Mutations in dhfr in Plasmodium falciparum infections selected by chlorproguanil-dapsone treatment.
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.
Curtis
J
J
London School of Hygiene and Tropical Medicine, London, United Kingdom.
Maxwell
C A
CA
Msuya
F H M
FH
Mkongewa
S
S
Alloueche
A
A
Warhurst
D C
DC
D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003622:Dapsone / Q000627:therapeutic use*; D004094:Dihydropteroate Synthase / Q000235:genetics; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D017125:Genes, Protozoan; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000201:enzymology; D020066:Merozoite Surface Protein 1 / Q000032:analysis; D009154:Mutation; D018512:Parasitemia; D010963:Plasmodium falciparum / Q000201:enzymology / Q000235:genetics*; D002727:Proguanil / Q000627:therapeutic use*; D013636:Tanzania; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
D000962:Antimalarials; D020066:Merozoite Surface Protein 1; D003622:Dapsone; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D002727:Proguanil