High-throughput analysis of antimalarial susceptibility data by the WorldWide Antimalarial Resistance Network (WWARN) in vitro analysis and reporting tool.

Charles J Woodrow (1, 2) , Sabina Dahlström (3) , Richard Cooksey (1) , Jennifer A Flegg (1) , Hervé Le Nagard (4) , France Mentré (4) , Claribel Murillo (5) , Didier Ménard (6) , François Nosten (7) , Kanlaya Sriprawat (7) , Lise Musset (8, 9, 10) , Neils B Quashie (11) , Pharath Lim (12, 13) , Rick M Fairhurst (12) , Sam L Nsobya (14) , Veronique Sinou (15) , Harald Noedl (16) , Bruno Pradines (17, 18) , Jacob D Johnson (19) , Philippe J Guerin (1) , Carol H Sibley (1, 20) , Jacques Le Bras (1, 21)

1 Nuffield Department of Clinical Medicine [Oxford]
2 Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine
3 WWARN - WorldWide Antimalarial Resistance Network In Vitro Module
4 U738 / UMR_S738 - Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques
5 CIDEIM - International Center for Medical Research and Training
6 Institut Pasteur du Cambodge
7 SMRU - Shoklo Malaria Research Unit [Mae Sot, Thailand]
8 Institut Pasteur de la Guyane
9 Laboratoire de Parasitologie [Cayenne, Guyane française]
10 CNR - laboratoire associé - Centre National de Référence du Paludisme [Cayenne, Guyane française]
11 Epidemiology Department, Noguchi Memorial Institute for Medical Research
12 Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases
13 National Center for Parasitology, Entomology and Malaria Control
14 Department of Medicine
15 IP-TPT - Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques
16 Institute of Specific Prophylaxis and Tropical Medicine
17 URMITE - Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes
18 Centre National de Référence du Paludisme
19 U.S. Army Medical Research Unit
20 GS - Department of Genome Sciences [Seattle]
21 MERIT - UMR_D 216 - Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique

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 Emax model-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.

Domaines: Maladies infectieuses

Charles J Woodrow, Sabina Dahlström, Richard Cooksey, Jennifer A Flegg, Hervé Le Nagard, et al.. High-throughput analysis of antimalarial susceptibility data by the WorldWide Antimalarial Resistance Network (WWARN) in vitro analysis and reporting tool.. Antimicrobial Agents and Chemotherapy, 2013, 57 (7), pp.3121-30. ⟨10.1128/AAC.02350-12⟩. ⟨pasteur-00861904⟩