Skip to main content
PMC home page
Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 1999 Apr 29;354(1384):739–749. doi: 10.1098/rstb.1999.0426

Antimalarial drug resistance and combination chemotherapy.

N White 1
PMCID: PMC1692562  PMID: 10365399

Abstract

Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly effective combination partners because (i) they are very active antimalarials, producing up to 10,000-fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using antimalarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives.

Full Text

The Full Text of this article is available as a PDF (219.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baird J. K., Basri H., Purnomo, Bangs M. J., Subianto B., Patchen L. C., Hoffman S. L. Resistance to chloroquine by Plasmodium vivax in Irian Jaya, Indonesia. Am J Trop Med Hyg. 1991 May;44(5):547–552. doi: 10.4269/ajtmh.1991.44.547. [DOI] [PubMed] [Google Scholar]
  2. Bloland P. B., Kazembe P. N., Oloo A. J., Himonga B., Barat L. M., Ruebush T. K. Chloroquine in Africa: critical assessment and recommendations for monitoring and evaluating chloroquine therapy efficacy in sub-Saharan Africa. Trop Med Int Health. 1998 Jul;3(7):543–552. doi: 10.1046/j.1365-3156.1998.00270.x. [DOI] [PubMed] [Google Scholar]
  3. Bonhoeffer S., Lipsitch M., Levin B. R. Evaluating treatment protocols to prevent antibiotic resistance. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12106–12111. doi: 10.1073/pnas.94.22.12106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brooks D. R., Wang P., Read M., Watkins W. M., Sims P. F., Hyde J. E. Sequence variation of the hydroxymethyldihydropterin pyrophosphokinase: dihydropteroate synthase gene in lines of the human malaria parasite, Plasmodium falciparum, with differing resistance to sulfadoxine. Eur J Biochem. 1994 Sep 1;224(2):397–405. doi: 10.1111/j.1432-1033.1994.00397.x. [DOI] [PubMed] [Google Scholar]
  5. Butcher G. A. Antimalarial drugs and the mosquito transmission of Plasmodium. Int J Parasitol. 1997 Sep;27(9):975–987. doi: 10.1016/s0020-7519(97)00079-9. [DOI] [PubMed] [Google Scholar]
  6. Canfield C. J., Pudney M., Gutteridge W. E. Interactions of atovaquone with other antimalarial drugs against Plasmodium falciparum in vitro. Exp Parasitol. 1995 May;80(3):373–381. doi: 10.1006/expr.1995.1049. [DOI] [PubMed] [Google Scholar]
  7. Carter R., Miller L. H. Evidence for environmental modulation of gametocytogenesis in Plasmodium falciparum in continuous culture. Bull World Health Organ. 1979;57 (Suppl 1):37–52. [PMC free article] [PubMed] [Google Scholar]
  8. Chawira A. N., Warhurst D. C., Robinson B. L., Peters W. The effect of combinations of qinghaosu (artemisinin) with standard antimalarial drugs in the suppressive treatment of malaria in mice. Trans R Soc Trop Med Hyg. 1987;81(4):554–558. doi: 10.1016/0035-9203(87)90404-4. [DOI] [PubMed] [Google Scholar]
  9. Cowman A. F., Galatis D., Thompson J. K. Selection for mefloquine resistance in Plasmodium falciparum is linked to amplification of the pfmdr1 gene and cross-resistance to halofantrine and quinine. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1143–1147. doi: 10.1073/pnas.91.3.1143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Curtis C. F., Otoo L. N. A simple model of the build-up of resistance to mixtures of anti-malarial drugs. Trans R Soc Trop Med Hyg. 1986;80(6):889–892. doi: 10.1016/0035-9203(86)90248-8. [DOI] [PubMed] [Google Scholar]
  11. Curtis J., Duraisingh M. T., Warhurst D. C. In vivo selection for a specific genotype of dihydropteroate synthetase of Plasmodium falciparum by pyrimethamine-sulfadoxine but not chlorproguanil-dapsone treatment. J Infect Dis. 1998 May;177(5):1429–1433. doi: 10.1086/517831. [DOI] [PubMed] [Google Scholar]
  12. Dorn A., Stoffel R., Matile H., Bubendorf A., Ridley R. G. Malarial haemozoin/beta-haematin supports haem polymerization in the absence of protein. Nature. 1995 Mar 16;374(6519):269–271. doi: 10.1038/374269a0. [DOI] [PubMed] [Google Scholar]
  13. Dye C. Population genetics of nonclonal, nonrandomly mating malaria parasites. Parasitol Today. 1991 Sep;7(9):236–240. doi: 10.1016/0169-4758(91)90236-h. [DOI] [PubMed] [Google Scholar]
  14. Dye C., Williams B. G. Multigenic drug resistance among inbred malaria parasites. Proc Biol Sci. 1997 Jan 22;264(1378):61–67. doi: 10.1098/rspb.1997.0009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Foote S. J., Cowman A. F. The mode of action and the mechanism of resistance to antimalarial drugs. Acta Trop. 1994 Mar;56(2-3):157–171. doi: 10.1016/0001-706x(94)90061-2. [DOI] [PubMed] [Google Scholar]
  16. Foote S. J., Galatis D., Cowman A. F. Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3014–3017. doi: 10.1073/pnas.87.8.3014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gay F., Ciceron L., Litaudon M., Bustos M. D., Astagneau P., Diquet B., Danis M., Gentilini M. In-vitro resistance of Plasmodium falciparum to qinghaosu derivatives in west Africa. Lancet. 1994 Apr 2;343(8901):850–851. doi: 10.1016/s0140-6736(94)92049-4. [DOI] [PubMed] [Google Scholar]
  18. Hassan Alin M., Ashton M., Kihamia C. M., Mtey G. J., Björkman A. Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients. Trans R Soc Trop Med Hyg. 1996 Jan-Feb;90(1):61–65. doi: 10.1016/s0035-9203(96)90480-0. [DOI] [PubMed] [Google Scholar]
  19. Hastings I. M. A model for the origins and spread of drug-resistant malaria. Parasitology. 1997 Aug;115(Pt 2):133–141. doi: 10.1017/s0031182097001261. [DOI] [PubMed] [Google Scholar]
  20. Hill W. G., Babiker H. A., Ranford-Cartwright L. C., Walliker D. Estimation of inbreeding coefficients from genotypic data on multiple alleles, and application to estimation of clonality in malaria parasites. Genet Res. 1995 Feb;65(1):53–61. doi: 10.1017/s0016672300033000. [DOI] [PubMed] [Google Scholar]
  21. Hogh B., Gamage-Mendis A., Butcher G. A., Thompson R., Begtrup K., Mendis C., Enosse S. M., Dgedge M., Barreto J., Eling W. The differing impact of chloroquine and pyrimethamine/sulfadoxine upon the infectivity of malaria species to the mosquito vector. Am J Trop Med Hyg. 1998 Feb;58(2):176–182. doi: 10.4269/ajtmh.1998.58.176. [DOI] [PubMed] [Google Scholar]
  22. JEFFERY G. M., EYLES D. E. Infectivity to mosquitoes of Plasmodium falciparum as related to gametocyte density and duration of infection. Am J Trop Med Hyg. 1955 Sep;4(5):781–789. doi: 10.4269/ajtmh.1955.4.781. [DOI] [PubMed] [Google Scholar]
