title: Prevention of increasing rates of treatment failure by combining sulfadoxine-pyrimethamine with artesunate or amodiaquine for the sequential treatment of malaria.
abstract: Combination antimalarial therapy may delay the spread of drug resistance, but clinical data supporting this notion are limited. For 1 year, we studied Ugandan children who were treated for uncomplicated malaria with sulfadoxine-pyrimethamine (SP), SP + amodiaquine (AQ), or SP + artesunate (AS). We compared treatment responses and the prevalence of resistance-conferring mutations of new infections with those of recrudescent infections due to parasites that survived prior treatment. Recrudescent infections were associated with the selection of SP resistance-conferring mutations in all treatment groups, but responses to repeat therapy differed. Compared with initial treatments, treatment of recrudescent infections was associated with a higher rate of treatment failure (hazard ratio [HR], 2.44; P=.01), for the SP group, but with a lower rate of treatment failure (HR, 0.40; P=.08), for the SP + AS group. Treatment failure in the SP + AQ group was uncommon, limiting the analysis of recrudescent parasites. Our results suggest that the use of combination antimalarial therapy in Africa may slow the spread of drug-resistant malaria and prolong the therapeutic life span of available treatment regimens.
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco 94143, USA. grantd@itsa.ucsf.edu.
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.forename: Jonathan
authors.initials: J
authors.lastname: Vlahos
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Staedke
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
mesh_terms: D000655:Amodiaquine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000077332:Artesunate; D002675:Child, Preschool; D004094:Dihydropteroate Synthase / Q000235:genetics; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D004359:Drug Therapy, Combination; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects; D011739:Pyrimethamine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013413:Sulfadoxine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D012717:Sesquiterpenes; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D000077332:Artesunate; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine