Molecular evidence of greater selective pressure for drug resistance exerted by the long-acting antifolate pyrimethaminel/sulfadoxine compared with the shorter-acting chlorproguanil/dapsone on Kenyan Plasmodium falciparum

Pyrimethamine (PM) plus sulfadoxine (SD) is the last remaining affordable d rug for treating uncomplicated malaria in Africa. The selective pressure ex erted by the slowly eliminated combination PM/SD was compared with that exe rted by the more rapidly eliminated combination chlorproguanil/dapsone (CPG /Dap) on Kenyan Plasmodium falciparum, Point mutations were analyzed in dih ydrofolate reductase and dihydropteroate synthase and in the genetic divers ity of 3 genes in isolates collected before and after CPG/Dap and PM/SD tre atments, PM/SD was associated strongly with the disappearance of fully drug -sensitive parasites and with a significant increase in the prevalence of r esistant parasites in subsequent parasitemias, However, this was not a char acteristic of treatment with CPG/Dap, Moreover, most of the patients who re turned with recrudescent infections were in the PM/SD-treated group. The da ta 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-re sistant falciparum malaria in sub-Saharan Africa.