title: Prediction of Plasmodium falciparum resistance to sulfadoxine/pyrimethamine in vivo by mutations in the dihydrofolate reductase and dihydropteroate synthetase genes: a comparative study between sites of differing endemicity.
abstract: Plasmodium falciparum resistance to sulfadoxine/pyrimethamine (S/P) is due to mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhfr) genes. Large-scale screening of the prevalence of these mutations could facilitate the surveillance of the level of S/P resistance in vivo. The prevalence of mutations in dhfr and dhps in relation to S/P efficacy was studied in four sites of differing endemicity in Sudan, Mozambique, and Tanzania. The sites were organized in order of increasing resistance and a significant increase in the prevalence of triple mutations in codons c51, c59, and c108 of dhfr was observed. A similar trend was observed when dhfr genotypes were combined with c437 of dhps. Since the differences in S/P resistance between the sites were minor, but nevertheless revealed major differences in dhfr genotype prevalence, the role of dhfr as a general molecular marker seems debatable. The differences may reflect variation in the duration and magnitude of S/P usage (or other antifolate drugs) between the sites. Thus, triple dhfr mutations may prove suitable only as a general guideline for detecting emerging S/P resistance in areas where S/P has been introduced recently. However, changes in susceptibility within the same area with moderate levels of resistance may be possible by longitudinal surveillance of a subset of dhfr/dhps mutations that has been associated with S/P resistance in vivo in a defined location.
authors.affiliation: Panum Institute, Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology, Copenhagen, Denmark. malif@biobase.dk
authors.forename: Michael
authors.initials: M
authors.lastname: Alifrangis
authors.forename: Sonja
authors.initials: S
authors.lastname: Enosse
authors.forename: Insaf F
authors.initials: IF
authors.lastname: Khalil
authors.forename: Donath S
authors.initials: DS
authors.lastname: Tarimo
authors.forename: Martha M
authors.initials: MM
authors.lastname: Lemnge
authors.forename: Richardo
authors.initials: R
authors.lastname: Thompson
authors.forename: Ib C
authors.initials: IC
authors.lastname: Bygbjerg
authors.forename: Anita M
authors.initials: AM
authors.lastname: Rønn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D015415:Biomarkers; D002648:Child; D004094:Dihydropteroate Synthase / Q000235:genetics; D004338:Drug Combinations; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019353:Endemic Diseases; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000469:parasitology / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D009154:Mutation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011159:Population Surveillance / Q000379:methods; D011237:Predictive Value of Tests; D015995:Prevalence; D011739:Pyrimethamine / Q000494:pharmacology*; D013413:Sulfadoxine / Q000494:pharmacology*; D013636:Tanzania / Q000453:epidemiology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
chemical_list: D000962:Antimalarials; D015415:Biomarkers; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine