Drug Resistance in Malaria in Developing Countries

  • Quique Bassat
  • Pedro L. Alonso


A combination of complementary strategies is needed to control malaria, the most important parasitic infection causing an enormous burden of disease throughout the world. Antimalarial drugs play a crucial role among such strategies, as they may be used both for the treatment of cases and for their prevention. In the recent years, the treatment of malaria has been hampered by the emergence of widespread drug resistance to many of the available antimalarial drugs. This review attempts to give an insight of the history of malarial treatment and to describe the current status of drug-resistant malaria. The general determinants of drug resistance and the potential confounding factors for treatment failure will be assessed before a more thorough description of the specific mechanisms among host, vector, parasite and environment is summarized. Finally, the most important molecular pathways of drug resistance will be reviewed for each of the main drug families, together with an outline on the current methods for drug resistance diagnosis and surveillance.


Drug Resistance Antimalarial Drug Artemisinin Combination Therapy Intermittent Preventive Treatment Drug Pressure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Aide, P., Q. Bassat and P.L. Alonso (2007). “Towards an effective malaria vaccine.” Archives Disease in Childhood 92, 476–479.CrossRefGoogle Scholar
  2. Ayisi, J.G., et al. (2003). “The effect of dual infection with HIV and malaria on pregnancy outcome in western Kenya.” AIDS 17, 585–594.CrossRefPubMedGoogle Scholar
  3. Babiker, H.A. and D. Walliker (1997). “Current views on the population structure of Plasmodium falciparum: Implications for control.” Parasitology Today 13, 262–267.CrossRefPubMedGoogle Scholar
  4. Baird, J.K. (2004). “Chloroquine resistance in Plasmodium vivax.” Antimicrobial Agents and Chemotherapy 48, 4075–4083.CrossRefPubMedGoogle Scholar
  5. Baird, J.K. (2005). “Effectiveness of antimalarial drugs.” New England Journal of Medicine 352, 1565–1577.CrossRefPubMedGoogle Scholar
  6. Bloland, P.B. (2001). “Drug resistance in malaria.” World Health Organization, Geneva.Google Scholar
  7. Bray, P.G., S.R. Hawley and S.A. Ward (1996). “4-Aminoquinoline resistance of Plasmodium falciparum: insights from the study of amodiaquine uptake.” Molecular Pharmacology 50, 1551–1558.PubMedGoogle Scholar
  8. Bruce-Chwatt, L.J. (1970). “Resistance of P. falciparum to chloroquine in Africa: true or false?” Transactions of the Royal Society of Tropical Medicine and Hygiene 64, 776–784.CrossRefPubMedGoogle Scholar
  9. Collins, W.E. and G.M. Jeffery (2002). “Extended clearance time after treatment of infections with Plasmodium malariae may not be indicative of resistance to chloroquine.” American Journal of Tropical Medicine and Hygiene 67, 406–410.PubMedGoogle Scholar
  10. Cross, A.P. and B. Singer (1991). “Modelling the development of resistance of Plasmodium falciparum to anti-malarial drugs.” Transactions of the Royal Society of Tropical Medicine and Hygiene 85, 349–355.CrossRefPubMedGoogle Scholar
  11. Curtis, C.F. and L.N. Otoo (1986). “A simple model of the build-up of resistance to mixtures of anti-malarial drugs.” Transactions of the Royal Society of Tropical Medicine and Hygiene 80, 889–892.CrossRefPubMedGoogle Scholar
  12. Djimde, A., et al. (2001). “A molecular marker for chloroquine-resistant falciparum malaria.” New England Journal of Medicine 344, 257–263.CrossRefPubMedGoogle Scholar
  13. Ekland, E.H. and D.A. Fidock (2007). Advances in understanding the genetic basis of antimalarial drug resistance. Current Opinion in Microbiology 10, 363–370.CrossRefPubMedGoogle Scholar
  14. Foote, S.J. and A.F. Cowman (1994). “The mode of action and the mechanism of resistance to antimalarial drugs.” Acta Tropica 56, 157–171.CrossRefPubMedGoogle Scholar
  15. Greenwood, B. (2006). “Review: intermittent preventive treatment – a new approach to the prevention of malaria in children in areas with seasonal malaria transmission.” Tropical Medicine and International Health 11, 983–991.CrossRefPubMedGoogle Scholar
  16. Gupta, S., et al. (1999). “Immunity to non-cerebral severe malaria is acquired after one or two infections.” Nature Medicine 5, 340–343.CrossRefPubMedGoogle Scholar
  17. Harinasuta, T., P. Suntharasamai and C. Viravan (1965). “Chloroquine-resistant falciparum malaria in Thailand.” Lancet 2, 657–660.CrossRefPubMedGoogle Scholar
