Low-dose treatment with sulfadoxine-pyrimethamine combinations selects for drug-resistant Plasmodium falciparum strains.
A total of 252 children were enrolled in a drug trial to assess the effect of minimal doses of sulfadoxine (Sdx) and pyrimethamine (Pyr). Parasite samples isolated from these patients were analyzed before and after treatment to investigate the level of drug-resistant strains. The parasite genes encoding dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) were assayed for point mutations that are associated with resistance against drugs. Before treatment, Pyr(r) genotypes of the DHFR gene were found in 42% of all samples, 8% of the patients harbored a mixed parasite population and 50% had a sensitive DHFR genotype. In terms of the DHPS gene, we found mutations in 45% of the parasites. Twenty-four percent had a Ser(436) mutation, and 26% had a Gly(437) mutation. Recrudescent parasites were highly enriched for both Pyr(r) and Sdx(r) strains after treatment (P < 0.001 and P = 0.029, respectively).
Kun
J F
JF
Department of Parasitology, Institute for Tropical Medicine, University of Tübingen, D-72074 Tübingen, Germany. juergen.kun@uni-tuebingen.de
Lehman
L G
LG
Lell
B
B
Schmidt-Ott
R
R
Kremsner
P G
PG
D000349:Africa; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000627:therapeutic use*; D002648:Child; D004094:Dihydropteroate Synthase / Q000187:drug effects / Q000235:genetics*; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D015767:Mefloquine / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011739:Pyrimethamine / Q000008:administration & dosage / Q000627:therapeutic use*; D013413:Sulfadoxine / Q000008:administration & dosage / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects / Q000235:genetics*
D000962:Antimalarials; D004338:Drug Combinations; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D015767:Mefloquine; D011739:Pyrimethamine