title: Principal role of dihydropteroate synthase mutations in mediating resistance to sulfadoxine-pyrimethamine in single-drug and combination therapy of uncomplicated malaria in Uganda.
abstract: Antimalarial resistance to sulfadoxine-pyrimethamine (SP) is mediated by mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) 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 dhps Glu-540 mutation was the strongest independent predictor of treatment failure. The dhfr Arg-59 mutation was only predictive of treatment failure in the presence of the dhps 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 dhfr Arg-59 and dhps Glu-540 mutations, and the addition of amodiaquine lowered this risk for all dhfr/dhps mutation patterns. The dhps Glu-540 mutation played a principal role and the dhfr Arg-59 mutation a secondary role in mediating resistance to SP alone and in combination.
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, USA. grantd@itsa.ucsf.edu
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.forename: Christian
authors.initials: C
authors.lastname: Dokomajilar
authors.forename: Moses
authors.initials: M
authors.lastname: Kiggundu
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Staedke
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
mesh_terms: D000483:Alleles; D000655:Amodiaquine / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000494:pharmacology; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004338:Drug Combinations; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004359:Drug Therapy, Combination; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D011739:Pyrimethamine / Q000494:pharmacology*; D013413:Sulfadoxine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D013997:Time Factors; D014454:Uganda
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D002738:Chloroquine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine