr1 resistance alleles in Ghanaian Plasmodium falciparum isolates after the change of anti-malarial drug treatment policy. Malar J. 2013;12:377.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Aubouy A, Fievet N, Bertin G, et al. Dramatically decreased therapeutic efficacy of chloroquine and sulfadoxine-pyrimethamine, but not mefloquine, in southern Benin. Trop Med Int Health. 2007;12:886–94.PubMedCrossRefGoogle Scholar
  154. 154.
    Sowunmi A, Gbotosho GO, Happi C, et al. Therapeutic efficacy and effects of artesunate-mefloquine and mefloquine alone on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in southwest Nigeria. Am J Trop Med Hyg. 2009;81:979–86.PubMedCrossRefGoogle Scholar
  155. 155.
    Gonzalez R, Mombo-Ngoma G, Ouédraogo S, et al. Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-negative women: a multicenter randomized controlled trial. PLoS Med. 2014;11:1001733.CrossRefGoogle Scholar
  156. 156.
    Gosling RD, Gesase S, Mosha JF, et al. Protective efficacy and safety of three antimalarial regimens for intermittent preventive treatment for malaria in infants: a randomized, double-blind, placebo-controlled trial. Lancet. 2009;374:1521–32.PubMedCrossRefGoogle Scholar
  157. 157.
    Faye B, Ndiaye JL, Tine R, et al. A randomized trial of artesunate mefloquine versus artemether lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Senegalese children. Am J Trop Med Hyg. 2010;82:140–4.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Tine RC, Faye B, Sylla K, et al. Efficacy and tolerability of a new formulation of artesunate-mefloquine for the treatment of uncomplicated malaria in adult in Senegal: open randomized trial. Malar J. 2012;11:416.PubMedCrossRefGoogle Scholar
  159. 159.
    Sagara I, Diallo A, Kone M, et al. A randomized trial of artesunate-mefloquine versus artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Mali. Am J Trop Med Hyg. 2008;79:655–61.PubMedGoogle Scholar
  160. 160.
    Lekana-Douki JB, Dinzouna Boutamba SD, Zatra R, et al. Increased prevalence of Plasmodium falciparum Pfmdr1 86N genotype among field isolates from Franceville, Gabon after replacement of chloroquine by artemether-lumefantrine and artesunate-mefloquine. Infect Genet Evol. 2011;11:512–7.PubMedCrossRefGoogle Scholar
  161. 161.
    Gobbi F, Rossanese A, Buonfrate D, et al. Failure of malaria chemoprophylaxis with mefloquine in an oversize traveler to Mozambique. Malar J. 2013;12:451.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Gari-Toussaint M, Pradines B, Mondain V, et al. Sénégal et paludisme. Echec prophylactique vrai de la méfloquine. Presse Med. 2002;31:1136.Google Scholar
  163. 163.
    Marquino W, MacArthur JR, Barat LM, et al. Efficacy of chloroquine, sulfadoxine-pyrimethamine, and mefloquine for the treatment of uncomplicated Plasmodium falciparum malaria on the north coast of Peru. Am J Trop Med Hyg. 2003;68:120–3.PubMedCrossRefGoogle Scholar
  164. 164.
    Avila JC, Villaroel R, Marquino W, et al. Efficacy of mefloquine and mefloquine-artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon region of Bolivia. Trop Med Int Health. 2004;9:217–21.PubMedCrossRefGoogle Scholar
  165. 165.
    Macedo de Oliveira A, Chavez J, Ponce de Leone G, et al. Efficacy and effectiveness of mefloquine and artesunate combination therapy for uncomplicated Plasmodium falciparum malaria in the Peruvian Amazon. Am J Trop Med Hyg. 2011;85:573–8.CrossRefGoogle Scholar
  166. 166.
    Griffing S, Syphard L, Sridaran S, et al. Pfmdr1 amplification and fixation of pfcrt chloroquine resistance alleles in Plasmodium falciparum in Venezuela. Antimicrob Agents Chemother. 2010;54:1572–9.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Legrand E, Yrinesi J, Ekala MT, et al. Discordant temporal evolution of Pfcrt and Pfmdr1 genotypes and Plasmodium falciparum in vitro drug susceptibility to 4-aminoquinolines after drug policy change in French Guiana. Antimicrob Agents Chemother. 2012;56:1382–9.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Labadie-Bracho M, Adhin MR. Increased pfmdr1 copy number in Plasmodium falciparum isolates from Suriname. Trop Med Int Health. 2013;18:796–9.PubMedCrossRefGoogle Scholar
  169. 169.
    Adhin MR, Labadie-Bracho M, Bretas G. Molecular surveillance as monitoring tool for drug-resistant Plasmodium falciparum in Suriname. Am J Trop Med Hyg. 2013;89:311–6.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Li GQ, Guo XB, Fu LC, et al. Clinical trials of artemisinin and its derivatives in the treatment of malaria in China. Trans R Soc Trop Med Hyg. 1994;88:5–6.CrossRefGoogle Scholar
  171. 171.
    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;12:851–8.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Amaratunga C, Mao S, Sreng S, et al. Slow parasite clearance rates in response to artemether in patients with severe malaria. Lancet Infect Dis. 2013;13:113–4.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Hien TT, Thuy-Nhien NT, Phu NH, et al. In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam. Malar J. 2012;11:355.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Phyo AP, Nkhoma S, Stepniewska K, et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet. 2012;379:1960–6.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Ashley EA, Dhorda M, Fairhurst RM, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014;371:411–23.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Maiga AW, Fofana B, Sagara I, et al. No evidence of delayed parasite clearance after oral artesunate treatment of uncomplicated falciparum malaria in Mali. Am J Trop Med Hyg. 2012;87:23–8.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Flegg JA, Guerin PJ, White NJ, et al. Standardizing the measurement of parasite clearance in falciparum malaria: the parasite clearance estimator. Malar J. 2011;10:339.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Noedl H, Socheat D, Satmai W. Artemisinin-resistant malaria in Asia. N Engl J Med. 2009;361:540–1.PubMedCrossRefGoogle Scholar
  179. 179.
    Pradines B, Bertaux L, Pomares C, et al. Reduced in vitro susceptibility to artemisinin derivatives associated with multi-resistance in a traveler returning from South-East Asia. Malar J. 2011;10:268.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    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;366:1960–3.PubMedCrossRefGoogle Scholar
  181. 181.
    Witkowsky B, Lelièvre J, Lopez Barragan MJ, et al. Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism. Antimicrob Agents Chemother. 2010;54:1872–7.CrossRefGoogle Scholar
  182. 182.
    Witkowski B, Amaratunga C, Khim N, et al. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies. Lancet Infect Dis. 2013;13:1043–9.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Witkowski B, Khim N, Chim P, et al. Reduced artemisinin susceptibility of Plasmodium falciparum ring stages in Western Cambodia. Antimicrob Agents Chemother. 2013;57:914–23.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Ariey F, Witkowski B, Amaratunga C, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014;505:50–5.PubMedCrossRefGoogle Scholar
  185. 185.
    Amaratunga C, Witkowski B, Khim N, et al. Artemisinin resistance in Plasmodium falciparum. Lancet Infect Dis. 2014;14:449–50.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Amaratunga C, Witkowski B, Dek D, et al. Plasmodium falciparum founder populations in Western Cambodia have reduced artemisinin sensitivity in vitro. Antimicrob Agents Chemother. 2014;58:4935–7.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Woodrow CJ, Krishna S. Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance. Cell Mol Life Sci. 2006;63:1586–96.PubMedCrossRefGoogle Scholar
  188. 188.
    Valderramos SG, Scanfeld D, Uhlemann AC, et al. Investigations into the role of the Plasmodium falciparum SERCA (PfATP6) L263E mutation in artemisinin action and resistance. Antimicrob Agents Chemother. 2010;54:3842–52.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Zhang G, Guan Y, Zheng B, et al. No PfATPase6 S769N mutation found in Plasmodium falciparum isolates from China. Malar J. 2008;8:122.CrossRefGoogle Scholar
  190. 190.
    Tahar R, Ringwald P, Basco LK. Molecular epidemiology of malaria in Cameroon. XXVIII. In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum and sequence analysis of the P. falciparum ATPase 6 gene. Am J Trop Med Hyg. 2009;81:13–8.PubMedCrossRefGoogle Scholar
  191. 191.
    Noedl H, Se Y, Sriwichai S, et al. Artemisinin resistance in Cambodia: a clinical trial designed to address an emerging problem in Southeast Asia. Clin Infect Dis. 2010;51:82–9.CrossRefGoogle Scholar
  192. 192.
