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Antimicrob. Agents Chemother. doi:10.1128/AAC.01334-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Determinants of in vitro drug susceptibility testing of Plasmodium vivax

International Health Program, Infectious Diseases Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia; Menzies School of Health Research-National Institute of Health Research and Development Malaria Research Program, Timika, Indonesia; National Institute of Health Research and Development, Ministry of Health, Jakarta, Indonesia; District Ministry of Health, Timika, Papua, Indonesia; Mitra Masyarakat Hospital, Timika, Indonesia; Department of Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia; Centre for Vaccinology & Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK

^* To whom correspondence should be addressed. Email: rnp{at}menzies.edu.au.

	Abstract

In Papua, Indonesia antimalarial susceptibility of P. vivax (n=216) and P. falciparum (n=277) was assessed using a modified schizont maturation assay for chloroquine, amodiaquine, artesunate, lumefantrine, mefloquine and piperaquine. The most effective antimalarial against P. vivax and P. falciparum was artesunate, with a geometric mean IC₅₀ [95%CI] of 1.31nM [1.07-1.59] and 0.64nM [0.53-0.79] respectively. In contrast the geometric mean IC50 of P. vivax to chloroquine was 295nM [227-384], compared to only 47.4nM [42.2-53.3] for P. falciparum. Two factors were found to influence significantly the in vitro drug response in P. vivax: the initial stage of the parasite and the duration of the assay. Isolates of P. vivax initially at the trophozoite stage had significantly higher chloroquine IC50s (478nM [95%CI: 316-722]), compared to those initially at the ring stage (84.7nM [95%CI: 45.7-157]); p<0.001. Synchronous isolates of P. vivax and P. falciparum which reached the target of 40% schizonts in the control wells within 30 hours had significantly higher geometric mean IC50s to chloroquine (435nM [95%CI 169-1,118] and 55.9nM [95%CI 48-64.9] respectively) compared to isolates taking more than 30 hours (39.9nM [14.6-110.4] and 36.9nM [31.2-43.7]); p<0.005. The results demonstrate the marked stage-specific activity of chloroquine on P. vivax and suggest that susceptibility to chloroquine maybe associated with variable growth rates. These findings have important implications for the phenotypic and downstream genetic characterisation of P. vivax.

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