• 1

    Maberti S, 1960. Desarrollo de resistencia a la pirimetamina. Presentacion de 15 casos estudiados en Trujillo, Venezuela. Arch Venezolanos Med Trop Parasitol Med 3 :239–259.

    • Search Google Scholar
    • Export Citation
  • 2

    Peters W, 1987. Chemotherapy and Drug Resistance in Malaria. Second edition. London: Academic Press.

  • 3

    Wernsdorfer WH, Payne D, 1991. The dynamics of drug resistance in Plasmodium falciparum.Pharmacol Ther 50 :95–121.

  • 4

    Curtis J, Duraisingh MT, Warhurst DC, 1998. In vivo selection for a specific genotype of dihydropteroate synthetase of Plasmodium falciparum by pyrimethamine-sulfadoxine but not chlorproguanil-dapsone treatment. J Infect Dis 177 :1429–1433.

    • Search Google Scholar
    • Export Citation
  • 5

    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.

    • Search Google Scholar
    • Export Citation
  • 6

    Foote SJ, Galatas D, Cowman AF, 1990. 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 USA 87 :3014–3017.

    • Search Google Scholar
    • Export Citation
  • 7

    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.

    • Search Google Scholar
    • Export Citation
  • 8

    Sirawaraporn W, Sathitkul T, Sirawaraporn R, Yuthavong Y, Santi DV, 1997. Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc Natl Acad Sci USA 94 :1124–1129.

    • Search Google Scholar
    • Export Citation
  • 9

    Basco L, Ringwald P, 1999. Molecular epidemiology of malaria in Yaounde, Cameroon. IV. Evolution of pyrimethamine resistance between 1994 and 1998. Am J Trop Med Hyg 61 :802–806.

    • Search Google Scholar
    • Export Citation
  • 10

    Wang P, Lee CS, Bayoumi R, Djimde A, Doumbo O, Swedberg G, Dao LD, Mshinda H, Tanner M, Watkins WM, Sims PFG, Hyde JE, 1997. Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. Mol Biochem Parasitol 89 :161–177.

    • Search Google Scholar
    • Export Citation
  • 11

    Diourte Y, Djimde A, Doumbo O, Sagara I, Coulibaly Y, Dicko A, Diallo M, Diakite M, Cortese J, Plowe C, 1999. Pyrimethamine-sulfadoxine efficacy and selection for mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase in Mali. Am J Trop Med Hyg 60 :475–478.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 13

    Basco LK, Ndounga M, Tejiokem M, Ngane VF, Youmba JC, Ringwald P, Soula G, 2002. Molecular epidemiology of malaria in Cameroon. XI. Geographic distribution of Plasmodium falciparum isolates with dihydrofolate reductase gene mutations in southern and central Cameroon. Am J Trop Med Hyg 67 :378–382.

    • Search Google Scholar
    • Export Citation
  • 14

    Robert V, AwonoAmbene HP, LeHesran JY, Trape JF, 2000. Gametocytemia and infectivity to mosquitoes of patients with uncomplicated Plasmodium falciparum malaria attacks treated with chloroquine or sulfadoxine plus pyrimethamine. Am J Trop Med Hyg 62 :210–216.

    • Search Google Scholar
    • Export Citation
  • 15

    Sokhna CS, Trape JF, Robert V, 2001. Gametocytaemia in Senegalese children with uncomplicated falciparum malaria treated with chloroquine, amodiaquine or sulfadoxine + pyrimethamine. Parasite 8 :243–250.

    • Search Google Scholar
    • Export Citation
  • 16

    von Seidlein L, Jawara M, Coleman R, Doherty T, Walraven G, Targett G, 2001. Parasitaemia and gametocytaemia after treatment with chloroquine, pyrimethamine/sulfadoxine, and pyrimethamine/sulfadoxine combined with artesunate in young Gambians with uncomplicated malaria. Trop Med Int Health 6 :92–98.

    • Search Google Scholar
    • Export Citation
  • 17

    Hogh B, Gamagemendis A, Butcher GA, Thompson R, Begtrup K, Mendis C, Enosse SM, Dgedge M, Barreto J, Eling W, Sinden RE, 1998. The differing impact of chloroquine and pyrimethamine/sulfadoxine upon the infectivity of malaria species to the mosquito vector. Am J Trop Med Hyg 58 :176–182.

    • Search Google Scholar
    • Export Citation
  • 18

    Ringwald P, Same Ekobo A, Keundjian A, Kedy Mangamba D, Basco LK, 2000. Chemoresistance of Plasmodium falciparum in urban areas of Yaounde, Cameroon. Part 1: Surveillance of in vitro and in vivo resistance of Plasmodium falciparum to chloroquine from 1994 to 1999 in Yaounde, Cameroon. Trop Med Int Hlth 5 :612–619.

    • Search Google Scholar
    • Export Citation
  • 19

    Fidock DA, Su XZ, Deitsch KW, Wellems TE, 1999. Genetic approaches to the determinants of drug response, pathogenesis, and infectivity in Plasmodium falciparum malaria. Wahlgren M, Perlmann P, eds. Malaria: Molecular and Clinical Aspects. Amsterdam: Harwood Academic Publishers, 217–248.

 

 

 

 

MOLECULAR EPIDEMIOLOGY OF MALARIA IN CAMEROON. XVI. LONGITUDINAL SURVEILLANCE OF IN VITRO PYRIMETHAMINE RESISTANCE IN PLASMODIUM FALCIPARUM

View More View Less
  • 1 Unité de Recherche Paludologie Afro-Tropicale, Institut de Recherche pour le Développement and Laboratoire de Recherche sur le Paludisme, Organisation de Coordination pour la Lutte contre les Endémies en Afrique Centrale, Yaounde, Cameroon

Clinical observations have shown that pyrimethamine resistance develops rapidly in endemic countries where antifolate drugs are used massively for the treatment of Plasmodium falciparum infections. To analyze this phenomenon, the in vitro response of clinical isolates to pyrimethamine and the dihydrofolate reductase (dhfr) gene sequence were analyzed in 2000–2001 and compared with the results obtained since 1994 in Yaounde, Cameroon. Of 139 samples obtained in 2000–2001, 10 (7.2%) isolates were of the wild-type, 116 had pure mutant alleles (2 [1.4%] with a single mutation, 11 [7.9%] with double mutations, and 103 [74.1%] with triple mutations), and 13 (9.4%) had mixed alleles. With the exception of a single isolate with triple mutations (50% inhibitory concentration [IC50] = 84.3 nM), all isolates with pure wild-type dhfr alleles (IC50 < 100 nM) and those with pure mutant dhfr alleles (between 1 and 3 point mutations; IC50 ≥ 100 nM) were clearly distinguished by in vitro drug sensitivity assays. The results of the two methods are highly correlated, and both methodologic approaches indicate an increasing proportion of pyrimethamine-resistant isolates in Yaounde over the past eight years (42–45% in 1994–1995, 63–67% in 1997–1998, and 88–92% in 2000–2001). At present, clinical isolates carrying triple dhfr mutations predominate in Yaounde. This situation calls for a regular surveillance of the efficacy of antifolate drugs by all available means, including clinical evaluation, in vitro drug sensitivity assays, molecular markers, and pharmacologic studies.

Save