    Chavchich M, Gerena L, Peters J, et al. Role of pfmdr1 amplification and expression in induction of resistance to artemisinin derivatives in Plasmodium falciparum. Antimicrob Agents Chemother. 2010;54:2455–64.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Ngalah BS, Ingasia LA, Cheruiyot AC, et al. Analysis of major genome loci underlying artemisinin resistance and pfmdr1 copy number in pre- and post-ACTs in Western Kenya. Sci Rep. 2015;5:8308.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Takala-Harrison S, Jacob CG, Arze C, et al. Independent emergence of Plasmodium falciparum artemisinin resistance mutations in Southeast Asia. J Infect Dis. 2015;211:670–9.PubMedCrossRefGoogle Scholar
  195. 195.
    Ghorbal M, Gorman M, Macpherson CR, et al. Genome editing in the human malaria parasite Plasmodium falciparum using the CRISP-Cas9 system. Nat Biotechnol. 2014;32:819–21.PubMedCrossRefGoogle Scholar
  196. 196.
    Straimer J, Gnädig NF, Witkowski B, et al. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science. 2015;347:428–31.PubMedCrossRefGoogle Scholar
  197. 197.
    Taylor SM, Parobek CM, DeConti DK, et al. Absence of putative Plasmodium falciparum artemisinin resistance mutations in sub-Saharan Africa: a molecular epidemiology study. J Infect Dis. 2015;211:680–8.PubMedCrossRefGoogle Scholar
  198. 198.
    Torrentino-Madamet M, Fall B, Benoit N, et al. Limited polymorphisms in k13 gene in Plasmodium falciparum isolates from Dakar, Senegal in 2012–2013. Malar J. 2014;13:472.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Kamau E, Campino S, Amenga-Etego L, et al. K13-propeller polymorphisms in Plasmodium falciparum parasites from sub-Saharan Africa. J Infect Dis. 2015;211(8):1352–5.PubMedGoogle Scholar
  200. 200.
    Isozumi R, Uemura H, Kimata I, et al. Novel mutations in K13 propeller gene of artemisinin-resistant Plasmodium falciparum. Emerg Infect Dis. 2015;21:490–2.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Mohon AN, Alam MS, Bayih AG, et al. Mutations in Plasmodium falciparum K13 propeller gene from Bangladesh (2009–2013). Malar J. 2014;13:431.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Mishra N, Prajapati SK, Kaitholia K, et al. Surveillance for artemisinin resistance in Plasmodium falciparum in India using the kelch13 molecular marker. Antimicrob Agents Chemother. 2015;59(5):2548–53.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Feng J, Zhou D, Lin Y, et al. (2015) Amplification of pfmdr1, pfcrt, pvmdr1 and K13-propeller polymorphism associated with Plasmodium falciparum and Plasmodium vivax at the China-Myamnar border. Antimicrob Agents Chemother. 2015;59(5):2554–9.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Conrad MD, Bigira V, Kapisi J, et al. Polymorphisms in K13 and falcipain-2 associated with artemisinin resistance are not prevalent in Plasmodium falciparum isolated from Ugandan children. PLoS One. 2014;9:105690.CrossRefGoogle Scholar
  205. 205.
    Plucinski MM, Talundzic E, Morton L, et al. Efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated malaria in children in Zaire and Uige Provinces, Angola. Antimicrob Agents Chemother. 2015;59:437–43.PubMedCrossRefGoogle Scholar
  206. 206.
    Denis MB, Tsuyuoka R, Poravuth Y, et al. Surveillance of the efficacy of artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria in Cambodia. Trop Med Int Health. 2006;11:1360–6.PubMedCrossRefGoogle Scholar
  207. 207.
    Vijaykadga S, Rojanawatsirivej C, Cholpol S, et al. In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003. Trop Med Int Health. 2006;11:211–9.PubMedCrossRefGoogle Scholar
  208. 208.
    Rogers WO, Sem R, Tero T, et al. Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia. Malar J. 2009;8:10.PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Na Bangchang K, Ruengweerayut R, Mahamad P, et al. Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border. Malar J. 2010;9:273.PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Adjuik M, Babiker A, Garner P, et al. Artesunate combinations for treatment of malaria: meta-analysis. Lancet. 2004;363:9–17.PubMedCrossRefGoogle Scholar
  211. 211.
    WHO African Region Country Antimalarial Drug Policies.
  212. 212.
    Zwang J, Olliaro P, Barennes H, et al. Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis. Malar J. 2009;8:203.PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Shayo A, Mandara CI, Shahada F, et al. Therapeutic efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in North-Eastern Tanzania. Malar J. 2014;13:376.PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Smithuis F, Kyau MF, Phe O, et al. Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. Lancet Infect Dis. 2010;10:673–81.PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Hasugian AR, Purba HL, Kenangalem E, et al. Dihydroartemisinin-piperaquine versus artesunate-amodiaquine: superior efficacy and posttreatment prophylaxis against multidrug-resistant Plasmodium falciparum and Plasmodium vivax malaria. Clin Infect Dis. 2007;44:1067–74.PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Durrani N, Leslie T, Rahim S, et al. Efficacy of combination therapy with artesunate plus amodiaquine compared to monotherapy with chloroquine, amodiaquine or sulfadoxine-pyrimethamine for treatment of uncomplicated Plasmodium falciparum in Afghanistan. Trop Med Int Health. 2005;10:521–9.PubMedCrossRefGoogle Scholar
  217. 217.
    Thanh NX, Trung TN, Phong NC, et al. Open label randomized comparison of dihydroartemisinin-piperaquine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in central Vietnam. Trop Med Int Health. 2009;14:504–11.PubMedCrossRefGoogle Scholar
  218. 218.
    Thanh NX, Trung TN, Phong NC, et al. The efficacy and tolerability of artemisinin-piperaquine (Artequick®) versus artesunate-amodiaquine (Coarsucam™) for the treatment of uncomplicated Plasmodium falciparum malaria in south-central Vietnam. Malar J. 2012;11:217.PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    De la Hoz Restrepo F, Porras Ramirez A, Rico Mendoza A, et al. Artesunate + amodiaquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in the Colombian Pacific region: a non-inferiority trial. Rev Soc Bras Med Trop. 2012;45:732–8.PubMedCrossRefGoogle Scholar
  220. 220.
    Cui W. Ancient Chinese anti-fever cure becomes panacea for malaria. Bull WHO. 2009;87:743–4.Google Scholar
  221. 221.
    Muhindo MK, Kahuru A, Jagannathan P, et al. Early parasite clearance following artemisinin-based combination therapy among Ugandan children with uncomplicated malaria. Malar J. 2014;13:32.PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Beshir KB, Sutherland CJ, Sawa P, et al. Residual Plasmodium falciparum parasitemia in Kenyan children after artemisinin-combination therapy is associated with increased transmission to mosquitoes and parasite recurrence. J Infect Dis. 2013;208:2017–24.PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Borrmann S, Sasi P, Mwai L, et al. Declining responsiveness of Plasmodium falciparum infections to artemisinin-based combination treatments on Kenyan coast. PLoS One. 2011;6:26005.CrossRefGoogle Scholar
  224. 224.
    Sawa P, Shekalaghe SA, Drakeley CJ, et al. Malaria transmission after artemether-lumefantrine and dihydroartemisinin-piperaquine: a randomized trial. J Infect Dis. 2013;207:1637–45.PubMedCrossRefGoogle Scholar
  225. 225.
    Tinto H, Diallo S, Zongo I, et al. Effectiveness of artesunate-amodiaquine vs. artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Nanoro, Burkina Faso: a non-inferiority randomised trial. Trop Med Int Health. 2014;19:469–75.PubMedCrossRefGoogle Scholar
  226. 226.
    Bell DJ, Wootton D, Mukaka M, et al. Measurement of adherence, drug concentrations and the effectiveness of artemether-lumefantrine, chlorproguanil-dapsone or sulphadoxine-pyrimethamine in the treatment of uncomplicated malaria in Malawi. Malar J. 2009;8:204.PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Abuaku B, Duah N, Quaye L, et al. Therapeutic efficacy of artemether-lumefantrine combination in the treatment of uncomplicated malaria among children under five years of age in three ecological zones in Ghana. Malar J. 2012;11:388.PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Repetto EC, Traverso A, Giacomazzi CG. Possible clinical failure of artemether-lumefantrine in an italian traveler with uncomplicated falciparum malaria. Mediterr J Hematol Infect Dis. 2011;3:2011041.CrossRefGoogle Scholar
  229. 229.
    Mizuno Y, Kato Y, Kudo K, et al. First case of treatment failure of artemether-lumefantrine in a Japanese traveler with imported falciparum malaria. Jpn J Infect Dis. 2009;62:139–41.PubMedGoogle Scholar
  230. 230.
    Sylla K, Abiola A, Tine RC, et al. Monitoring the efficacy and safety of three artemisinin based-combinations therapies in Senegal: results from two years surveillance. BMC Infect Dis. 2013;13:598.PubMedPubMedCentralCrossRefGoogle Scholar
  231. 231.
    Onyamboko MA, Fanello CI, Wongsaen K, et al. Randomized comparison of the efficacies and tolerabilities of three artemisinin-based combination treatments for children with acute Plasmodium falciparum malaria in the Democratic Republic of the Congo. Antimicrob Agents Chemother. 2014;58:5228–36.CrossRefGoogle Scholar
  232. 232.
    Song J, Socheat D, Tan B, et al. Randomized trials of artemisinin-piperaquine, dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine for the treatment of multi-drug resistant falciparum malaria in Cambodia-Thailand border area. Malar J. 2011;10:231.PubMedPubMedCentralCrossRefGoogle Scholar
  233. 233.
    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;11:1800–7.PubMedCrossRefGoogle Scholar
  234. 234.
    Ezzet F, Mull R, Karbwang J. Population pharmacokinetics and therapeutic response of CGP 56697 (artemether + benflumetol) in malaria patients. Br J Clin Pharmacol. 1998;46:553–61.PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    White NJ, van Vugt M, Ezzet F. Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether–lumefantrine. Clin Pharmacokinet. 1999;37:105–25.PubMedCrossRefGoogle Scholar
  236. 236.
    Ashley EA, Stepiewska K, Lindegardh N, et al. Pharmacokinetic study of artemether-lumefantrine given once daily for the treatment of uncomplicated multidrug-resistant falciparum malaria. Trop Med Int Health. 2007;12:201–8.PubMedCrossRefGoogle Scholar
  237. 237.
    Mayxay M, Khanthavong M, Chanthongthip O, et al. Efficacy of artemether-lumefantrine, the nationally-recommended artemisinin combination for the treatment of uncomplicated falciparum malaria, in southern Laos. Malar J. 2012;11:184.PubMedPubMedCentralCrossRefGoogle Scholar
  238. 238.
    Carrasquilla G, Baron C, Monsell EM, et al. Randomized, prospective, three-arm study to confirm the auditory safety and efficacy of artemether-lumefantrine in Colombian patients with uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg. 2012;86:75–83.PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Mwai L, Kiara SM, Abdirahman A, et al. In vitro activities of piperaquine, lumefantrine, and dihydroartemisinin in Kenyan Plasmodium falciparum isolates and polymorphisms in pfcrt and pfmdr1. Antimicrob Agents Chemother. 2009;53:5069–73.PubMedPubMedCentralCrossRefGoogle Scholar
  240. 240.
    Ngo T, Duraisingh M, Reed M, et al. Analysis of pfcrt, pfmdr1, dhfr, and dhps mutations and drug sensitivities in Plasmodium falciparum isolates from patients in Vietnam before and after treatment with artemisinin. Am J Trop Med Hyg. 2003;68:350–6.PubMedGoogle Scholar
  241. 241.
    Mungthin M, Khositnithikul R, Sitthichot N, et al. Association between the pfmdr1 gene and in vitro artemether and lumefantrine sensitivity in Thai isolates of Plasmodium falciparum. Am J Trop Med Hyg. 2010;83:1005–9.PubMedPubMedCentralCrossRefGoogle Scholar
  242. 242.
    Sisowath C, Ferreira PE, Bustamante LY, et al. The role of pfmdr1 in Plasmodium falciparum tolerance to artemether-lumefantrine in Africa. Trop Med Int Health. 2007;12:736–42.PubMedCrossRefGoogle Scholar
  243. 243.
    Sisowath C, Stromberg J, Martensson A, et al. In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem). J Infect Dis. 2005;191:1014–7.PubMedCrossRefGoogle Scholar
  244. 244.
    Martensson A, Stromberg J, Sisowath C, et al. Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis. 2005;41:1079–86.PubMedCrossRefGoogle Scholar
  245. 245.
    Dokomajilar C, Nsobya SL, Greenhouse B, et al. Selection of Plasmodium falciparum pfmdr1 alleles following therapy wiyh artemether-lumefantrine in an area of Uganda where malaria is highly endemic. Antimicrob Agents Chemother. 2006;50:1893–5.PubMedPubMedCentralCrossRefGoogle Scholar
  246. 246.
    Davis TM, Hung TY, Sim IK, et al. Piperaquine: a resurgent antimalarial drug. Drugs. 2005;65:75–87.PubMedCrossRefGoogle Scholar
  247. 247.
    Bassat Q, Mulenga M, Tinto H, et al. Dihydroartemisinin-piperaquine and artemether-lumefantrine for treating uncomplicated malaria in African children: a randomised, non-inferiority trial. PLoS One. 2009;4:7871.CrossRefGoogle Scholar
  248. 248.
    Zwang J, Ashley EA, Karema C, et al. Safety and efficacy of dihydroartemisinin-piperaquine in falciparum malaria: a prospective multi-centre individual patient data analysis. PLoS One. 2009;4:6358.CrossRefGoogle Scholar
  249. 249.
    Valecha N, Phyo AP, Mayxay M, et al. An open-label, randomised study of dihydroartemisinin-piperaquine versus artesunate–mefloquine for falciparum malaria in Asia. PLoS One. 2010;5:11880.CrossRefGoogle Scholar
  250. 250.
    Karema C, Fanello CI, van Overmeir C, et al. Safety and efficacy of dihydroartemisinin/piperaquine (Artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children. Trans R Soc Trop Med Hyg. 2006;100:1105–11.PubMedCrossRefGoogle Scholar
  251. 251.
    Agarwal A, McMorrow M, Onyango P, et al. A randomized trial of artemether-lumefantrine and dihydroartemisinin-piperaquine in the treatment of uncomplicated malaria among children in western Kenya. Malar J. 2013;12:254.PubMedPubMedCentralCrossRefGoogle Scholar
  252. 252.
    Wanzira H, Kakuru A, Arinaitwe E, et al. Longitudinal outcomes in a cohort of Ugandan children randomized to artemether-lumefantrine versus dihydroartemisinin-piperaquine for the treatment of malaria. Clin Infect Dis. 2014;59:509–16.PubMedCrossRefGoogle Scholar
  253. 253.
    Zongo I, Somé FA, Somda SA, et al. Efficacy and day 7 plasma piperaquine concentrations in African children treated for uncomplicated malaria with dihydroartemisinin-piperaquine. PLoS One. 2014;9:103200.CrossRefGoogle Scholar
  254. 254.
    Zongo I, Dorsey G, Rovamba N, et al. Randomized comparison of amodiaquine plus sulfadoxine-pyrimethamine, artemether-lumefantrine, and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in BurkinaFaso. Clin Infect Dis. 2007;45:1453–61.PubMedCrossRefGoogle Scholar
  255. 255.
    Nambozi M, van Geertruyden JP, Hachizovu S, et al. Safety and efficacy of dihydroartemisinin-piperaquine versus artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Zambian children. Malar J. 2011;10:50.PubMedPubMedCentralCrossRefGoogle Scholar
  256. 256.
    Lon C, Manning JE, Vanachayangkul P, et al. Efficacy of two versus three-day regimens of dihydroartemisinin-piperaquine for uncomplicated malaria in military personnel in northern Cambodia: an open-label randomized trial. PLoS One. 2014;9:93138.CrossRefGoogle Scholar
  257. 257.
    Saunders DL, Vanachayangkul P, Lon C, et al. Dihydroartemisinin-piperaquine failure in Cambodia. N Engl J Med. 2014;371:484–5.PubMedCrossRefGoogle Scholar
  258. 258.
    Leang R, Barrette A, Bouth DM, et al. Efficacy of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax in Cambodia, 2008 to 2010. Antimicrob Agents Chemother. 2013;57:818–26.PubMedPubMedCentralCrossRefGoogle Scholar
  259. 259.
    Thriemer K, Hong NV, Rosanas-Urgell A, et al. Delayed parasite clearance after treatment with dihydroartemisinin-piperaquine in Plasmodium falciparum malaria patients in central Vietnam. Antimicrob Agents Chemother. 2014;58:7049–55.PubMedPubMedCentralCrossRefGoogle Scholar
  260. 260.
    Grande T, Bernasconi A, Erhart A, et al. A randomised controlled trial to assess the efficacy of dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Peru. PLoS One. 2007;2:1101.CrossRefGoogle Scholar
  261. 261.
    Looareesuwan S, Chulay JD, Canfield CJ, et al. Malarone™ (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group. Am J Trop Med Hyg. 1999;60:533–41.PubMedCrossRefGoogle Scholar
  262. 262.
    Boggild AK, Lau R, Reynaud D, et al. Failure of atovaquone-proguanil malaria chemoprophylaxis in a traveler to Ghana. Travel Med Infect Dis. 2015;13:89–93.PubMedCrossRefGoogle Scholar
  263. 263.
    De Schacht C, Moerman F, Clerinx J, et al. Severe Plasmodium falciparum malaria despite adequate prophylaxis with atovaquone/proguanil. BMJ. 2003;326:628.CrossRefGoogle Scholar
  264. 264.
    Sutherland CJ, Laundy M, Price N, et al. Mutations in the Plasmodium falciparum cytochrome b gene are associated with delayed parasite recrudescence in malaria patients treated with atovaquone-proguanil. Malar J. 2008;7:240.PubMedPubMedCentralCrossRefGoogle Scholar
  265. 265.
    Fivelman QL, Butcher GA, Adagu IS, et al. Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria. Malar J. 2002;1:1.PubMedPubMedCentralCrossRefGoogle Scholar
  266. 266.
    Plucinski MM, Huber CS, Akinyi S et al (2014) Novel mutation in cytochrome B of Plasmodium falciparum in one of two atovaquone-proguanil treatment failures in travelers returning from same site in Nigeria. Open Forum Infect Dis 2:ofu059Google Scholar
  267. 267.
    Wurtz N, Pascual A, Marin-Jauffre A, et al. Early treatment failure during treatment of Plasmodium falciparum with atovaquone-proguanil in the Republic of Ivory Coast. Malar J. 2012;11:146.PubMedPubMedCentralCrossRefGoogle Scholar
  268. 268.
    Rose GW, Suh KN, Kain KC, et al. Atovaquone-proguanil resistance in imported falciparum malaria in a young child. Pediatr Infect Dis J. 2008;27:567–9.PubMedCrossRefGoogle Scholar
  269. 269.
    Savini H, Bogreau H, Bertaux L, et al. First case of emergence of atovaquone-proguanil resistance in Plasmodium falciparum during treatment in a traveler in Comoros. Antimicrob Agents Chemother. 2008;52:2283–4.PubMedPubMedCentralCrossRefGoogle Scholar
  270. 270.
    Durand R, Prendki V, Cailhol J, et al. Plasmodium falciparum malaria and atovaquone-proguanil treatment failure. Emerg Infect Dis. 2008;14:320–2.PubMedPubMedCentralCrossRefGoogle Scholar
  271. 271.
    Schwartz E, Bujanover S, Kain KC. Genetic confirmation of atovaquone-proguanil resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa. Clin Infect Dis. 2003;37:450–1.PubMedCrossRefGoogle Scholar
  272. 272.
    Perry TL, Pandey P, Grant JM, et al. Severe atovaquone-resistant Plasmodium falciparum malaria in a Canadian traveler returned from the Indian subcontinent. Open Med. 2009;3:e10–6.PubMedPubMedCentralCrossRefGoogle Scholar
  273. 273.
    Cordel H, Cailhol J, Matheron S, et al. Atovaquone-proguanil in the treatment of imported uncomplicated Plasmodium falciparum malaria: a prospective observational study of 553 cases. Malar J. 2013;12:399.PubMedPubMedCentralCrossRefGoogle Scholar
  274. 274.
    Grynberg S, Lachish T, Kopel E, et al. Artemether-lumefantrine compared to atovaquone-proguanil as a treatment for uncomplicated Plasmodium falciparum malaria in travelers. Am J Trop Med Hyg. 2015;92:13–7.PubMedPubMedCentralCrossRefGoogle Scholar
  275. 275.
    Krudsood S, Patel SN, Tangpukdee N, et al. Efficacy of atovaquone-proguanil for treatment of acute multidrug-resistant Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg. 2007;76:655–8.PubMedGoogle Scholar
  276. 276.
    Patel SN, Kain KC. Atovaquone/proguanil for the prophylaxis and treatment of malaria. Expert Rev Anti Infect Ther. 2005;3:849–61.PubMedCrossRefGoogle Scholar
  277. 277.
    Korsinczky M, Chen N, Kotecka B, et al. Mutations in Plasmodium falcip arum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob Agents Chemother. 2000;44:2100–8.PubMedPubMedCentralCrossRefGoogle Scholar
  278. 278.
    Schwöbel B, Alifrangis M, Salanti A, et al. Different mutation patterns of atovaquone resistance to Plasmodium falciparum in vitro and in vivo: rapid detection of codon 268 polymorphisms in the cytochrome b as potential in vivo resistance marker. Malar J. 2003;2:5.PubMedPubMedCentralCrossRefGoogle Scholar
  279. 279.
    Wichmann O, Muehlberger N, Jelinek T, et al. Screening for mutations related to atovaquone/proguanil resistance in treatment failures and other imported isolates of Plasmodium falciparum in Europe. J Infect Dis. 2004;190:1541–6.PubMedCrossRefGoogle Scholar
  280. 280.
    Musset L, Bouchaud O, Matheron S, et al. Clinical atovaquone-proguanil resistance of Plasmodium falciparum associated with cytochrome b codon mutations. Microbes Infect. 2006;8:2599–604.PubMedCrossRefGoogle Scholar
  281. 281.
    Khositnithikul R, Tan-Ariya P, Mungthin M. In vitro atovaquone/proguanil susceptibility and characterization of the cytochrome b gene of Plasmodium falciparum from different endemic regions of Thailand. Malar J. 2008;7:23.PubMedPubMedCentralCrossRefGoogle Scholar
  282. 282.
    Cottrel G, Musset L, Hubert V, et al. Emergence of resistance to atovaquone-proguanil in malaria parasites: insights from computational modeling and clinical case reports. Antimicrob Agents Chemother. 2014;58:4504–14.CrossRefGoogle Scholar
  283. 283.
    Musset L, Pradines B, Parzy D, et al. Apparent absence of atovaquone/proguanil resistance in 477 Plasmodium falciparum isolates from untreated French travellers. J Antimicrob Chemother. 2006;57:110–5.PubMedCrossRefGoogle Scholar
  284. 284.
    Basco LK, Ringwald P. Molecular epidemiology of malaria in Yaounde, Cameroon. VI. Sequence variations in the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene and in vitro resistance to pyrimethamine and cycloguanil. Am J Trop Med Hyg. 2000;62:271–6.PubMedCrossRefGoogle Scholar
  285. 285.
    Hyde JE. Drug-resistant malaria-an insight. Fed Eur Biochem Soc J. 2007;274:4688–98.Google Scholar
  286. 286.
    Naidoo I, Roper C. Mapping ‘partially resistant’, ‘fully resistant’, and ‘super resistant’ malaria. Trends Parasitol. 2013;29:505–15.PubMedCrossRefGoogle Scholar
  287. 287.
    Dokomajilar C, Lankoande ZM, Dorsey G, et al. Roles of specific Plasmodium falciparum mutations in resistance to amodiaquine and sulfadoxine-pyrimethamine in Burkina Faso. Am J Trop Med Hyg. 2006;75:162–5.PubMedGoogle Scholar
  288. 288.
    Andriantsoanirina V, Ratsimbasoa A, Bouchier C, et al. Plasmodium falciparum drug resistance in Madagascar: facing the spread of unusual pfdhfr and pfmdr-1 haplotypes and the decrease of dihydroartemisinin susceptibility. Antimicrob Agents Chemother. 2009;53:4588–97.PubMedPubMedCentralCrossRefGoogle Scholar
  289. 289.
    Fortes F, Dimbu R, Figueiredo P, et al. Evaluation of prevalences of pfdhfr and pfdhps mutations in Angola. Malar J. 2011;10:22.PubMedPubMedCentralCrossRefGoogle Scholar
  290. 290.
    Schunk M, Kumma WP, Miranda IB, et al. High prevalence of drug-resistance mutations in Plasmodium falciparum and Plasmodium vivax in southern Ethiopia. Malar J. 2006;5:54.PubMedPubMedCentralCrossRefGoogle Scholar
  291. 291.
    Zhong D, Afrane Y, Githeka A, et al. Molecular epidemiology of drug-resistant malaria in western Kenya highlands. BMC Infect Dis. 2008;8:105.PubMedPubMedCentralCrossRefGoogle Scholar
  292. 292.
    Nkhoma S, Molyneux M, Ward S. Molecular surveillance for drug-resistant Plasmodium falciparum malaria in Malawi. Acta Trop. 2007;102:138–42.PubMedCrossRefGoogle Scholar
  293. 293.
    Karema C, Imwong M, Fanello CI, et al. Molecular correlates of high level antifolate resistance in Rwandan children with Plasmodium falciparum malaria. Antimicrob Agents Chemother. 2010;54:477–83.PubMedCrossRefGoogle Scholar
  294. 294.
    Salgueiro P, Vicente JL, Feirrera C, et al. Tracing the origins and signatures of selection of antifolate resistance in island populations of Plasmodium falciparum. BMC Infect Dis. 2010;10:163.PubMedPubMedCentralCrossRefGoogle Scholar
  295. 295.
    Alifrangis M, Lusingu JP, Mmbando B, et al. Five-year surveillance of molecular markers of Plasmodium falciparum antimalarial drug resistance in Korogwe District, Tanzania: accumulation of the 581G mutation in the P. falciparum dihydropteroate synthase gene. Am J Trop Med Hyg. 2009;80:523–7.PubMedGoogle Scholar
  296. 296.
    Lynch C, Pearce R, Pota H, et al. Emergence of a dhfr mutation conferring high-level drug resistance in Plasmodium falciparum populations from southwest Uganda. J Infect Dis. 2008;197:1598–604.PubMedCrossRefGoogle Scholar
  297. 297.
    Société de Pathologie Infectieuse de Langue Française, Collège des Universitaires de Maladies Infectieuses et Tropicales, Société de Médecine des Armées, et al. Management and prevention of imported Plasmodium falciparum malaria: recommendations for clinical practice 2007 (revision 2007 of the 1999 consensus conference). Med Mal Infect. 2008 ;38:68–117.Google Scholar
  298. 298.
    World Health Organization. WHO guidelines for the treatment of malaria. WHO/HTM/MAL/2006.1108.Google Scholar
  299. 299.
    Chin W, Intraprasert R. The evaluation of quinine alone or in combination with tetracycline and pyrimethamine against falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health. 1973;4:245–9.PubMedGoogle Scholar
  300. 300.
    Colwell EJ, Hickman RL, Kosakal S. Quinine-tetracycline and quinine-bactrim treatment of acute falciparum malaria in Thailand. Ann Trop Med Parasitol. 1973;67:125–32.PubMedCrossRefGoogle Scholar
  301. 301.
    Noeypatimanond S, Malikul S, Benjapong W, et al. Treatment of Plasmodium falciparum malaria with a combination of amodiaquine and tetracycline in Central Thailand. Trans R Soc Trop Med Hyg. 1983;77:338–40.PubMedCrossRefGoogle Scholar
  302. 302.
    Pukrittayakamee S, Chotivanich K, Chantra A, et al. Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicrob Agents Chemother. 2004;48:1329–34.PubMedPubMedCentralCrossRefGoogle Scholar
  303. 303.
    Pang LW, Limsomwong N, Boudreau EF, Singharaj P. Doxycycline prophylaxis for falciparum malaria. Lancet. 1987;1:1161–4.PubMedCrossRefGoogle Scholar
  304. 304.
    Watanasook C, Singharaj P, Suriyamongkol V, et al. Malaria prophylaxis with doxycycline in soldiers deployed to the Thai-Kampuchean border. Southeast Asian J Trop Med Public Health. 1989;20:61–4.PubMedGoogle Scholar
  305. 305.
    Pang L, Limsomwong N, Singharaj P. Prophylactic treatment of vivax and falciparum malaria with low-dose doxycycline. J Infect Dis. 1988;158:1124–7.PubMedCrossRefGoogle Scholar
  306. 306.
    Rieckmann KH, Yeo AE, Davis DR, et al. Recent military experience with malaria chemoprophylaxis. Med J Aust. 1993;158:446–9.PubMedGoogle Scholar
  307. 307.
    Shanks GD, Barnett A, Edstein MD, et al. Effectiveness of doxycycline combined with primaquine for malaria prophylaxis. Med J Aust. 1995;162:306–7.PubMedGoogle Scholar
  308. 308.
    Baudon D, Martet G, Pascal B, et al. Efficacy of daily antimalarial chemoprophylaxis in tropical Africa using either doxycycline or chloroquine-proguanil; a study conducted in 1996 in the French Army. Trans R Soc Trop Med Hyg. 1999;93:302–3.PubMedCrossRefGoogle Scholar
  309. 309.
    Weiss WR, Oloo AJ, Johnson A, et al. Daily primaquine is effective for prophylaxis against falciparum malaria in Kenya: comparison with mefloquine, doxycycline, and chloroquine plus proguanil. J Infect Dis. 1995;171:1569–75.PubMedCrossRefGoogle Scholar
  310. 310.
    Wallace MR, Sharp TW, Smoak B, et al. Malaria among United States troops in Somalia. Am J Med. 1996;100:49–55.PubMedCrossRefGoogle Scholar
  311. 311.
    Shanks GD, Roessler P, Edstein M, et al. Doxycycline for malaria prophylaxis in Australian soldiers deployed to United Nations missions in Somalia and Cambodia. Mil Med. 1995;160:443–4.PubMedGoogle Scholar
  312. 312.
    Migliani R, Josse R, Hovette R, et al. Le paludisme vu des tranchées: le cas de la Côte d’Ivoire en 2002–2003. Med Trop. 2003;63:282–6.Google Scholar
  313. 313.
    Migliani R, Ollivier L, Romand O, et al. Paludisme chez les militaires français en Côte d’Ivoire de 1998 à 2006. Bull Epidemiol Hebd (Paris). 2008;23–24:209–12.Google Scholar
  314. 314.
    Shmuklarsky MJ, Boudreau EF, Pang LW, et al. Failure of doxycycline as a causal prophylactic agent against Plasmodium falciparum malaria in healthy nonimmune volunteers. Ann Intern Med. 1994;120:294–9.PubMedCrossRefGoogle Scholar
  315. 315.
    Jacobs RL, Koontz LC. Plasmodium berghei: development of resistance to clindamycin and minocycline in mice. Exp Parasitol. 1976;40:116–23.PubMedCrossRefGoogle Scholar
  316. 316.
    Briolant S, Baragatti M, Parola P, et al. Multinormal in vitro distribution model suitable for the distribution of Plasmodium falciparum chemosusceptibility to doxycycline. Antimicrob Agents Chemother. 2009;53:688–95.PubMedCrossRefGoogle Scholar
  317. 317.
    Gaillard T, Briolant S, Houzé S, et al. PftetQ and pfmdt copy numbers as predictive molecular markers of decreased ex vivo doxycycline susceptibility in imported Plasmodium falciparum malaria. Malar J. 2013;12:414.PubMedPubMedCentralCrossRefGoogle Scholar
  318. 318.
    Briolant S, Wurtz N, Zettor A, et al. Susceptibility of Plasmodium falciparum isolates do doxycycline is associated with pftetQ sequence polymorphisms and pftetQ and pfmdt copy numbers. J Infect Dis. 2010;2010:152–9.Google Scholar
  319. 319.
    Achieng AO, Ingasia LA, Juma DW, et al. Doxycycline reduced in vitro susceptibility in Plasmodium falciparum Kenyan field isolates is associated with PftetQ KYNNNN sequence polymorphism. Antimicrob Agents Chemother. 2014;58:5894–9.PubMedPubMedCentralCrossRefGoogle Scholar
  320. 320.
    Organisation mondiale de la Santé: Surveillance de la résistance aux antipaludiques. Rapport d’une consultation de l’OMS, Genève, Suisse, 3–5 décembre 2001. WHO/CDS/CSR/EPH/2002.17/WHO/CDS/RBM. 2002:39.
  321. 321.
    Mombo-Ngoma G, Oyakhiroma S, Ord R, et al. High prevalence of dhfr triple mutant and correlation with high rates of sulphadoxine-pyrimethamine treatment failures in vivo in Gabonese children. Malar J. 2011;10:123.PubMedPubMedCentralCrossRefGoogle Scholar
  322. 322.
    Ringwald P, Keundjian A, Same Ekobo A, et al. Chemoresistance of Plasmodium falciparum in the urban region of Yaounde, Cameroon. Part 2: Evaluation of the efficacy of amodiaquine and sulfadoxine-pyrimethamine combination in the treatment of uncomplicated Plasmodium falciparum malaria in Yaounde, Cameroon. Trop Med Int Health. 2000;5:620–7.PubMedCrossRefGoogle Scholar
  323. 323.
    Mbacham W, Evehe M, Mbulli A, et al. Therapeutic efficacy of Sulfadoxine-Pyrimethamine (Fansidar®) and mutation rates to Anti-folate genes in different regions of Cameroon. Acta Trop. 2005;95S:337.Google Scholar
  324. 324.
    Myint HY, Tipmanee P, Nosten F, et al. A systematic overview of published antimalarial drug trials. Trans R Soc Trop Med Hyg. 2004;98:73–81.PubMedCrossRefGoogle Scholar
  325. 325.
    Hurwitz ES, Johnson D, Cambell CC. Resistance of Plasmodium falciparum malaria to sulfadoxine-pyrimethamine (‘Fansidar’) in a refugee camp in Thailand. Lancet. 1981;1:1068–70.PubMedCrossRefGoogle Scholar
  326. 326.
    Johnson DE, Roendej P, Williams RG. Falciparum malaria acquired in the area of the Thai-Khmer border resistant to treatment with Fansidar. Am J Trop Med Hyg. 1983;31:907–12.CrossRefGoogle Scholar
  327. 327.