  18. Hastings, I.M. and U. D'Alessandro (2000). “Modelling a predictable disaster: the rise and spread of drug-resistant malaria.” Parasitology Today 16, 340–347.CrossRefPubMedGoogle Scholar
  19. Hastings, I.M., E.L. Korenromp and P.B. Bloland (2007). “The anatomy of a malaria disaster: drug policy choice and mortality in African children.” Lancet Infectious Diseases 7, 739–748.CrossRefPubMedGoogle Scholar
  20. Hastings, I.M., W.M. Watkins and N.J. White (2002). “The evolution of drug-resistant malaria: the role of drug elimination half-life.” Philosophical Transactions of the Royal Society London B (Biological Sciences) 357, 505–519.CrossRefGoogle Scholar
  21. Jambou, R., et al. (2005). “Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6.” Lancet 366, 1960–1963.CrossRefPubMedGoogle Scholar
  22. Korenromp, E.L., et al. (2003). “Measurement of trends in childhood malaria mortality in Africa: an assessment of progress toward targets based on verbal autopsy.” Lancet Infectious Diseases 3, 349–358.CrossRefPubMedGoogle Scholar
  23. Korsinczky, M., et al. (2000). “Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site.” Antimicrobial Agents and Chemotherapy 44, 2100–2108.CrossRefPubMedGoogle Scholar
  24. Laufer, M.K., A.A. Djimde and C.V. Plowe (2007). “Monitoring and deterring drug-resistant malaria in the era of combination therapy.” American Journal of Tropical Medicine and Hygiene 77, 160–169.PubMedGoogle Scholar
  25. Laufer, M.K., et al. (2006). “Return of chloroquine antimalarial efficacy in Malawi.” New England Journal of Medicine 355, 1959–1966.CrossRefPubMedGoogle Scholar
  26. Laufer, M.K., et al. (2007). “Malaria treatment efficacy among people living with HIV: the role of host and parasite factors.” American Journal of Tropical Medicine and Hygiene 77, 627–632.PubMedGoogle Scholar
  27. Mackinnon, M.J. and I.M. Hastings (1998). “The evolution of multiple drug resistance in malaria parasites.” Transactions of the Royal Society of Tropical Medicine and Hygiene, 92, 188–195.Google Scholar
  28. Magesa, S.M., et al. (2001). “Distinguishing Plasmodium falciparum treatment failures from re-infections by using polymerase chain reaction genotyping in a holoendemic area in northeastern Tanzania.” American Journal of Tropical Medicine and Hygiene 65, 477–483.PubMedGoogle Scholar
  29. Maguire, J.D., et al. (2002). “Chloroquine-resistant Plasmodium malariae in south Sumatra, Indonesia.” Lancet 360, 58–60.CrossRefPubMedGoogle Scholar
  30. Marsh, K. (1998). “Malaria disaster in Africa.” Lancet 352, 924.CrossRefPubMedGoogle Scholar
  31. McGready, R., et al. (2003). “Pregnancy and use of oral contraceptives reduces the biotransformation of proguanil to cycloguanil.” European Journal of Clinical Pharmacology 59, 553–557.CrossRefPubMedGoogle Scholar
  32. Molyneux, D.H., et al. (1999). “Transmission control and drug resistance in malaria: a crucial interaction.” Parasitology Today 15, 238–240.CrossRefPubMedGoogle Scholar
  33. Mutabingwa, T.K. (2005). “Artemisinin-based combination therapies (ACTs): best hope for malaria treatment but inaccessible to the needy!” Acta Tropica 95, 305–315.CrossRefPubMedGoogle Scholar
  34. Myint, H.Y., et al. (2007). “Efficacy and safety of dihydroartemisinin-piperaquine.” Transactions of the Royal Society of Tropical Medicine and Hygiene 101, 858–866.CrossRefPubMedGoogle Scholar
  35. Newton, P.N., et al. (2006). “Manslaughter by fake artesunate in Asia – will Africa be next?” PLoS Medicine 3, e197.CrossRefPubMedGoogle Scholar
  36. Nosten, F. and N.J. White (2007). “Artemisinin-based combination treatment of falciparum malaria.” American Journal of Tropical Medicine and Hygiene 77, 181–192.PubMedGoogle Scholar
  37. O'Neill, P.M., et al. (1998). “4-Aminoquinolines – past, present, and future: a chemical perspective.” Pharmacology and Therapeutics 77, 29–58.CrossRefPubMedGoogle Scholar
  38. Payne, D. (1988). “Did medicated salt hasten the spread of chloroquine resistance in Plasmodium falciparum?” Parasitology Today 4, 112–115.CrossRefPubMedGoogle Scholar
  39. Piola, P., et al. (2005). “Supervised versus unsupervised intake of six-dose artemether-lumefantrine for treatment of acute, uncomplicated Plasmodium falciparum malaria in Mbarara, Uganda: a randomised trial.” Lancet 365, 1467–1473.CrossRefPubMedGoogle Scholar
  40. Plowe, C.V., et al. (1995). “Pyrimethamine and proguanil resistance-conferring mutations in Plasmodium falciparum dihydrofolate reductase: polymerase chain reaction methods for surveillance in Africa.” American Journal of Tropical Medicine and Hygiene 52, 565–568.PubMedGoogle Scholar
  41. Sibley, C.H., et al. (2001). “Pyrimethamine–sulfadoxine resistance in Plasmodium falciparum: what next?” Trends in Parasitology 17, 582–588.CrossRefPubMedGoogle Scholar
  42. Snow, R.W., et al. (2005). “The global distribution of clinical episodes of Plasmodium falciparum malaria.” Nature 434, 214–217.CrossRefPubMedGoogle Scholar
  43. Sucharit, S., et al. (1977). “Chloroquine resistant Plasmodium falciparum in Thailand: susceptibility of Anopheles.” Journal of the Medical Association of Thailand 60, 648–654.PubMedGoogle Scholar
  44. Talisuna, A.O., P. Bloland and U. D'Alessandro (2004). “History, dynamics, and public health importance of malaria parasite resistance.” Clinical Microbiology Reviews 17, 235–254.CrossRefPubMedGoogle Scholar
  45. Talisuna, A.O., et al. (2007). “Intensity of malaria transmission and the spread of Plasmodium falciparum resistant malaria: a review of epidemiologic field evidence.” American Journal of Tropical Medicine and Hygiene 77, 170–180.PubMedGoogle Scholar
  46. Trape, J.F., et al. (1998). “Impact of chloroquine resistance on malaria mortality.” C R Acad Sci III 321, 689–697.PubMedGoogle Scholar
  47. Trouiller, P., et al. (2002). “Drug development for neglected diseases: a deficient market and a public-health policy failure.” Lancet 359, 2188–2194.CrossRefPubMedGoogle Scholar
  48. UNICEF (2007). Malaria and Children, Progress in Intervention Coverage. United Nations Children's Fund, New York.Google Scholar
  49. Vallely, A., et al. (2007). “Intermittent preventive treatment for malaria in pregnancy in Africa: what's new, what's needed?” Malaria Journal 6, 16.CrossRefPubMedGoogle Scholar
  50. Watkins, W.M. and M. Mosobo (1993). “Treatment of Plasmodium falciparum malaria with pyrimethamine–sulfadoxine: selective pressure for resistance is a function of long elimination half-life.” Transactions of the Royal Society of Tropical Medicine and Hygiene 87, 75–78.CrossRefPubMedGoogle Scholar
  51. Wernsdorfer, W.H. (1994). “Epidemiology of drug resistance in malaria.” Acta Tropica 56, 143–156.CrossRefPubMedGoogle Scholar
  52. Wernsdorfer, W.H. and H. Noedl (2003). “Molecular markers for drug resistance in malaria: use in treatment, diagnosis and epidemiology.” Current Opinion in Infectious Diseases 16, 553–558.CrossRefPubMedGoogle Scholar
  53. White, N. (1999a). “Antimalarial drug resistance and combination chemotherapy.” Philosophical Transactions of the Royal Society London B (Biological Sciences) 354, 739–749.Google Scholar
  54. White, N.J. (1999b). “Delaying antimalarial drug resistance with combination chemotherapy.” Parassitologia 41, 301–308.Google Scholar
  55. White, N.J. (2004). “Antimalarial drug resistance.” Journal of Clinical Investigation 113, 1084–1092.PubMedGoogle Scholar
  56. Wolday, D., et al. (1995). “Sensitivity of Plasmodium falciparum in vivo to chloroquine and pyrimethamine–sulfadoxine in Rwandan patients in a refugee camp in Zaire.” Transactions of the Royal Society of Tropical Medicine and Hygiene 89, 654–656.CrossRefPubMedGoogle Scholar
  57. Wongsrichanalai, C., et al. (2002). “Epidemiology of drug-resistant malaria.” Lancet Infectious Diseases 2, 209–218.CrossRefPubMedGoogle Scholar
  58. World Health Organization (1973). “Chemotherapy of malaria and resistance to antimalarials.” (ed. World Health Organization), World Health Organization, Geneva, Switzerland.Google Scholar
  59. World Health Organization (1996). “Assessment of therapeutic efficacy of antimalarial drugs for uncomplicated malaria in areas with intense transmission.” WHO/MAL/96.1077. (ed. World Health Organization), World Health Organization, Geneva, Switzerland.Google Scholar
  60. World Health Organization (2003). “Assessment and monitoring of antimalarial efficacy for the treatment of uncomplicated falciparum malaria.” (ed. World Health Organization), World Health Organization, Geneva, Switzerland.Google Scholar
  61. World Health Organization (2005a). “Susceptibility of Plasmodium falciparum to antimalarial drugs: report on global monitoring 1996–2004.” World Health Organization, Geneva.Google Scholar
  62. World Health Organization (2005b). “World malaria report.” World Health Organization, Geneva, Switzerland.Google Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Barcelona Center for International Health Research (CRESIB), Hospital Clínic/Institut d’Investigacions Biomèdiques August Pi i Sunyer, Universitat de BarcelonaBarcelonaSpain
  2. 2.Centro de Investigação em Saúde de Manhiça (CISM)MaputoMozambique

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