An analytical method for assessing stage-specific drug activity in Plasmodium vivax malaria: implications for ex vivo drug susceptibility testing

The emergence of highly chloroquine (CQ) resistant P. vivax in Southeast Asia has created an urgent need for an improved understanding of the mechanisms of drug resistance in these parasites, the development of robust tools for defining the spread of resistance, and the discovery of new antimalarial...

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Bibliographic Details
Published in:	PLoS neglected tropical diseases Vol. 6; no. 8; p. e1772
Main Authors:	Kerlin, Douglas H, Boyce, Kane, Marfurt, Jutta, Simpson, Julie A, Kenangalem, Enny, Cheng, Qin, Price, Ric N, Gatton, Michelle L
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 01-08-2012 Public Library of Science (PLoS)
Subjects:	Adult Analysis Antimalarials - pharmacology Antimalarials - therapeutic use Antiparasitic agents Asia, Southeastern Biological assay Case studies Child Child, Preschool Chloroquine - pharmacology Drug resistance Drug therapy Humans Malaria Malaria, Vivax - parasitology Medicine Methods Parasites Parasitic Sensitivity Tests - methods Plasmodium vivax - drug effects Plasmodium vivax - isolation & purification Statistical methods Time Factors Tropical diseases Vector-borne diseases Asia, Southeastern United Kingdom Southeast Asia Asia, Southeastern Plasmodium vivax Malaria, Vivax Parasitic Sensitivity Tests Time Factors Chloroquine Humans Antimalarials Child, Preschool Adult Child
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Summary:	The emergence of highly chloroquine (CQ) resistant P. vivax in Southeast Asia has created an urgent need for an improved understanding of the mechanisms of drug resistance in these parasites, the development of robust tools for defining the spread of resistance, and the discovery of new antimalarial agents. The ex vivo Schizont Maturation Test (SMT), originally developed for the study of P. falciparum, has been modified for P. vivax. We retrospectively analysed the results from 760 parasite isolates assessed by the modified SMT to investigate the relationship between parasite growth dynamics and parasite susceptibility to antimalarial drugs. Previous observations of the stage-specific activity of CQ against P. vivax were confirmed, and shown to have profound consequences for interpretation of the assay. Using a nonlinear model we show increased duration of the assay and a higher proportion of ring stages in the initial blood sample were associated with decreased effective concentration (EC(50)) values of CQ, and identify a threshold where these associations no longer hold. Thus, starting composition of parasites in the SMT and duration of the assay can have a profound effect on the calculated EC(50) for CQ. Our findings indicate that EC(50) values from assays with a duration less than 34 hours do not truly reflect the sensitivity of the parasite to CQ, nor an assay where the proportion of ring stage parasites at the start of the assay does not exceed 66%. Application of this threshold modelling approach suggests that similar issues may occur for susceptibility testing of amodiaquine and mefloquine. The statistical methodology which has been developed also provides a novel means of detecting stage-specific drug activity for new antimalarials.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Undefined-2 Conceived and designed the experiments: DHK QC RNP MLG. Performed the experiments: JM DHK KB JAS EK. Analyzed the data: DHK KB JAS. Wrote the paper: DHK QC RNP MLG. The authors have declared that no competing interests exist.
ISSN:	1935-2735 1935-2727 1935-2735
DOI:	10.1371/journal.pntd.0001772