    Pinichpongse S, Doberstyn EB, Cullen JR, et al. An evaluation of five regimens for the outpatient therapy of falciparum malaria in Thailand 1980–81. Bull World Health Organ. 1982;60:907–12.PubMedPubMedCentralGoogle Scholar
  328. 328.
    Walker AJ, Lopez-Antunano FJ. Response to drugs of South America, strains of Plasmodium falciparum. Trans R Soc Trop Med Hyg. 1968;62:654–67.PubMedCrossRefGoogle Scholar
  329. 329.
    Alecrim M d G, Alecrim WD, de Albuquerque BC, et al. Resistance of Plasmodium falciparum in the Brazilian Amazonas to the combination of sulfadoxine and pyrimethamine. Rev Inst Med Trop Sao Paulo. 1982;24:44–7.PubMedGoogle Scholar
  330. 330.
    Alecrim WD, Dourado H, Alecrim M d G, et al. In vivo resistance of Plasmodium falciparum to the combination of sulfadoxine and pyrimethamine, at RIII level, in Amazonas, Brazil. Rev Inst Med Trop Sao Paulo. 1982;24:52–3.PubMedGoogle Scholar
  331. 331.
    De Souza JM. Epidemiological distribution of Plasmodium falciparum drug resistance in Brazil and its relevance to the treatment and control of malaria. Mem Inst Oswaldo Cruz. 1992;87:343–8.PubMedCrossRefGoogle Scholar
  332. 332.
    Oostburg BF, Jozefzoon LM. Fansidar resistant Plasmodium falciparum infection in Surinam. Trop Geogr Med. 1983;35:243–7.PubMedGoogle Scholar
  333. 333.
    Botero D, Restrepo M, Montoya A. Prospective double-blind trial of two different doses of mefloquine plus pyrimethamine-sulfadoxine compared with pyrimethamine-sulfadoxine alone in the treatment of falciparum malaria. Bull World Health Organ. 1983;63:731–7.Google Scholar
  334. 334.
    Magill AJ, Zegarra J, Garcia C, et al. Efficacy of sulfadoxine-pyrimethamine and mefloquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon basin of Peru. Rev Soc Bras Med Trop. 2004;37:279–81.PubMedCrossRefGoogle Scholar
  335. 335.
    Laufer MK, Plowe CV. Withdrawing antimalarial drugs: impact on parasite resistance and implications for malaria treatment policies. Drug Resist Updat. 2004;7:279–88.PubMedCrossRefGoogle Scholar
  336. 336.
    Alifrangis M, Lemnge MM, Rønn AM, et al. Increasing prevalence of wild-types in the dihydrofolate reductase gene of Plasmodium falciparum in an area with high levels of sulfadoxine/pyrimethamine resistance after introduction of treated bed nets. Am J Trop Med Hyg. 2003;69:238–43.PubMedGoogle Scholar
  337. 337.
    Hastings IM, Nsanzabana C, Smith TA. A comparison of methods to detect and quantify the markers of antimalarial drug resistance. Am J Trop Med Hyg. 2010;83:489–95.PubMedPubMedCentralCrossRefGoogle Scholar
  338. 338.
    Kublin JG, Witzig RS, Shankar AH, et al. Molecular assays for surveillance of antifolate-resistant malaria. Lancet. 1998;351:1629–30.PubMedCrossRefGoogle Scholar
  339. 339.
    Zhou Z, Griffing SM, de Oliveira AM, et al. Decline in sulfadoxine–pyrimethamine-resistant alleles after change in drug policy in the Amazon region of Peru. Antimicrob Agents Chemother. 2008;52:739–41.PubMedCrossRefGoogle Scholar
  340. 340.
    Talisuna AO, Langi P, Mutabingwa TK, et al. Intensity of transmission and spread of gene mutations linked to chloroquine and sulphadoxine-pyrimethamine resistance in falciparum malaria. Int J Parasitol. 2003;33:1051–8.PubMedCrossRefGoogle Scholar
  341. 341.
    Sibley CH, Hyde JE, Sims PF, et al. Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? Trends Parasitol. 2001;17:582–8.PubMedCrossRefGoogle Scholar
  342. 342.
    Zhang Y, Meshnick SR. Inhibition of Plasmodium falciparum dihydropteroate synthetase and growth in vitro by sulfa drugs. Antimicrob Agents Chemother. 1991;35:267–71.PubMedPubMedCentralCrossRefGoogle Scholar
  343. 343.
    Wang P, Read M, Sims PF, et al. Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilisation. Mol Microbiol. 1997;23:979–86.PubMedCrossRefGoogle Scholar
  344. 344.
    Kublin JG, Dzinjalamala FK, Kamwendo DD, et al. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis. 2002;185:380–8.PubMedCrossRefGoogle Scholar
  345. 345.
    Bacon DJ, Tang D, Salas C, et al. Effects of point mutations in Plasmodium falciparum dihydrofolate reductase and dihydropterate synthase genes on clinical outcomes and in vitro susceptibility to sulfadoxine and pyrimethamine. PLoS One. 2009;4:6762.CrossRefGoogle Scholar
  346. 346.
    Mendez F, Munoz A, Carrasquilla G, et al. Determinants of treatment response to sulfadoxine-pyrimethamine and subsequent transmission potential in falciparum malaria. Am J Epidemiol. 2002;156:230–8.PubMedCrossRefGoogle Scholar
  347. 347.
    Ndiaye D, Dieye B, Ndiaye YD, et al. Polymorphism in dhfr/dhps genes, parasite density and ex vivo response to pyrimethamine in Plasmodium falciparum malaria parasites in Thies, Senegal. Int J Parasitol Drugs Drug Resist. 2013;3:135–42.PubMedPubMedCentralCrossRefGoogle Scholar
  348. 348.
    Hailemeskel E, Kassa M, Taddesse G, et al. Prevalence of sulfadoxine-pyrimethamine resistance-associated mutations in dhfr and dhps genes of Plasmodium falciparum three years after SP withdrawal in Bahir Dar, Northwest Ethiopia. Acta Trop. 2013;128:636–41.PubMedCrossRefGoogle Scholar
  349. 349.
    Naidoo I, Roper C. Drug resistance maps to guide intermittent preventive treatment of malaria in African infants. Parasitology. 2011;138:1469–79.PubMedPubMedCentralCrossRefGoogle Scholar
  350. 350.
    Artimovich E, Schneider K, Taylor TE, et al. Persistence of sulfadoxine-pyrimethamine resistance despite reduction of drug pressure in Malawi. J Infect Dis. 2015;212(5):694–701.PubMedPubMedCentralCrossRefGoogle Scholar
  351. 351.
    World Health and Organisation. World Health Organisation policy recommendation on intermittent preventive treatment during infancy with sulphadoxine-pyrimethamine (SP-IPTi) for Plasmodium falciparum malaria control in Africa. World Health Organisation; 2010.Google Scholar
  352. 352.
    White NJ. Antimalarial drug resistance. J Clin Invest. 2004;113:1084–92.PubMedPubMedCentralCrossRefGoogle Scholar
  353. 353.
    Hastings IM. A model for the origins and spread of drug-resistant malaria. Parasitology. 1997;115:133–41.PubMedCrossRefGoogle Scholar
  354. 354.
    Smith T, Schellenberg JA, Hayes R. Attributable fraction estimates and case definitions for malaria in endemic areas. Stat Med. 1994;13:2345–58.PubMedCrossRefGoogle Scholar
  355. 355.
    White NJ, Pongtavornpinyo W. The de novo selection of drug-resistant malaria parasites. Proc Biol Sci. 2003;270:545–54.PubMedPubMedCentralCrossRefGoogle Scholar
  356. 356.
    White N. Antimalarial drug resistance and combination chemotherapy. Philos Trans R Soc Lond B Biol Sci. 1999;354:739–49.PubMedPubMedCentralCrossRefGoogle Scholar
  357. 357.
    Austin DJ, Kristinsson KG, Anderson RM. The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proc Natl Acad Sci U S A. 1999;96:1152–6.PubMedPubMedCentralCrossRefGoogle Scholar
  358. 358.
    O’Meara WP, Smith DL, McKenzie FE. Potential impact of intermittent preventive treatment (IPT) on spread of drug-resistant malaria. PLoS Med. 2006;3:141.CrossRefGoogle Scholar
  359. 359.
    Jiang H, Patel JJ, Yi M, et al. Genome-wide compensatory changes accompany drug-selected mutations in the Plasmodium falciparum crt gene. PLoS One. 2008;3:2484.CrossRefGoogle Scholar
  360. 360.
    Looareesuwan S, Viravan C, Webster HK, et al. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg. 1996;54:62–6.PubMedCrossRefGoogle Scholar
  361. 361.
    Mackinnon MJ, Hastings IM. The evolution of multiple drug resistance in malaria parasites. Trans R Soc Trop Med Hyg. 1998;92:188–95.PubMedCrossRefGoogle Scholar
  362. 362.
    Cross AP, Singer B. Modelling the development of resistance of Plasmodium falciparum to anti-malarial drugs. Trans R Soc Trop Med Hyg. 1991;85:349–55.PubMedCrossRefGoogle Scholar
  363. 363.
    Hastings IM, Watkins WM, White NJ. The evolution of drug-resistant malaria: the role of drug elimination half-life. Philos Trans R Soc Lond B Biol Sci. 2002;357:505–19.PubMedPubMedCentralCrossRefGoogle Scholar
  364. 364.
    Klein EY. The impact of heterogeneous transmission on the establishment and spread of antimalarial drug resistance. J Theor Biol. 2014;340:177–85.PubMedCrossRefGoogle Scholar
  365. 365.
    Smith DL, Dushoff J, McKenzie FE. The risk of a mosquito-borne infection in a heterogeneous environment. PLoS Med. 2004;2:368.CrossRefGoogle Scholar
  366. 366.
    Stoddard ST, Morrison AC, Vazquez-Prokopec GM, et al. The role of human movement in the transmission of vector-borne pathogens. PLoS Neg Trop Dis. 2009;3:481.CrossRefGoogle Scholar
  367. 367.
    Knols BGJ, de Jong R, Takken W. Differential attractiveness of isolated humans to mosquitoes in Tanzania. Trans R Soc Trop Med Hyg. 1995;B89:604–6.CrossRefGoogle Scholar
  368. 368.
    Port GR, Boreham PFL, Bryan JH. The relationship of host size to feeding by mosquitoes of the Anopheles gambiae Giles complex (Diptera: Culicidae). Bull Entomol Res. 1980;70:133–44.CrossRefGoogle Scholar
  369. 369.
    Gatton ML, Hogarth W, Saul A. Time of treatment influences the appearance of drug-resistant parasites in Plasmodium falciparum infections. Parasitology. 2003;123:537–46.Google Scholar
  370. 370.
    Plowe CV, Kublin JG, Doumbo OK. P. falciparum dihydrofolate reductase and dihydropteroate synthase mutations: epidemiology and role in clinical resistance to antifolates. Drug Resist Updat. 1998;1:389–96.PubMedCrossRefGoogle Scholar
  371. 371.
    Klein EY, Smith DL, Boni MF, et al. Clinically immune hosts as a refuge for drug-sensitive malaria parasites. Malar J. 2008;7:67.PubMedPubMedCentralCrossRefGoogle Scholar
  372. 372.
    Babiker HA, Gadalla AAH, Ranford-Cartwright LC. The role of asymptomatic P. falciparum parasitaemia in the evolution of antimalarial drug resistance in areas of seasonal transmission. Drug Resist Updat. 2013;16:1–9.PubMedCrossRefGoogle Scholar
  373. 373.
    Babiker HA, Abdel-Muhsin AM, Ranford-Cartwright LC, et al. Characteristics of Plasmodium falciparum parasites that survive the lengthy dry season in eastern Sudan where malaria transmission is markedly seasonal. Am J Trop Med Hyg. 1998;59:582–90.PubMedCrossRefGoogle Scholar
  374. 374.
    Diallo A, Ndam NT, Moussiliou A, et al. Asymptomatic carriage of Plasmodium in urban Dakar: the risk of malaria should not be underestimated. PLoS One. 2012;7:31100.CrossRefGoogle Scholar
  375. 375.
    Kaneko A, Taleo G, Kalkoa M, et al. Malaria eradication on islands. Lancet. 2000;356:1560.PubMedCrossRefGoogle Scholar
  376. 376.
    El-Sayed B, El-Zaki S-E, Babiker H H, et al. A randomized open-label trial of artesunate-sulfadoxine-pyrimethamine with or without primaquine for elimination of sub-microscopic P. falciparum parasitaemia and gametocyte carriage in eastern Sudan. PLoS One. 2007;2:1311.CrossRefGoogle Scholar
  377. 377.
    von Seidlein L, Walraven G, Milligan PJ, et al. The effect of mass administration of sulfadoxine-pyrimethamine combined with artesunate on malaria incidence: a double-blind, community-randomized, placebo-controlled trial in The Gambia. Trans R Soc Trop Med Hyg. 2003;97:217–25.CrossRefGoogle Scholar
  378. 378.
    Wargo AR, de Roode JC, Huijben S, et al. Transmission stage investment of malaria parasites in response to in-host competition. Proc R Soc B Biol Sci. 2007;274:2629–38.CrossRefGoogle Scholar
  379. 379.
    Huijben S, Sim DG, Nelson WA, et al. The fitness of drug-resistant malaria parasites in a rodent model: multiplicity of infection. J Evol Biol. 2011;24:2410–22.PubMedPubMedCentralCrossRefGoogle Scholar
  380. 380.
    Baliraine FN, Afrane YA, Amenya DA, et al. High prevalence of asymptomatic Plasmodium falciparum infections in a highland area of western Kenya: a cohort study. J Infect Dis. 2009;200:66–74.PubMedPubMedCentralCrossRefGoogle Scholar
  381. 381.
    Franks S, Koram KA, Wagner GE, et al. Frequent and persistent, asymptomatic Plasmodium falciparum infections in African infants, characterized by multilocus genotyping. J Infect Dis. 2001;183:796–804.PubMedCrossRefGoogle Scholar
  382. 382.
    Kritsiriwuthinan K, Ngrenngarmlert W. Asymptomatic malaria infections among foreign migrant workers in Thailand. Asian Pac J Trop Med. 2011;4:560–3.PubMedCrossRefGoogle Scholar
  383. 383.
    da Silva-Nunes M, Moreno M, Conn JE, et al. Amazonian malaria: asymptomatic human reservoirs, diagnostic challenges, environmentally driven changes in mosquito vector populations, and the mandate for sustainable control strategies. Acta Trop. 2012;121:281–91.PubMedCrossRefGoogle Scholar
  384. 384.
    Lozovsky ER, Chookajorn T, Brown KM, et al. Stepwise acquisition of pyrimethamine resistance in the malaria parasite. Proc Natl Acad Sci U S A. 2009;106:12025–30.PubMedPubMedCentralCrossRefGoogle Scholar
  385. 385.
    Read AF, Day T, Huijben S. The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy. Proc Natl Acad Sci USA. 2011;108:10871–7.PubMedPubMedCentralCrossRefGoogle Scholar
  386. 386.
    Barclay VC, Smith RA, Findeis JL. Surveillance considerations for malaria elimination. Malar J. 2012;11:304.PubMedPubMedCentralCrossRefGoogle Scholar
  387. 387.
    Kelly GC, Tanner M, Vallely A, Clements A. Malaria elimination: moving forward with spatial decision support systems. Trends Parasitol. 2012;28:297–304.PubMedCrossRefGoogle Scholar
  388. 388.
    Kazembe LN. Spatial modelling and risk factors of malaria incidence in northern Malawi. Acta Trop. 2007;102:126–37.PubMedCrossRefGoogle Scholar
  389. 389.
    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;12:888–96.PubMedPubMedCentralCrossRefGoogle Scholar
  390. 390.
    Antimalarial Resistance Stakeholders Meeting. Eastern African scientists pledge immediate action to confront the threat of malaria drug resistance. 2012. Accessed 25 May 2012.
  391. 391.
    Steenkeste N, Rogers WO, Okell L, et al. Sub-microscopic malaria cases and mixed malaria infection in a remote area of high malaria endemicity in Rattanakiri province, Cambodia: implication for malaria elimination. Malar J. 2010;9:108.PubMedPubMedCentralCrossRefGoogle Scholar
  392. 392.
    Kaireh BA, Brioland S, Pascual A, et al. Plasmodium vivax and Plasmodium falciparum infections in the Republic of Djibouti: evaluation of their prevalence and potential determinants. Malar J. 2012;11:395.CrossRefGoogle Scholar
  393. 393.
    Greenwood BM, Targett GA. Malaria vaccines and the new malaria agenda. Clin Microbiol Infect. 2011;17:1600–7.PubMedCrossRefGoogle Scholar
  394. 394.
    Agnandji ST, Lell B, Soulanoudjingar SS, et al. First results of phase 3 trial of RTS, S/AS01 malaria vaccine in African children. N Engl J Med. 2011;365:1863–75.PubMedCrossRefGoogle Scholar
  395. 395.
    Fowkes FJ, Simpson JA, Beeson JG. Implications of the licensure of a partially efficacious malaria vaccine on evaluating second-generation vaccines. BMC Med. 2013;11:232.PubMedPubMedCentralCrossRefGoogle Scholar
  396. 396.
    Gardner MJ, Hall N, Fung E, et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature. 2002;419:498–511.PubMedCrossRefGoogle Scholar
  397. 397.
    Carlton JM, Adams JH, Silva JC, et al. Comparative genomics of the neglected human malaria Plasmodium vivax. Nature. 2008;455:757–63.PubMedPubMedCentralCrossRefGoogle Scholar
  398. 398.
    White NJ, Pukrittayakamee S, Hien TT, et al. Malaria. Lancet. 2014;383:723–35.PubMedCrossRefGoogle Scholar
  399. 399.
    Llanos-Cuentas A, Lacerda MV, Rueangweerayut R, et al. Tafenoquine plus chloroquine fort he treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study. Lancet. 2014;383:1049–58.PubMedCrossRefGoogle Scholar
  400. 400.
    Miller AK, Harrell E, Ye L, et al. Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects. Br J Clin Pharmacol. 2013;76:858–67.PubMedPubMedCentralCrossRefGoogle Scholar
  401. 401.
    Dow GS, McCarthy WF, Reid M, et al. A retrospective analysis oft he protective efficacy of tafenoquine and mefloquine as prophylactic anti-malarials in non-immune individuals during deployment to a malaria-endemic area. Malar J. 2014;13:49.PubMedPubMedCentralCrossRefGoogle Scholar
  402. 402.
    Moehrle JJ, Duparc S, Siethoff C, et al. First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials. Br J Clin Pharmacol. 2013;75:524–37.PubMedCrossRefGoogle Scholar
  403. 403.
    Charman SA, Arbe-Barnes S, Bathurst IC, et al. Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. Proc Natl Acad Sci U S A. 2011;108:4400–5.PubMedPubMedCentralCrossRefGoogle Scholar
  404. 404.
    Vennerstrom JL, Arbe-Barnes S, Brun R, et al. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature. 2004;430:900–4.PubMedCrossRefGoogle Scholar
  405. 405.
    Held J, Jeyaraj S, Kreidenweiss A. Antimalarial compounds in phase II clinical development. Expert Opin Investig Drugs. 2015;24:363–82.PubMedCrossRefGoogle Scholar
  406. 406.
    Rottmann M, McNamara C, Yeung BK, et al. Spiroindolones, a potent compound class for the treatment of malaria. Science. 2010;329:1175–80.PubMedPubMedCentralCrossRefGoogle Scholar
  407. 407.
    van Pelt-Koops JC, Pett HE, Graumans W, et al. The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector. Antimicrob Agents Chemother. 2012;56:3544–8.PubMedPubMedCentralCrossRefGoogle Scholar
  408. 408.
    Spillman NJ, Allen RJ, McNamara CW, et al. Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host Microbe. 2013;13:227–37.PubMedPubMedCentralCrossRefGoogle Scholar
  409. 409.
    White NJ, Pukrittayakamee S, Phyo AP, et al. Spiroindolone KAE609 for falciparum and vivax malaria. N Engl J Med. 2014;371:403–10.PubMedPubMedCentralCrossRefGoogle Scholar
  410. 410.
    Leong FJ, Li R, Jain JP, Lefèvre G, et al. A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel antimalarial Spiroindolone KAE609 (Cipargamin) to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers. Antimicrob Agents Chemother. 2014;58:6209–14.PubMedPubMedCentralCrossRefGoogle Scholar
  411. 411.
    Nagle A, Wu T, Kuhen K, Gagaring K, et al. Imidazolopiperazines: lead optimization of the second-generation antimalarial agents. J Med Chem. 2012;55:4244–73.PubMedPubMedCentralCrossRefGoogle Scholar
  412. 412.
    Kuhen KL, Chatterjee AK, Rottmann M, et al. KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission. Antimicrob Agents Chemother. 2014;58:5060–7.PubMedPubMedCentralCrossRefGoogle Scholar
  413. 413.
    Leong FJ, Zhao R, Zeng S, et al. A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel Imidazolopiperazine KAF156 to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers. Antimicrob Agents Chemother. 2014;58:6437–43.PubMedPubMedCentralCrossRefGoogle Scholar
  414. 414.
    Gujjar R, Marwaha A, El Mazouni F, et al. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J Med Chem. 2009;52:1864–72.PubMedPubMedCentralCrossRefGoogle Scholar
  415. 415.
    Coteron JM, Marco M, Esquivias J, et al. Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J Med Chem. 2011;54:5540–61.PubMedPubMedCentralCrossRefGoogle Scholar
  416. 416.
    Yuthavong Y, Tarnchompoo B, Vilaivan T, et al. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc Natl Acad Sci U S A. 2012;109:16823–8.PubMedPubMedCentralCrossRefGoogle Scholar
  417. 417.
    Abbat S, Jain V, Bharatam PV. Origins of the specificity of inhibitor P218 toward wild-type and mutant PfDHFR: a molecular dynamics analysis. J Biomol Struct Dyn. 2014;17:1–16.Google Scholar
  418. 418.
    Guttmann P, Ehrlich P. Ueber die wirkung des methylenblau bei malaria. Berlin Kin Wochenschr. 1891;28:953–6.Google Scholar
  419. 419.
    Anonymous. Methylene blue in grave malaria cachexia. J Am Med Assoc. 1900;34:1409.Google Scholar
  420. 420.
    Pascual A, Henry M, Briolant S, et al. In vitro activity of Proveblue (methylene blue) on Plasmodium falciparum strains resistant to standard antimalarial drugs. Antimicrob Agents Chemother. 2011;55:2472–4.PubMedPubMedCentralCrossRefGoogle Scholar
  421. 421.
    Dormoi J, Pascual A, Briolant S, et al. Proveblue (methylene blue) as antimalarial agent: in vitro synergy with dihydroartemisinin and atorvastatin. Antimicrob Agents Chemother. 2012;56:3467–9.PubMedPubMedCentralCrossRefGoogle Scholar
  422. 422.
    Dormoi J, Briolant S, Desgrouas C, et al. Efficacy of Proveblue (methylene blue) in an experimental cerebral murine model. Antimicrob Agents Chemother. 2013;57:3412–4.PubMedPubMedCentralCrossRefGoogle Scholar
  423. 423.
    Dormoi J, Briolant S, Desgrouas C, et al. Impact of methylene blue and atorvastatin combination therapy on the apparition of cerebral malaria in a murine model. Malar J. 2013;12:127.PubMedPubMedCentralCrossRefGoogle Scholar
  424. 424.
    Dormoi J, Pradines B. Dose responses of Proveblue methylene blue in an experimental murine cerebral malaria model. Antimicrob Agents Chemother. 2013;57:4080–1.PubMedPubMedCentralCrossRefGoogle Scholar
  425. 425.
    Ademowo OG, Nneji CM, Adedapo AD. In vitro antimalarial activity of methylene blue against field isolates of Plasmodium falciparum from children in Southeast Nigeria. Indian J Med Res. 2007;126:45–9.PubMedGoogle Scholar
  426. 426.
    Okombo J, Kiara SM, Mwai L, et al. Baseline of the activities of the antimalarials pyronaridine and methylene blue against Plasmodium falciparum isolates from Kenya. Antimicrob Agents Chemother. 2012;56:1105–7.PubMedPubMedCentralCrossRefGoogle Scholar
  427. 427.
    Suwanarusk R, Russel B, Ong A, et al. Methylene blue inhibits the asexual development of vivax malaria parasites from a region of increasing chloroquine resistance. J Antimicrob Chemother. 2014;70:124–9.PubMedPubMedCentralCrossRefGoogle Scholar
  428. 428.
    Adjalley SH, Jonhston GL, Li T, et al. Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue. Proc Natl Acad Sci U S A. 2011;108:1214–23.CrossRefGoogle Scholar
  429. 429.
    Delves MJ, Ruecker A, Straschil U, et al. Male and female Plasmodium falciparum mature gametocytes show different responses to antimalarial drugs. Antimicrob Agents Chemother. 2013;57:3268–74.PubMedPubMedCentralCrossRefGoogle Scholar
  430. 430.
    Coulibaly B, Zoungrana A, Mockenhaupt FP, et al. Strong gametocytocidal effect of methylene blue-based combination therapy against falciparum malaria: a randomized control trial. Plos One. 2009;4:5318.CrossRefGoogle Scholar
  431. 431.
    Coulibaly B, Pritsch M, Bountogo M, et al. Efficacy and safety of triple combination therapy with artesunate-amodiaquine-methylene blue for falciparum malaria in children: a randomized controlled trial in Burkina Faso. J Infect Dis. 2015;211:689–97.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Unité de Parasitologie et d’Entomologie, Département des Maladies InfectieusesInstitut de Recherche Biomédicale des ArméesBrétigny sur OrgeFrance

Personalised recommendations