  23. JEFFERY G. M., YOUNG M. D., EYLES D. E. The treatment of Plasmodium falciparum infection with chloroquine, with a note on infectivity to mosquitoes of primaquine- and pyrimethamine-treated cases. Am J Hyg. 1956 Jul;64(1):1–11. doi: 10.1093/oxfordjournals.aje.a119818. [DOI] [PubMed] [Google Scholar]
  24. Kamchonwongpaisan S., Meshnick S. R. The mode of action of the antimalarial artemisinin and its derivatives. Gen Pharmacol. 1996 Jun;27(4):587–592. doi: 10.1016/0306-3623(95)02047-0. [DOI] [PubMed] [Google Scholar]
  25. Koella J. C. Costs and benefits of resistance against antimalarial drugs. Parasitol Today. 1998 Sep;14(9):360–364. doi: 10.1016/s0169-4758(98)01297-6. [DOI] [PubMed] [Google Scholar]
  26. Lipsitch M., Levin B. R. The population dynamics of antimicrobial chemotherapy. Antimicrob Agents Chemother. 1997 Feb;41(2):363–373. doi: 10.1128/aac.41.2.363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Looareesuwan S., Viravan C., Webster H. K., Kyle D. E., Hutchinson D. B., Canfield C. J. 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 Jan;54(1):62–66. doi: 10.4269/ajtmh.1996.54.62. [DOI] [PubMed] [Google Scholar]
  28. Mackinnon M. J., Hastings I. M. The evolution of multiple drug resistance in malaria parasites. Trans R Soc Trop Med Hyg. 1998 Mar-Apr;92(2):188–195. doi: 10.1016/s0035-9203(98)90745-3. [DOI] [PubMed] [Google Scholar]
  29. Marsh K. Malaria disaster in Africa. Lancet. 1998 Sep 19;352(9132):924–924. doi: 10.1016/S0140-6736(05)61510-3. [DOI] [PubMed] [Google Scholar]
  30. Meshnick S. R., Taylor T. E., Kamchonwongpaisan S. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol Rev. 1996 Jun;60(2):301–315. doi: 10.1128/mr.60.2.301-315.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Nosten F., ter Kuile F., Chongsuphajaisiddhi T., Luxemburger C., Webster H. K., Edstein M., Phaipun L., Thew K. L., White N. J. Mefloquine-resistant falciparum malaria on the Thai-Burmese border. Lancet. 1991 May 11;337(8750):1140–1143. doi: 10.1016/0140-6736(91)92798-7. [DOI] [PubMed] [Google Scholar]
  32. Olliaro P., Nevill C., LeBras J., Ringwald P., Mussano P., Garner P., Brasseur P. Systematic review of amodiaquine treatment in uncomplicated malaria. Lancet. 1996 Nov 2;348(9036):1196–1201. doi: 10.1016/S0140-6736(96)06217-4. [DOI] [PubMed] [Google Scholar]
  33. Paul R. E., Packer M. J., Walmsley M., Lagog M., Ranford-Cartwright L. C., Paru R., Day K. P. Mating patterns in malaria parasite populations of Papua New Guinea. Science. 1995 Sep 22;269(5231):1709–1711. doi: 10.1126/science.7569897. [DOI] [PubMed] [Google Scholar]
  34. Peel S. A., Merritt S. C., Handy J., Baric R. S. Derivation of highly mefloquine-resistant lines from Plasmodium falciparum in vitro. Am J Trop Med Hyg. 1993 Mar;48(3):385–397. doi: 10.4269/ajtmh.1993.48.385. [DOI] [PubMed] [Google Scholar]
  35. Peters W., Robinson B. L. The chemotherapy of rodent malaria XXXV. Further studies on the retardation of drug resistance by the use of a triple combination of mefloquine, pyrimethamine and sulfadoxine in mice infected with P. berghei and 'P. berghei NS'. Ann Trop Med Parasitol. 1984 Oct;78(5):459–466. doi: 10.1080/00034983.1984.11811850. [DOI] [PubMed] [Google Scholar]
  36. Peters W. The prevention of antimalarial drug resistance. Pharmacol Ther. 1990;47(3):499–508. doi: 10.1016/0163-7258(90)90067-c. [DOI] [PubMed] [Google Scholar]
  37. Peterson D. S., Walliker D., Wellems T. E. Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9114–9118. doi: 10.1073/pnas.85.23.9114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Price R. N., Nosten F., Luxemburger C., van Vugt M., Phaipun L., Chongsuphajaisiddhi T., White N. J. Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria. Trans R Soc Trop Med Hyg. 1997 Sep-Oct;91(5):574–577. doi: 10.1016/s0035-9203(97)90032-8. [DOI] [PubMed] [Google Scholar]
  39. Rathod P. K., McErlean T., Lee P. C. Variations in frequencies of drug resistance in Plasmodium falciparum. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9389–9393. doi: 10.1073/pnas.94.17.9389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Reeder J. C., Rieckmann K. H., Genton B., Lorry K., Wines B., Cowman A. F. Point mutations in the dihydrofolate reductase and dihydropteroate synthetase genes and in vitro susceptibility to pyrimethamine and cycloguanil of Plasmodium falciparum isolates from Papua New Guinea. Am J Trop Med Hyg. 1996 Aug;55(2):209–213. doi: 10.4269/ajtmh.1996.55.209. [DOI] [PubMed] [Google Scholar]
  41. Rieckmann K. H., Davis D. R., Hutton D. C. Plasmodium vivax resistance to chloroquine? Lancet. 1989 Nov 18;2(8673):1183–1184. doi: 10.1016/s0140-6736(89)91792-3. [DOI] [PubMed] [Google Scholar]
  42. Rosario V. E., Hall R., Walliker D., Beale G. H. Persistence of drug-resistant malaria parasites. Lancet. 1978 Jan 28;1(8057):185–187. doi: 10.1016/s0140-6736(78)90616-5. [DOI] [PubMed] [Google Scholar]
  43. Sinden R. E., Butcher G. A., Billker O., Fleck S. L. Regulation of infectivity of Plasmodium to the mosquito vector. Adv Parasitol. 1996;38:53–117. doi: 10.1016/s0065-308x(08)60033-0. [DOI] [PubMed] [Google Scholar]
  44. Slater A. F. Chloroquine: mechanism of drug action and resistance in Plasmodium falciparum. Pharmacol Ther. 1993 Feb-Mar;57(2-3):203–235. doi: 10.1016/0163-7258(93)90056-j. [DOI] [PubMed] [Google Scholar]
  45. Snow R. W., Peshu N., Forster D., Mwenesi H., Marsh K. The role of shops in the treatment and prevention of childhood malaria on the coast of Kenya. Trans R Soc Trop Med Hyg. 1992 May-Jun;86(3):237–239. doi: 10.1016/0035-9203(92)90290-s. [DOI] [PubMed] [Google Scholar]
  46. Su X., Kirkman L. A., Fujioka H., Wellems T. E. Complex polymorphisms in an approximately 330 kDa protein are linked to chloroquine-resistant P. falciparum in Southeast Asia and Africa. Cell. 1997 Nov 28;91(5):593–603. doi: 10.1016/s0092-8674(00)80447-x. [DOI] [PubMed] [Google Scholar]
  47. Trape J. F., Pison G., Preziosi M. P., Enel C., Desgrées du Loû A., Delaunay V., Samb B., Lagarde E., Molez J. F., Simondon F. Impact of chloroquine resistance on malaria mortality. C R Acad Sci III. 1998 Aug;321(8):689–697. doi: 10.1016/s0764-4469(98)80009-7. [DOI] [PubMed] [Google Scholar]
  48. Wang P., Read M., Sims P. F., Hyde J. E. Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization. Mol Microbiol. 1997 Mar;23(5):979–986. doi: 10.1046/j.1365-2958.1997.2821646.x. [DOI] [PubMed] [Google Scholar]
