title: Countrywide survey shows very high prevalence of Plasmodium falciparum multilocus resistance genotypes in Cambodia.
abstract: Cambodia is located in an area of resistance to multiple antimalarials and has been the first country to implement the systematic use of an artesunate-mefloquine combination as first-line treatment for Plasmodium falciparum malaria. Little is known, however, about the prevalence of resistance mutations within the natural parasite populations, impeding rational drug policy in this context. Using direct sequencing of PCR products, we have analyzed sequence polymorphism of the dihydrofolate reductase-thymidylate synthase, dihydropteroate synthetase, and multidrug resistance 1 genes in a large number of clinical P. falciparum isolates collected in various areas of Cambodia. This highlighted a 100% prevalence of haplotypes with multiple mutations in the target genes of antifolates after more than a decade without use of antifolates for malaria therapy. A high prevalence of mutations in Pfmdr1, including mutations associated with decreased in vitro susceptibility to mefloquine and quinine, was also observed. In addition, novel, low-frequency mutations were detected in Pfmdr1. Our findings show an alarming rate of multilocus resistance genotypes in Cambodia, requiring diligent surveillance and imposing limitations on possible future drug combinations.
authors.affiliation: Faculté de Pharmacie, UFR sciences pharmaceutiques, UMR INRA-Université d'Immunologie Parasitaire et de Vaccinologie, 31, avenue Monge Parc Grandmont, 37200 Tours, France. thierry.fandeur@univ-tours.fr
authors.forename: Nimol
authors.initials: N
authors.lastname: Khim
authors.forename: Christiane
authors.initials: C
authors.lastname: Bouchier
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Ekala
authors.forename: Sandra
authors.initials: S
authors.lastname: Incardona
authors.forename: Pharath
authors.initials: P
authors.lastname: Lim
authors.forename: Eric
authors.initials: E
authors.lastname: Legrand
authors.forename: Ronan
authors.initials: R
authors.lastname: Jambou
authors.forename: Socheat
authors.initials: S
authors.lastname: Doung
authors.forename: Odile Mercereau
authors.initials: OM
authors.lastname: Puijalon
authors.forename: Thierry
authors.initials: T
authors.lastname: Fandeur
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002160:Cambodia / Q000453:epidemiology; D004094:Dihydropteroate Synthase / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D017125:Genes, Protozoan; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000453:epidemiology* / Q000469:parasitology; D009154:Mutation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D015995:Prevalence; D015800:Protozoan Proteins / Q000235:genetics*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D004094:Dihydropteroate Synthase