1921
Volume 71, Issue 6
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Antimalarial resistance to sulfadoxine-pyrimethamine (SP) is mediated by mutations in the dihydrofolate reductase () and dihydropteroate synthase () genes. However, the relative importance of different mutations is incompletely understood and has not been studied with combination therapy. Samples from 812 patients treated for uncomplicated malaria in Kampala, Uganda were tested for the presence of mutations commonly found in Africa. The Glu-540 mutation was the strongest independent predictor of treatment failure. The Arg-59 mutation was only predictive of treatment failure in the presence of the Glu-540 mutation. Comparing combination regimens with SP monotherapy, the addition of chloroquine to SP did not improve efficacy, the addition of artesunate lowered the risk of treatment failure only for infections with both the Arg-59 and dhps Glu-540 mutations, and the addition of amodiaquine lowered this risk for all / mutation patterns. The Glu-540 mutation played a principal role and the Arg-59 mutation a secondary role in mediating resistance to SP alone and in combination.

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2004-12-01
2017-09-23
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References

  1. AFRO, Global AMDP Database. http://rbm.who.int/amdp/amdp_afro.htm.
  2. Sibley CH, Hyde JE, Sims PF, Plowe CV, Kublin JG, Mberu EK, Cowman AF, Winstanley PA, Watkins WM, Nzila AM, 2001. Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? Trends Parasitol 17 : 582–588.
  3. White NJ, Nosten F, Looareesuwan S, Watkins WM, Marsh K, Snow RW, Kokwaro G, Ouma J, Hien TT, Molyneux ME, Taylor TE, Newbold CI, Ruebush TK, Danis M, Greenwood BM, Anderson RM, Olliaro P, 1999. Averting a malaria disaster. Lancet 353 : 1965–1967.
  4. Roper C, Pearce R, Bredenkamp B, Gumede J, Drakeley C, Mosha F, Chandramohan D, Sharp B, 2003. Antifolate anti-malarial resistance in southeast Africa: a population-based analysis. Lancet 361 : 1174–1181.
  5. World Health Organization, Position of WHO’s Roll Back Malaria Department on Malaria Treatment Policy. http://www.emro.who.int/rbm/.
  6. Wang P, Read M, Sims PF, Hyde JE, 1997. 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 23 : 979–986.
  7. Peterson DS, Walliker D, Wellems TE, 1988. Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proc Natl Acad Sci USA 85 : 9114–9118.
  8. Wang P, Sims PF, Hyde JE, 1997. A modified in vitro sulfadoxine susceptibility assay for Plasmodium falciparum suitable for investigating Fansidar resistance. Parasitology 115 : 223–230.
  9. Triglia T, Menting JG, Wilson C, Cowman AF, 1997. Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum. Proc Natl Acad Sci USA 94 : 13944–13949.
  10. Rallon NI, Osorio LE, Giraldo LE, 1999. Lack of an association between the ASN-108 mutation in the dihydrofolate reductase gene and in vivo resistance to sulfadoxine/pyrimethamine in Plasmodium falciparum. Am J Trop Med Hyg 61 : 245–248.
  11. Nzila AM, Nduati E, Mberu EK, Hopkins Sibley C, Monks SA, Winstanley PA, Watkins WM, 2000. Molecular evidence of greater selective pressure for drug resistance exerted by the long-acting antifolate pyrimethamine/sulfadoxine compared with the shorter-acting chlorproguanil/dapsone on Kenyan Plasmodium falciparum. J Infect Dis 181 : 2023–2028.
  12. Basco LK, Tahar R, Keundjian A, Ringwald P, 2000. Sequence variations in the genes encoding dihydropteroate synthase and dihydrofolate reductase and clinical response to sulfadoxine-pyrimethamine in patients with acute uncomplicated falciparum malaria. J Infect Dis 182 : 624–628.
  13. Alifrangis M, Enosse S, Khalil IF, Tarimo DS, Lemnge MM, Thompson R, Bygbjerg IC, Ronn AM, 2003. Prediction of Plasmodium falciparum resistance to sulfadoxine/pyrimethamine in vivo by mutations in the dihydrofolate reductase and dihydropteroate synthetase genes: a comparative study between sites of differing endemicity. Am J Trop Med Hyg 69 : 601–606.
  14. Aubouy A, Jafari S, Huart V, Migot-Nabias F, Mayombo J, Durand R, Bakary M, Le Bras J, Deloron P, 2003. DHFR and DHPS genotypes of Plasmodium falciparum isolates from Gabon correlate with in vitro activity of pyrimethamine and cycloguanil, but not with sulfadoxine-pyrimethamine treatment efficacy. J Antimicrob Chemother 52 : 43–49.
  15. Kyabayinze D, Cattamanchi A, Kamya MR, Rosenthal PJ, Dorsey G, 2003. Validation of a simplified method for using molecular markers to predict sulfadoxine-pyrimethamine treatment failure in African children with falciparum malaria. Am J Trop Med Hyg 69 : 247–252.
  16. Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, Mukadam RA, Rogerson SJ, Lescano AG, Molyneux ME, Winstanley PA, Chimpeni P, Taylor TE, Plowe CV, 2002. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis 185 : 380–388.
  17. Kamya MR, Dorsey G, Gasasira A, Ndeezi G, Babirye JN, Staedke SG, Rosenthal PJ, 2001. The comparative efficacy of chloroquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in Kampala, Uganda. Trans R Soc Trop Med Hyg 95 : 50–55.
  18. Dorsey G, Njama D, Kamya MR, Cattamanchi A, Kyabayinze D, Staedke SG, Gasasira A, Rosenthal PJ, 2002. Sulfadoxine/pyrimethamine alone or with amodiaquine or artesunate for treatment of uncomplicated malaria: a longitudinal randomised trial. Lancet 360 : 2031–2038.
  19. Warrell DA, Molyneux ME, Beales PF, 1990. Severe and complicated malaria. World Health Organization, Division of Control of Tropical Diseases. Trans R Soc Trop Med Hyg 84 : 1–65.
  20. World Health Organization, 1996. Assessment of Therapeutic Efficacy of Antimalarial Drugs for Uncomplicated Falciparum Malaria in Areas with Intense Transmission. Geneva: World Health Organization.
  21. Cattamanchi A, Kyabayinze D, Hubbard A, Rosenthal PJ, Dorsey G, 2003. Distinguishing recrudescence from reinfection in a longitudinal antimalarial drug efficacy study: comparison of results based on genotyping of msp-1, msp-2, and glurp. Am J Trop Med Hyg 68 : 133–139.
  22. Plowe CV, Djimde A, Bouare M, Doumbo O, Wellems TE, 1995. Pyrimethamine and proguanil resistance-conferring mutations in Plasmodium falciparum dihydrofolate reductase: polymerase chain reaction methods for surveillance in Africa. Am J Trop Med Hyg 52 : 565–568.
  23. Duraisingh MT, Curtis J, Warhurst DC, 1998. Plasmodium falciparum: detection of polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes by PCR and restriction digestion. Exp Parasitol 89 : 1–8.
  24. Staedke SG, Sendagire H, Lamola S, Kamya MR, Dorsey G, Rosenthal PJ, 2004. Relationship between age, molecular markers, and response to sulfadoxine-pyrimethamine treatment in Kampala, Uganda. Trop Med Int Health 9 : 624–629.
  25. Plowe CV, 2001. Folate Antagonists and Mechanisms of Resistance. Totowa, NJ: Humana Press.
  26. Khalil I, Ronn AM, Alifrangis M, Gabar HA, Satti GM, Bygbjerg IC, 2003. Dihydrofolate reductase and dihydropteroate synthase genotypes associated with in vitro resistance of Plasmodium falciparum to pyrimethamine, trimethoprim, sulfadoxine, and sulfamethoxazole. Am J Trop Med Hyg 68 : 586–589.
  27. Nzila AM, Mberu EK, Sulo J, Dayo H, Winstanley PA, Sibley CH, Watkins WM, 2000. Towards an understanding of the mechanism of pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: genotyping of dihydrofolate reductase and dihydropteroate synthase of Kenyan parasites. Antimicrob Agents Chemother 44 : 991–996.
  28. Hastings IM, Watkins WM, White NJ, 2002. The evolution of drug-resistant malaria: the role of drug elimination half-life. Philos Trans R Soc Lond B Biol Sci 357 : 505–519.
  29. Kamya MR, Bakyaita NN, Talisuna AO, Were WM, Staedke SG, 2002. Increasing antimalarial drug resistance in Uganda and revision of the national drug policy. Trop Med Int Health 7 : 1031–1041.
  30. Dorsey G, Kamya MR, Ndeezi G, Babirye JN, Phares CR, Olson JE, Katabira ET, Rosenthal PJ, 2000. Predictors of chloroquine treatment failure in children and adults with falciparum malaria in Kampala, Uganda. Am J Trop Med Hyg 62 : 686–692.
  31. Dorsey G, Kamya MR, Singh A, Rosenthal PJ, 2001. Polymorphisms in the Plasmodium falciparum pfcrt and pfmdr-1 genes and clinical response to chloroquine in Kampala, Uganda. J Infect Dis 183 : 1417–1420.
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  • Received : 05 May 2004
  • Accepted : 15 Jul 2004

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