  49. Ward S. A., Bray P. G., Mungthin M., Hawley S. R. Current views on the mechanisms of resistance to quinoline-containing drugs in Plasmodium falciparum. Ann Trop Med Parasitol. 1995 Apr;89(2):121–124. doi: 10.1080/00034983.1995.11812942. [DOI] [PubMed] [Google Scholar]
  50. Watkins W. M., Brandling-Bennett A. D., Nevill C. G., Carter J. Y., Boriga D. A., Howells R. E., Koech D. K. Chlorproguanil/dapsone for the treatment of non-severe Plasmodium falciparum malaria in Kenya: a pilot study. Trans R Soc Trop Med Hyg. 1988;82(3):398–403. doi: 10.1016/0035-9203(88)90133-2. [DOI] [PubMed] [Google Scholar]
  51. Watkins W. M., Mberu E. K., Winstanley P. A., Plowe C. V. The efficacy of antifolate antimalarial combinations in Africa: a predictive model based on pharmacodynamic and pharmacokinetic analyses. Parasitol Today. 1997 Dec;13(12):459–464. doi: 10.1016/s0169-4758(97)01124-1. [DOI] [PubMed] [Google Scholar]
  52. Watkins W. M., Mosobo M. Treatment of Plasmodium falciparum malaria with pyrimethamine-sulfadoxine: selective pressure for resistance is a function of long elimination half-life. Trans R Soc Trop Med Hyg. 1993 Jan-Feb;87(1):75–78. doi: 10.1016/0035-9203(93)90431-o. [DOI] [PubMed] [Google Scholar]
  53. Wernsdorfer W. H., Landgraf B., Wiedermann G., Kollaritsch H. Inverse correlation of sensitivity in vitro of Plasmodium falciparum to chloroquine and mefloquine in Ghana. Trans R Soc Trop Med Hyg. 1994 Jul-Aug;88(4):443–444. doi: 10.1016/0035-9203(94)90426-x. [DOI] [PubMed] [Google Scholar]
  54. White N. J. Antimalarial drug resistance: the pace quickens. J Antimicrob Chemother. 1992 Nov;30(5):571–585. doi: 10.1093/jac/30.5.571. [DOI] [PubMed] [Google Scholar]
  55. White N. J. Antimalarial pharmacokinetics and treatment regimens. Br J Clin Pharmacol. 1992 Jul;34(1):1–10. doi: 10.1111/j.1365-2125.1992.tb04100.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. White N. J. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother. 1997 Jul;41(7):1413–1422. doi: 10.1128/aac.41.7.1413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. White N. J., Krishna S. Treatment of malaria: some considerations and limitations of the current methods of assessment. Trans R Soc Trop Med Hyg. 1989 Nov-Dec;83(6):767–777. doi: 10.1016/0035-9203(89)90322-2. [DOI] [PubMed] [Google Scholar]
  58. White N. J. Preventing antimalarial drug resistance through combinations. Drug Resist Updat. 1998 Mar;1(1):3–9. doi: 10.1016/s1368-7646(98)80208-2. [DOI] [PubMed] [Google Scholar]
  59. Wilson C. M., Volkman S. K., Thaithong S., Martin R. K., Kyle D. E., Milhous W. K., Wirth D. F. Amplification of pfmdr 1 associated with mefloquine and halofantrine resistance in Plasmodium falciparum from Thailand. Mol Biochem Parasitol. 1993 Jan;57(1):151–160. doi: 10.1016/0166-6851(93)90252-s. [DOI] [PubMed] [Google Scholar]
  60. Zucker J. R., Lackritz E. M., Ruebush T. K., 2nd, Hightower A. W., Adungosi J. E., Were J. B., Metchock B., Patrick E., Campbell C. C. Childhood mortality during and after hospitalization in western Kenya: effect of malaria treatment regimens. Am J Trop Med Hyg. 1996 Dec;55(6):655–660. doi: 10.4269/ajtmh.1996.55.655. [DOI] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES