Nothing Special   »   [go: up one dir, main page]
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Artemisinin resistance: current status and scenarios for containment

Nature Reviews Microbiology volume 8, pages 272–280 (2010)Cite this article

Subjects

An Erratum to this article was published on 24 May 2010

Key Points

  • Malaria, caused by Plasmodium spp., remains a tremendous disease burden worldwide, causing nearly one million deaths and 250 million cases of disease.

  • Artemisinin and artemisinin derivatives are effective antimalarials, especially when coupled with a second, unrelated antimalarial.

  • Owing to the use of artemisinin as a monotherapy, strains of Plasmodium falciparum have emerged that have a decreased sensitivity to the drug.

  • Several strategies to prevent the spread of the less resistant parasites have been put in place, such as a multifaceted approach that includes early diagnosis and appropriate treatment, decreasing drug pressure, optimising vector control, targeting the mobile population, strengthening of management and surveillance systems, and operations research.

  • Other, broader strategies can target the emergence and spread of drug resistance. These include mass drug administration, using multiple first-line therapies simultaneously, surveillance, active case investigation and focal control

Abstract

Artemisinin combination therapies are the first-line treatments for uncomplicated Plasmodium falciparum malaria in most malaria-endemic countries. Recently, partial artemisinin-resistant P. falciparum malaria has emerged on the Cambodia–Thailand border. Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years, and the availability of substandard artemisinins, have probably been the main driving force in the selection of the resistant phenotype in the region. A multifaceted containment programme has recently been launched, including early diagnosis and appropriate treatment, decreasing drug pressure, optimising vector control, targeting the mobile population, strengthening management and surveillance systems, and operational research. Mathematical modelling can be a useful tool to evaluate possible strategies for containment.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Chemical structure of artemisinins.
Figure 2: The life cycle of Plasmodium falciparum.
Figure 3: The study site in Pailin, western Cambodia.
Figure 4: Parasite clearance rates.

Similar content being viewed by others

References

  1. World Health Organisation. WHO guidelines for the treatment of malaria. (WHO, Geneva, 2006).

  2. Baird, J. K. Effectiveness of antimalarial drugs. N. Engl. J. Med. 352, 1565–1577 (2005).

    Article  CAS  Google Scholar 

  3. Korenromp, E. L., Williams, B. G., Gouws, E., Dye, C. & Snow, R. W. Measurement of trends in childhood malaria mortality in Africa: an assessment of progress toward targets based on verbal autopsy. Lancet Infect. Dis. 3, 349–358 (2003). One of the few studies directly linking antimalarial drug resistance to an increase in mortality of African children that is due to malaria.

    Article  Google Scholar 

  4. Trape, J. F. et al. Impact of chloroquine resistance on malaria mortality. C. R. Acad. Sci. III 321, 689–697 (1998).

    Article  CAS  Google Scholar 

  5. Barnes, K. I. et al. Effect of artemether-lumefantrine policy and improved vector control on malaria burden in KwaZulu-Natal, South Africa. PLoS Med. 2, e330 (2005). The first of several studies from a wide range of geographical areas showing the contribution ACTs to a reduction in malaria burden,

    Article  Google Scholar 

  6. Bhattarai, A. et al. Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Zanzibar. PLoS Med. 4, e309 (2007).

    Article  Google Scholar 

  7. Carrara, V. I. et al. Deployment of early diagnosis and mefloquine-artesunate treatment of falciparum malaria in Thailand: the Tak Malaria Initiative. PLoS Med. 3, e183 (2006).

    Article  Google Scholar 

  8. O'Meara, W. P. et al. Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya. Lancet 372, 1555–1562 (2008).

    Article  Google Scholar 

  9. Dondorp, A., Nosten, F., Stepniewska, K., Day, N. & White, N. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366, 717–725 (2005). Large trial from Southeast Asia showing a 35% reduction in mortality in patients with severe malaria that were treated with artesunate compared with those treated with quinine.

    Article  Google Scholar 

  10. Meshnick, S. R., Taylor, T. E. & Kamchonwongpaisan, S. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol. Rev. 60, 301–315 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. White, N. J. Qinghaosu (artemisinin): the price of success. Science 320, 330–334 (2008). Excellent overview on the artemisinin derivatives as the most potent antimalarial drugs to date.

    Article  CAS  Google Scholar 

  12. Adjuik, M. et al. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 363, 9–17 (2004). Meta-analysis showing the superiority of ACTs for the treatment of uncomplicated P. falciparum malaria.

    Article  CAS  Google Scholar 

  13. Okell, L. C., Drakeley, C. J., Ghani, A. C., Bousema, T. & Sutherland, C. J. Reduction of transmission from malaria patients by artemisinin combination therapies: a pooled analysis of six randomized trials. Malar. J. 7, 125 (2008).

    Article  Google Scholar 

  14. Pukrittayakamee, S. et al. Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicrob. Agents Chemother. 48, 1329–1334 (2004).

    Article  CAS  Google Scholar 

  15. Stepniewska, K. & White, N. J. Pharmacokinetic determinants of the window of selection for antimalarial drug resistance. Antimicrob. Agents Chemother. 52, 1589–1596 (2008).

    Article  CAS  Google Scholar 

  16. White, N. J. & Olliaro, P. L. Strategies for the prevention of antimalarial drug resistance: rationale for combination chemotherapy for malaria. Parasitol. Today 12, 399–401 (1996).

    Article  CAS  Google Scholar 

  17. White, N. J. Antimalarial drug resistance. J. Clin.Invest. 113, 1084–1092 (2004). Review on the theoretical background and mechanisms underlying emergence and spread of antimalarial drug resistance.

    Article  CAS  Google Scholar 

  18. White, N. J. et al. Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance. Malar. J. 8, 253 (2009).

    Article  Google Scholar 

  19. World Health Organisation. World Malaria Report 2008. (WHO, Geneva, 2008).

  20. Olliaro, P. & Wells, T. N. The global portfolio of new antimalarial medicines under development. Clin. Pharmacol. Ther. 85, 2584–595 (2009). Overview of the current portfolio of new antimalarial drugs, almost exclusively relying on ACTs.

    Article  Google Scholar 

  21. Resistance to artemisinin derivatives along the Thai-Cambodian border. Wkly Epidemiol. Rec. 82, 360 (2007).

  22. Denis, M. B. et al. Surveillance of the efficacy of artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria in Cambodia. Trop. Med. Int. Health 11, 1360–1366 (2006).

    Article  CAS  Google Scholar 

  23. Alker, A. P. et al. Pfmdr1 and in vivo resistance to artesunate-mefloquine in falciparum malaria on the Cambodian-Thai border. Am. J. Trop. Med. Hyg. 76, 641–647 (2007).

    Article  CAS  Google Scholar 

  24. Wongsrichanalai, C. & Meshnick, S. R. Declining artesunate-mefloquine efficacy against falciparum malaria on the Cambodia-Thailand border. Emerg. Infect. Dis. 14, 716–719 (2008).

    Article  Google Scholar 

  25. Noedl, H., Socheat, D. & Satimai, W. Artemisinin-resistant malaria in Asia. N. Engl. J. Med. 361, 540–541 (2009). One of the first detailed reports on emerging artemisinin resistance in western Cambodia.

    Article  CAS  Google Scholar 

  26. Dondorp, A. M. et al. Artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 361, 455–467 (2009). Hallmark study showing a clear reduction in in vivo P. falciparum susceptibility to artesunate on the Cambodia–Thailand border.

    Article  CAS  Google Scholar 

  27. Anderson, T. et al. High heritability of malaria parasite clearance rates indicates a genetic basis for artemisinin resistance in Western Cambodia. J. Infect. Dis. (in the press).

  28. Yeung, S., Van Damme, W., Socheat, D., White, N. J. & Mills, A. Access to artemisinin combination therapy for malaria in remote areas of Cambodia. Malar. J. 7, 96 (2008). Study showing that treatment of uncomplicated P. falciparum malaria in remote areas of Cambodia is mainly through the less well-controlled private sector, in which artemisinin monotherapies are widely available.

    Article  Google Scholar 

  29. Newton, P. N., Dondorp, A., Green, M., Mayxay, M. & White, N. J. Counterfeit artesunate antimalarials in southeast Asia. Lancet 362, 169 (2003). Article highlighting the terrible problem of the wide availability of counterfeited artemisinins in Southeast Asia.

    Article  Google Scholar 

  30. Rathod, P. K., McErlean, T. & Lee, P. C. Variations in frequencies of drug resistance in Plasmodium falciparum. Proc. Natl Acad. Sci. USA 94, 9389–9393 (1997).

    Article  CAS  Google Scholar 

  31. Pongtavornpinyo, W. et al. Spread of anti-malarial drug resistance: mathematical model with implications for ACT drug policies. Malar. J. 7, 229 (2008). Modelling paper investigating the minimal public health conditions, such as ACT coverage rates, that are necessary to delay the spread of antimalarial drug resistance.

    Article  Google Scholar 

  32. Maude, R. J. et al. The role of mathematical modelling in malaria elimination and eradication. Trans. R. Soc. Trop. Med. Hyg. 103, 643–644 (2009).

    Article  Google Scholar 

  33. Verdrager, J. Epidemiology of the emergence and spread of drug-resistant falciparum malaria in South-East Asia and Australasia. J. Trop. Med. Hyg. 89, 277–289 (1986).

    CAS  PubMed  Google Scholar 

  34. Verdrager, J. Localized permanent epidemics: the genesis of chloroquine resistance in Plasmodium falciparum. Southeast Asian J. Trop.Med. Public Health 26, 23–28 (1995).

    CAS  PubMed  Google Scholar 

  35. Carrara, V. I. et al. Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS ONE 4, e4551 (2009). First study reporting a slight decrease in treatment responses to an ACT for uncomplicated P. falciparum malaria in an area outside the Cambodia–Thailand border region.

    Article  Google Scholar 

  36. Achan, J. et al. Effectiveness of quinine versus artemether-lumefantrine for treating uncomplicated falciparum malaria in Ugandan children: randomised trial. BMJ 339, b2763 (2009).

    Article  Google Scholar 

  37. Gebru, T., Hailu, A., Kremsner, P. G., Kun, J. F. & Grobusch, M. P. Molecular surveillance of mutations in the cytochrome b gene of Plasmodium falciparum in Gabon and Ethiopia. Malar. J. 5, 112 (2006).

    Article  Google Scholar 

  38. Olliaro, P. & Mussano, P. Amodiaquine for treating malaria. Cochrane Database Syst. Rev. 2003, CD000016 (2003).

    Google Scholar 

  39. Gesase, S. et al. High resistance of Plasmodium falciparum to sulphadoxine/pyrimethamine in northern Tanzania and the emergence of dhps resistance mutation at codon 581. PLoS ONE 4, e4569 (2009).

    Article  Google Scholar 

  40. Pilz, J. B. et al. In vitro sensitivity of Plasmodium falciparum to lumefantrine in north-western Thailand. Wien. Klin. Wochenschr. 116 (Suppl. 4), 41–46 (2004).

    CAS  PubMed  Google Scholar 

  41. Wongsrichanalai, C., Pickard, A. L., Wernsdorfer, W. H. & Meshnick, S. R. Epidemiology of drug-resistant malaria. Lancet Infect. Dis. 2, 209–218 (2002).

    Article  CAS  Google Scholar 

  42. von Seidlein, L. & Greenwood, B. M. Mass administrations of antimalarial drugs. Trends Parasitol. 19, 452–460 (2003).

    Article  Google Scholar 

  43. Tran, T. H. et al. Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium falciparum malaria in Vietnam: randomised clinical trial. Lancet 363, 18–22 (2004).

    Article  Google Scholar 

  44. Ramharter, M. et al. Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon. J. Infect. Dis. 198, 911–919 (2008).

    Article  CAS  Google Scholar 

  45. Vivas, L. et al. Anti-malarial efficacy of pyronaridine and artesunate in combination in vitro and in vivo. Acta Trop. 105, 222–228 (2008).

    Article  CAS  Google Scholar 

  46. Ringwald, P., Bickii, J. & Basco, L. Randomised trial of pyronaridine versus chloroquine for acute uncomplicated falciparum malaria in Africa. Lancet 347, 24–28 (1996).

    Article  CAS  Google Scholar 

  47. Carr, A. & Amin, J. Efficacy and tolerability of initial antiretroviral therapy: a systematic review. AIDS 23, 343–353 (2009).

    Article  Google Scholar 

  48. Grant, A., Gothard, P. & Thwaites, G. Managing drug resistant tuberculosis. BMJ 337, a1110 (2008).

    Article  Google Scholar 

  49. Lawpoolsri, S. et al. Optimally timing primaquine treatment to reduce Plasmodium falciparum transmission in low endemicity Thai-Myanmar border populations. Malar. J. 8, 159 (2009).

    Article  Google Scholar 

  50. Vale, N., Moreira, R. & Gomes, P. Primaquine revisited six decades after its discovery. Eur. J. Med. Chem. 44, 937–953 (2009).

    Article  CAS  Google Scholar 

  51. Cappellini, M. D. & Fiorelli, G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 371, 64–74 (2008).

    Article  CAS  Google Scholar 

  52. [No authors listed]. Roll Back Malaria Partnership. Global Malaria Action Plan for a malaria-free world[online] (2009).

  53. Samarasekera, U. Countries race to contain resistance to key antimalarial. Lancet 374, 277–280 (2009).

    Article  Google Scholar 

  54. Maude, R. J. et al. The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia. Malar. J. 8, 31 (2009). Modelling paper showing that the absolute number of artemisinin-resistant malaria cases will decrease, but the proportion of artemisinin-resistant malaria cases will increase over time when elimination of resistant malaria is attempted.

    Article  Google Scholar 

  55. Korsinczky, M. et al. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob. Agents Chemother. 44, 2100–2108 (2000).

    Article  CAS  Google Scholar 

  56. Okell, L. C., Drakeley, C. J., Bousema, T., Whitty, C. J. & Ghani, A. C. Modelling the impact of artemisinin combination therapy and long-acting treatments on malaria transmission intensity. PLoS Med. 5, e226 (2008).

    Article  Google Scholar 

  57. Castle, S. J., Toscano, N. C., Prabhaker, N., Henneberry, T. J. & Palumbo, J. C. Field evaluation of different insecticide use strategies as resistance management and control tactics for Bemisia tabaci (Hemiptera: Aleyrodidae). Bull. Entomol. Res. 92, 449–460 (2002).

    Article  CAS  Google Scholar 

  58. Boni, M. F., Smith, D. L. & Laxminarayan, R. Benefits of using multiple first-line therapies against malaria. Proc. Natl Acad. Sci. USA 105, 14216–14221 (2008). Modelling paper showing the delay in development of antimalarial drug resistance with regional deployment of MFTs.

    Article  CAS  Google Scholar 

  59. Shretta, R., Omumbo, J., Rapuoda, B. & Snow, R. W. Using evidence to change antimalarial drug policy in Kenya. Trop. Med. Int. Health 5, 755–764 (2000).

    Article  CAS  Google Scholar 

  60. Coatney, G. R. Pitfalls in a discovery: the chronicle of chloroquine. Am. J. Trop. Med. Hyg. 12, 121–128 (1963).

    Article  CAS  Google Scholar 

  61. Jensen, M. & Mehlhorn, H. Seventy-five years of Resochin in the fight against malaria. Parasitol. Res. 105, 609–627 (2009).

    Article  Google Scholar 

  62. Greenwood, B. M. et al. Malaria: progress, perils, and prospects for eradication. J. Clin. Invest. 118, 1266–1276 (2008).

    Article  CAS  Google Scholar 

  63. Payne, D. Spread of chloroquine resistance in Plasmodium falciparum. Parasitol.Today 3, 241–246 (1987).

    Article  CAS  Google Scholar 

  64. Djimde, A. et al. A molecular marker for chloroquine-resistant falciparum malaria. N. Engl. J. Med. 344, 257–263 (2001).

    Article  CAS  Google Scholar 

  65. Fidock, D. A. et al. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6, 861–871 (2000).

    Article  CAS  Google Scholar 

  66. Wootton, J. C. et al. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418, 320–323 (2002).

    Article  CAS  Google Scholar 

  67. Kublin, J. G. et al. Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J. Infect. Dis. 187, 1870–1875 (2003).

    Article  Google Scholar 

  68. Laufer, M. K. et al. Return of chloroquine antimalarial efficacy in Malawi. N. Engl. J. Med. 355, 1959–1966 (2006).

    Article  CAS  Google Scholar 

  69. Plowe, C. V. The evolution of drug-resistant malaria. Trans. R. Soc. Trop. Med. Hyg. 103, S11–S14 (2009).

    Article  Google Scholar 

Download references

Acknowledgements

We thank N. J. White for his critical review of the paper. This work was supported by the Wellcome Trust.

Author information

Authors and Affiliations

  1. Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand

    Arjen M. Dondorp, Shunmay Yeung, Lisa White, Nicholas P.J. Day & Lorenz von Seidlein

  2. Centre for Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, OX3 7LJ, UK

    Arjen M. Dondorp, Lisa White & Nicholas P.J. Day

  3. London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK

    Shunmay Yeung, Chea Nguon & Duong Socheat

  4. The National Center for Parasitology Entomology and Malaria Control, Phnom Penh, Cambodia

    Duong Socheat

  5. Joint Malaria Project, Tanga, Tanzania

    Lorenz von Seidlein

Authors
  1. Arjen M. Dondorp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shunmay Yeung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lisa White
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chea Nguon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nicholas P.J. Day
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Duong Socheat
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lorenz von Seidlein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arjen M. Dondorp.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Genome Project

Plasmodium falciparum

FURTHER INFORMATION

Arjen M. Dondorp's homepage

AMFm website

Glossary

Parenteral

Administered by injection.

Recrudescence

Reoccurence of a disease after treatment. This can be caused by parasites that were not completely eliminated during the treatment.

Hypnozoite

A dormant form of the liver stage parasites found in several Plasmodium spp., including the human parasites Plasmodium vivax and Plasmodium ovale.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dondorp, A., Yeung, S., White, L. et al. Artemisinin resistance: current status and scenarios for containment. Nat Rev Microbiol 8, 272–280 (2010). https://doi.org/10.1038/nrmicro2331

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro2331

This article is cited by

Search

Advanced search

Quick links

Nature Briefing AI and Robotics

Sign up for the Nature Briefing: AI and Robotics newsletter — what matters in AI and robotics research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: AI and Robotics