title: Epidemiological dynamics of antimonial resistance in Leishmania donovani: genotyping reveals a polyclonal population structure among naturally-resistant clinical isolates from Nepal.
abstract: Pentavalent antimonials (SbV) are the first line drug against leishmaniasis worldwide, but drug resistance is increasingly reported, particularly in the Indian sub-continent, where it represents a major threat for the control of anthroponotic visceral leishmaniasis (VL). In order to understand the epidemiological dynamics of antimonial resistance in anthroponotic VL, we analysed here the population structure of 24 Leishmania donovani stocks isolated from anthroponotic VL-patients from Eastern Nepal: 13 SbV-naturally resistant and 11 SbV-sensitive, as demonstrated by in vitro drug susceptibility assays. The parasites were genotyped by PCR-RFLP analysis of kDNA minicircles and by microsatellite analysis and the encountered polymorphism revealed a polyclonal structure among resistant isolates. Furthermore, analysis of paired samples obtained from the same patients before treatment and after failure revealed primary as well as acquired resistance. The hypothesis of independent events of drug resistance emergence is proposed and confronted to alternative explanations. Our results show the dynamics of drug resistance epidemiology and highlight the importance of surveillance networks.
authors.affiliation: Department of Parasitology, Unit of Molecular Parasitology, Institute of Tropical Medicine, Antwerp B-2000, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Laurent
authors.forename: Suman
authors.initials: S
authors.lastname: Rijal
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Simon
authors.initials: S
authors.lastname: Croft
authors.forename: Simonne
authors.initials: S
authors.lastname: De Doncker
authors.forename: Saskia
authors.initials: S
authors.lastname: Decuypere
authors.forename: Basudha
authors.initials: B
authors.lastname: Khanal
authors.forename: Rupa
authors.initials: R
authors.lastname: Singh
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schönian
authors.forename: Katrin
authors.initials: K
authors.lastname: Kuhls
authors.forename: François
authors.initials: F
authors.lastname: Chappuis
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dujardin
mesh_terms: D000666:Amphotericin B / Q000627:therapeutic use; D000818:Animals; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D001853:Bone Marrow / Q000469:parasitology; D018105:DNA, Kinetoplast / Q000235:genetics; D004351:Drug Resistance; D005838:Genotype; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology*; D009390:Nepal; D010802:Phylogeny; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D000981:Antiprotozoal Agents; D018105:DNA, Kinetoplast; D000666:Amphotericin B