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.
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.
Alifrangis
Michael
M
Panum Institute, Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology, Copenhagen, Denmark. malif@biobase.dk
Enosse
Sonja
S
Khalil
Insaf F
IF
Tarimo
Donath S
DS
Lemnge
Martha M
MM
Thompson
Richardo
R
Bygbjerg
Ib C
IC
Rønn
Anita M
AM
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
D000962:Antimalarials; D015415:Biomarkers; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine