title: Increasing prevalence of a novel triple-mutant dihydropteroate synthase genotype in Plasmodium falciparum in western Kenya.
abstract: The molecular basis of sulfadoxine-pyrimethamine (SP) resistance lies in a combination of single-nucleotide polymorphisms (SNPs) in two genes coding for Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and P. falciparum dihydropteroate synthase (Pfdhps), targeted by pyrimethamine and sulfadoxine, respectively. The continued use of SP for intermittent preventive treatment in pregnant women in many African countries, despite SP's discontinuation as a first-line antimalarial treatment option due to high levels of drug resistance, may further increase the prevalence of SP-resistant parasites and/or lead to the selection of new mutations. An antimalarial drug resistance surveillance study was conducted in western Kenya between 2010 and 2013. A total of 203 clinical samples from children with uncomplicated malaria were genotyped for SNPs associated with SP resistance. The prevalence of the triple-mutant Pfdhfr C50 I51R59N108: I164 genotype and the double-mutant Pfdhps S436 G437E540: A581A613 genotype was high. Two triple-mutant Pfdhps genotypes, S436 G437E540G581: A613 and H436G437E540: A581A613, were found, with the latter thus far being uniquely found in western Kenya. The prevalence of the S436 G437E540G581: A613 genotype was low. However, a steady increase in the prevalence of the Pfdhps triple-mutant H436G437E540: A581A613 genotype has been observed since its appearance in early 2000. Isolates with these genotypes shared substantial microsatellite haplotypes with the most common double-mutant allele, suggesting that this triple-mutant allele may have evolved locally. Overall, these findings show that the prevalence of the H436G437E540: A581A613 triple mutant may be increasing in this population and could compromise the efficacy of SP for intermittent preventive treatment in pregnant women if it increases the resistance threshold further.
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA NLucchi@cdc.gov.
authors.forename: Naomi W
authors.initials: NW
authors.lastname: Lucchi
authors.affiliation: Atlanta Research and Education Foundation, Decatur, Georgia, USA.
authors.forename: Sheila Akinyi
authors.initials: SA
authors.lastname: Okoth
authors.affiliation: Kenya Medical Research Institute-Centers for Disease Control and Prevention Collaboration, Kisumu, Kenya.
authors.forename: Franklin
authors.initials: F
authors.lastname: Komino
authors.affiliation: Kenya Medical Research Institute-Centers for Disease Control and Prevention Collaboration, Kisumu, Kenya.
authors.forename: Philip
authors.initials: P
authors.lastname: Onyona
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Ira F
authors.initials: IF
authors.lastname: Goldman
authors.affiliation: Atlanta Research and Education Foundation, Decatur, Georgia, USA.
authors.forename: Dragan
authors.initials: D
authors.lastname: Ljolje
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Ya Ping
authors.initials: YP
authors.lastname: Shi
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Barnwell
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Venkatachalam
authors.initials: V
authors.lastname: Udhayakumar
authors.affiliation: Kenya Medical Research Institute-Centers for Disease Control and Prevention Collaboration, Kisumu, Kenya.
authors.forename: Simon
authors.initials: S
authors.lastname: Kariuki
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007630:Kenya / Q000453:epidemiology; D016778:Malaria, Falciparum / Q000453:epidemiology* / Q000469:parasitology*; D018895:Microsatellite Repeats; D009154:Mutation / Q000235:genetics; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D015995:Prevalence; D011739:Pyrimethamine / Q000494:pharmacology*; D013413:Sulfadoxine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D055815:Young Adult
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine