Volume 78, Issue 2
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


The prevalence and frequency of the dihydrofolate reductase () and dihydropteroate synthetase () mutations associated with sulfadoxine–pyrimethamine (SP) resistance at 13 sentinel surveillance sites in southern Mozambique were examined regularly between 1999 and 2004. Frequency of the triple mutation increased from 0.26 in 1999 to 0.96 in 2003, remaining high in 2004. The double mutation frequency peaked in 2001 (0.22) but declined to baseline levels (0.07) by 2004. Similarly, parasites with both triple and double mutations had increased in 2001 (0.18) but decreased by 2004 (0.05). The peaking of SP resistance markers in 2001 coincided with a SP–resistant malaria epidemic in neighboring KwaZulu-Natal, South Africa. The decline in (but not ) mutations corresponded with replacement of SP with artemether–lumefantrine as malaria treatment policy in KwaZulu-Natal. Our results show that drug pressure can exert its influence at a regional level rather than merely at a national level.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Trape JF, Pison G, Preziosi MP, Enel C, Desgrees du Lou A, Delaunay V, Samb B, Lagarde E, Molez JF, Simondon F, 1998. Impact of chloroquine resistance on malaria mortality. CR Acad Sci III 321 : 689–697. [Google Scholar]
  2. Snow RW, Trape JF, Marsh K, 2001. The past, present and future of childhood malaria mortality in Africa. Trends Parasitol 17 : 593–597. [Google Scholar]
  3. Sachs J, Malaney P, 2002. The economic and social burden of malaria. Nature 415 : 680–685. [Google Scholar]
  4. Barat LM, 2006. Four malaria success stories: how malaria burden was successfully reduced in Brazil, Eritrea, India and Vietnam. Am J Trop Med Hyg 74 : 12–16. [Google Scholar]
  5. Barnes KI, Durrheim DN, Little F, Jackson A, Mehta U, Dlamini SS, Tsoka J, Bredenkamp B, Mthembu DJ, White NJ, Sharp BL, 2005. Effect of artemether–lumefantrine policy and improved vector control on malaria burden in Kwazulu-Natal, South Africa. PloS Med 2 : e330. [Google Scholar]
  6. Mabaso MLH, Sharp B, Lengeler C, 2004. Historical review of malarial control in southern Africa with emphasis on the use of indoor residual house-spraying. Trop Med Int Health 9 : 846–856. [Google Scholar]
  7. Sharp BL, Kleinschmidt I, Streat E, Maharaj R, Barnes KI, Durrheim DN, Ridl FC, Morris N, Seocharan I, Kunene S, La Grange JJ, Mtembu JD, Maartens F, Martin CL, Barreto A, 2007. Seven years of regional malaria control collaboration—Mozambique, South Africa and Swaziland. Am J Trop Med Hyg 76 : 42–47. [Google Scholar]
  8. Hansford CF, 1989. Chloroquine resistance in Plasmodium falciparum in KwaZulu, 1983–1988. S Afr Med J 76 : 546–547. [Google Scholar]
  9. Freese JA, Sharp BL, Ngxongo SM, Markus MB, 1988. In vitro confirmation of chloroquine-resistant Plasmodium falciparum malaria in KwaZulu. S Afr Med J 74 : 576–578. [Google Scholar]
  10. Bredenkamp B, Sharp B, Mthembu SD, Durrheim DN, Barnes KI, 2001. Failure of sulfadoxine–pyrimethamine in treating Plasmodium falciparum malaria in KwaZulu-Natal. S Afr Med J 91 : 970–971. [Google Scholar]
  11. Peterson DS, Milhous WK, Wellems TE, 1990. Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria. Proc Natl Acad Sci USA 87 : 3018–3022. [Google Scholar]
  12. 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. [Google Scholar]
  13. 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. [Google Scholar]
  14. Mendez F, Munoz A, Carrasquilla G, Jurado D, Arevalo-Herrera M, Cortese JF, Plowe CV, 2002. Determinants of treatment response to sulfadoxine–pyrimethamine and subsequent transmission potential in falciparum malaria. Am J Epidemiol 156 : 230–238. [Google Scholar]
  15. Happi CT, Gbotosho GO, Folarin OA, Akinboye DO, Yusuf BO, Ebong OO, Sowunmi A, Kyle DE, Milhous WK, Wirth DF, Oduola AMJ, 2005. Polymorphisms in Plasmodium falciparum dhfr and dhps genes and age related in vivo sulfadoxine–pyrimethamine resistance in malaria-infected patients from Nigeria. Acta Trop 95 : 183–193. [Google Scholar]
  16. 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. [Google Scholar]
  17. Roper C, Pearce R, Nair S, Sharp B, Nosten F, Anderson TJC, 2004. Intercontinental spread of pyrimethamine-resistant malaria. Science 305 : 1124. [Google Scholar]
  18. Wooden J, Kyes S, Sibley CH, 1993. PCR and strain identification in Plasmodium falciparum. Parasitol Today 9 : 303–305. [Google Scholar]
  19. Snounou G, Viriyakosol S, Zhu XP, Jarra W, Pinheiro L, do Rosario VE, Thaithong S, Brown KN, 1993. High sensitivity to detection of human malaria parasites by the use of nested polymerase chain reaction. Mol Biochem Parasitol 61 : 315–320. [Google Scholar]
  20. Plowe CV, Cortese JF, Djimde A, Nwanyanwu OC, Watkins WM, Winstanley PA, Estrada-France JG, Mollinedo R, Avila JC, Cespedes JL, Carter D, Doumbo OK, 1997. Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine–sulfadoxine use and resistance. J Infect Dis 176 : 1590–1596. [Google Scholar]
  21. Duraisingh MT, Curtis J, Warhurst DC, 1998. Plasmodium falciparum: detection of polymorphisms in the dihydrofolate reductase and dihydropteroate synthase genes by PCR and restriction digestion. Exp Parasitol 89 : 1–8. [Google Scholar]
  22. Abacassamo F, Enosse S, Aponte JJ, Gomez-Olive FX, Quinte L, Mabunda S, Barreto A, Magnussen P, Ronn AM, Thompson R, Alonso PL, 2004. Efficacy of chloroquine and combination therapy with artesunate in Mozambican children with non-complicated malaria. Trop Med Int Health 9 : 200–208. [Google Scholar]
  23. Fernandes N, Figueiredo P, do Rosario VE, Cravo P, 2007. Analysis of sulphadoxine–pyrimethamine resistance-conferring mutations of Plasmodium falciparum from Mozambique reveals the absence of the dihydrofolate reductase 164L mutant. Malaria J 6 : 1–4. [Google Scholar]
  24. Walliker D, Hunt P, Babiker H, 2005. Fitness of drug-resistant malaria parasites. Acta Trop 94 : 251–259. [Google Scholar]
  25. Laufer MK, Thesing PC, Eddington ND, Masonga R, Dzinjalamala FK, Takala SL, Taylor TE, Plowe CV, 2006. Return of chloroquine antimalarial efficacy in Malawi. N Engl J Med 355 : 1959–1966. [Google Scholar]
  26. Nair S, Williams JT, Brockman A, Paiphun L, Mayxay M, Newton PN, Guthman J-P, Smithuis FM, Hien TT, White NJ, Nosten F, Anderson TJC, 2003. A selective sweep driven by pyrimethamine treatment in SE Asian malaria parasites. Mol Biol Evol 20 : 1526–1536. [Google Scholar]
  27. Nair S, Brockman A, Paiphum L, Nosten F, Anderson TJC, 2002. Rapid genotyping of loci involved in antifolate drug resistance in Plasmodium falciparum by primer extension. Int J Parasitol 32 : 852–858. [Google Scholar]
  28. White NJ, 2004. Antimalarial drug resistance. J Clin Invest 113 : 1084–1092. [Google Scholar]
  29. Watkins WM, Mberu EK, Winstanley PA, Plowe CV, 1997. The efficacy of antifolate antimalarial combinations in Africa: a predictive model based on pharmacodynamic and pharmacokinetic analyses. Parasitol Today 13 : 459–464. [Google Scholar]
  30. Clyde DF, 1968. Antimalarial effect of diaphenylsulfone and three sulfonamides among semi-immune Africans. Am J Trop Med Hyg 16 : 7–10. [Google Scholar]
  31. World Health Organisation, 2006. Guidelines for the Treatment of Malaria. WHO/HTM/MAL/2006.1108.
  32. Yeka A, Banek K, Bakyaita N, Staedke SG, Kamya MR, Talisuna A, Kironde F, Nsobya SL, Kilian A, Slater M, Reingold A, Rosenthal PJ, Wabwire-Mangen F, Dorsey G, 2005. Artemisinins versus nonartemisinin combination therapy for uncomplicated malaria: randomised clinical trials from four sites in Uganda. PloS Med 2 : e190. [Google Scholar]
  33. Watkins WM, Mosobo M, 1993. 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 87 : 75–78. [Google Scholar]
  34. Mabuza A, Govere J, La Grange K, Mngomezulu N, Allen E, Zitha A, Mbokazi F, Durrheim D, Barnes K, 2005. Therapeutic efficacy of sulfadoxine–pyrimethamine for Plasmodium falciparum malaria. S Afr Med J 95 : 346–349. [Google Scholar]
  35. Barnes KI, White NJ, 2005. Population biology and antimalarial resistance: the transmission of antimalarial drug resistance in Plasmodium falciparum. Acta Trop 94 : 230–240. [Google Scholar]

Data & Media loading...

  • Received : 15 May 2007
  • Accepted : 21 Sep 2007

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error