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.
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.
Nzila
A M
AM
Wellcome Trust Research Laboratory, Nairobi, Kenya. anzila@wtrl.or.ke
Nduati
E
E
Mberu
E K
EK
Hopkins Sibley
C
C
Monks
S A
SA
Winstanley
P A
PA
Watkins
W M
WM
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
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