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Title: High-throughput analysis of antimalarial susceptibility data by the worldwide antimalarial resistance network (WWARN) In Vitro analysis and reporting tool
Authors: Charles J. Woodrow
Sabina Dahlström
Richard Cooksey
Jennifer A. Flegg
Hervé Le Nagard
France Mentré
Claribel Murillo
Didier Ménard
François Nosten
Kanlaya Sriprawat
Lise Musset
Neils B. Quashie
Pharath Lim
Rick M. Fairhurst
Sam L. Nsobya
Veronique Sinou
Harald Noedl
Bruno Pradines
Jacob D. Johnson
Philippe J. Guerin
Carol H. Sibley
Jacques Le Bras
Nuffield Department of Clinical Medicine
Mahidol University
Hopital Bichat-Claude-Bernard AP-HP
Universite Paris 7- Denis Diderot
Centro Internacional de Entrenamiento e Investigaciones Medicas
Institut Pasteur du Cambodge
Shoklo Malaria Research Unit
Institut Pasteur de la Guyane
University of Ghana
National Institute of Allergy and Infectious Diseases
National Center for Parasitology, Entomology and Malaria Control
Makerere University
Aix Marseille Universite
Medizinische Universitat Wien
Institut de recherche biomedicale des armees
Unite de Recherche sur les Maladies Infectieuses et Tropicales emergentes
Centre National de Référence du Paludisme
Walter Reed Project
University of Washington, Seattle
Universite Paris Descartes
IRD Institut de Recherche pour le Developpement
Keywords: Medicine;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-Jul-2013
Citation: Antimicrobial Agents and Chemotherapy. Vol.57, No.7 (2013), 3121-3130
Abstract: Assessment of in vitro susceptibility is a fundamental component of antimalarial surveillance studies, but wide variations in the measurement of parasite growth and the calculation of inhibitory constants make comparisons of data from different laboratories difficult. Here we describe a Web-based, high-throughput in vitro analysis and reporting tool (IVART) generating inhibitory constants for large data sets. Fourteen primary data sets examining laboratory-determined susceptibility to artemisinin derivatives and artemisinin combination therapy partner drugs were collated from 11 laboratories. Drug concentrations associated with half-maximal inhibition of growth (IC50s) were determined by a modified sigmoid Emaxmodel-fitting algorithm, allowing standardized analysis of 7,350 concentration-inhibition assays involving 1,592 isolates. Examination of concentration-inhibition data revealed evidence of apparent paradoxical growth at high concentrations of nonartemisinin drugs, supporting amendment of the method for calculating the maximal drug effect in each assay. Criteria for defining more-reliable IC50s based on estimated confidence intervals and growth ratios improved correlation coefficients for the drug pairs mefloquine-quinine and chloroquine-desethylamodiaquine in 9 of 11 and 8 of 8 data sets, respectively. Further analysis showed that maximal drug inhibition was higher for artemisinins than for other drugs, particularly in ELISA (enzyme-linked immunosorbent assay)-based assays, a finding consistent with the earlier onset of action of these drugs in the parasite life cycle. This is the first high-throughput analytical approach to apply consistent constraints and reliability criteria to large, diverse antimalarial susceptibility data sets. The data also illustrate the distinct biological properties of artemisinins and underline the need to apply more sensitive approaches to assessing in vitro susceptibility to these drugs. Copyright © 2013, American Society for Microbiology.
ISSN: 10986596
Appears in Collections:Scopus 2011-2015

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