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Title: Plasmodium falciparum drug resistance phenotype as assessed by patient antimalarial drug levels and its association with pfmdr1 polymorphisms
Authors: Maja Malmberg
Pedro E. Ferreira
Joel Tarning
Johan Ursing
Billy Ngasala
Anders Björkman
Andreas Mårtensson
José P. Gil
Karolinska Institutet
Division of Global Health
Universidade do Algarve
Mahidol University
Nuffield Department of Clinical Medicine
Muhimbili University of Health and Allied Sciences
Binghamton University State University of New York
Karolinska University Hospital
Nagasaki University
Keywords: Medicine
Issue Date: 1-Mar-2013
Citation: Journal of Infectious Diseases. Vol.207, No.5 (2013), 842-847
Abstract: Background. Multidrug-resistant Plasmodium falciparum is a major threat to global malaria control. Parasites develop resistance by gradually acquiring genetic polymorphisms that decrease drug susceptibility. The aim of this study was to investigate the extent to which parasites with different genetic characteristics are able to withstand individual drug blood concentrations. Methods. We analyzed 2 clinical trials that assessed the efficacy and effectiveness of artemether-lumefantrine. As a proof of concept, we used measured day 7 lumefantrine concentrations to estimate the concentrations at which reinfections multiplied. P. falciparum multidrug resistance gene 1 (pfmdr1) genotypes of these parasites were then correlated to drug susceptibility.Results. Reinfecting parasites with the pfmdr1 N86/184F/D1246 haplotype were able to withstand lumefantrine blood concentrations 15-fold higher than those with the 86Y/Y184/1246Y haplotype.Conclusions. By estimating drug concentrations, we were able to quantify the contribution of pfmdr1 single-nucleotide polymorphisms to reduced lumefantrine susceptibility. The method can be applied to all long-half-life antimalarial drugs, enables early detection of P. falciparum with reduced drug susceptibility in vivo, and represents a novel way for unveiling molecular markers of antimalarial drug resistance. © 2012 The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
ISSN: 00221899
Appears in Collections:Scopus 2011-2015

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