MUTATIONS IN PLASMODIUM-FALCIPARUM DIHYDROFOLATE-REDUCTASE AND DIHYDROPTEROATE SYNTHASE AND EPIDEMIOLOGIC PATTERNS OF PYRIMETHAMINE-SULFADOXINE USE AND RESISTANCE

To assess the relationship between mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) and clinical pyrimethamine-sulfadoxine resistance, polymerase chain react ion surveys and analyses for new mutations were conducted in four coun tries with increasing levels of pyrimethamine-sulfadoxine resistance: Mali, Kenya, Malawi, and Bolivia, Prevalence of mutations at DHFR codo n 108 and a new mutation at DHPS 540 correlated with increased pyrimet hamine-sulfadoxine resistance (P < .05), Mutations at DHFR 51, DHFR 59 , and DHPS 437 correlated with resistance without achieving statistica l significance; Mutations at DHFR 164 and DHPS 581 were common in Boli via, where pyrimethamine-sulfadoxine resistance is widespread, but abs ent in African sites, Two new DHFR mutations, a point mutation at codo n 50 and an insert at codon 30, were found only in Bolivia. DHFR and D HPS mutations occur in a progressive, stepwise fashion. Identification of specific sets of mutations causing in vivo drug failure may lead t o the development of molecular surveillance methods for pyrimethamine- sulfadoxine resistance.