Mutations in dhfr in Plasmodium falciparum infections selected by chlorproguanil-dapsone treatment

J Infect Dis. 2002 Dec 15;186(12):1861-4. doi: 10.1086/345765. Epub 2002 Nov 15.


Treatment with the novel antifolate drug combination chlorproguanil-dapsone effectively cleared asymptomatic Plasmodium falciparum infections in 246 (93.5%) of 263 children in the Usambara Mountains of Tanzania during the course of a 2-week follow-up. Samples from 71 recurrent infections, collected over a 9-week follow-up, showed selection for parasites with the triple mutant Ile(51)-Arg(59)-Asn(108) in dihydrofolate reductase. There was no selection for mutations in dihydropteroate synthetase, the target enzyme of dapsone. Search for complete identity in the highly polymorphic genes coding for merozoite surface proteins 1 and 2 in parasite samples collected before and after treatment indicated that the majority of recurrent parasitemias were new infections. These observations on selection in Tanzania and the lack of selection reported from a less endemic area suggest that the active metabolite of chlorproguanil, which has a short half-life in the blood, may persist in the liver, where it exerts selective pressure on growing preerythrocytic stages.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / therapeutic use*
  • Child
  • Child, Preschool
  • Dapsone / therapeutic use*
  • Dihydropteroate Synthase / genetics
  • Drug Therapy, Combination
  • Follow-Up Studies
  • Genes, Protozoan
  • Humans
  • Infant
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / enzymology
  • Merozoite Surface Protein 1 / analysis
  • Mutation
  • Parasitemia
  • Plasmodium falciparum / enzymology
  • Plasmodium falciparum / genetics*
  • Proguanil / therapeutic use*
  • Tanzania
  • Tetrahydrofolate Dehydrogenase / genetics*


  • Antimalarials
  • Merozoite Surface Protein 1
  • Dapsone
  • Tetrahydrofolate Dehydrogenase
  • Dihydropteroate Synthase
  • Proguanil