title: Molecular evidence of greater selective pressure for drug resistance exerted by the long-acting antifolate Pyrimethamine/Sulfadoxine compared with the shorter-acting chlorproguanil/dapsone on Kenyan Plasmodium falciparum.
abstract: Pyrimethamine (PM) plus sulfadoxine (SD) is the last remaining affordable drug for treating uncomplicated malaria in Africa. The selective pressure exerted by the slowly eliminated combination PM/SD was compared with that exerted by the more rapidly eliminated combination chlorproguanil/dapsone (CPG/Dap) on Kenyan Plasmodium falciparum. Point mutations were analyzed in dihydrofolate reductase and dihydropteroate synthase and in the genetic diversity of 3 genes in isolates collected before and after CPG/Dap and PM/SD treatments. PM/SD was associated strongly with the disappearance of fully drug-sensitive parasites and with a significant increase in the prevalence of resistant parasites in subsequent parasitemias. However, this was not a characteristic of treatment with CPG/Dap. Moreover, most of the patients who returned with recrudescent infections were in the PM/SD-treated group. The data predict a longer useful therapeutic life for CPG/Dap than for PM/SD, and, thus, CPG/Dap is a preferable alternative for treatment of chloroquine-resistant falciparum malaria in sub-Saharan Africa.
authors.affiliation: Wellcome Trust Research Laboratory, Nairobi, Kenya. anzila@wtrl.or.ke
authors.forename: A M
authors.initials: AM
authors.lastname: Nzila
authors.forename: E
authors.initials: E
authors.lastname: Nduati
authors.forename: E K
authors.initials: EK
authors.lastname: Mberu
authors.forename: C
authors.initials: C
authors.lastname: Hopkins Sibley
authors.forename: S A
authors.initials: SA
authors.lastname: Monks
authors.forename: P A
authors.initials: PA
authors.lastname: Winstanley
authors.forename: W M
authors.initials: WM
authors.lastname: Watkins
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage*; D003622:Dapsone / Q000008:administration & dosage*; D004338:Drug Combinations; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000008:administration & dosage*; D010453:Peptide Synthases / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects*; D002727:Proguanil / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011739:Pyrimethamine / Q000008:administration & dosage*; D013413:Sulfadoxine / Q000008:administration & dosage*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D005493:Folic Acid Antagonists; D013413:Sulfadoxine; C007030:chlorproguanil; D003622:Dapsone; D013762:Tetrahydrofolate Dehydrogenase; D010453:Peptide Synthases; C020041:dihydrofolate synthetase; D002727:Proguanil; D011739:Pyrimethamine