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<jats:title>ABSTRACT</jats:title><jats:p>Conventional 48-h<jats:italic>in vitro</jats:italic>susceptibility tests have low sensitivity in identifying artemisinin-resistant<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium falciparum</jats:named-content>, defined phenotypically by low<jats:italic>in vivo</jats:italic>parasite clearance rates. We hypothesized originally that this discrepancy was explained by a loss of ring-stage susceptibility and so developed a simple field-adapted 24-h trophozoite maturation inhibition (TMI) assay focusing on the ring stage and compared it to the standard 48-h schizont maturation inhibition (WHO) test. In Pailin, western Cambodia, where artemisinin-resistant<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>is prevalent, the TMI test mean (95% confidence interval) 50% inhibitory concentration (IC<jats:sub>50</jats:sub>) for artesunate was 6.8 (5.2 to 8.3) ng/ml compared with 1.5 (1.2 to 1.8) ng/ml for the standard 48-h WHO test (<jats:italic>P</jats:italic>= 0.001). TMI IC<jats:sub>50</jats:sub>s correlated significantly with the<jats:italic>in vivo</jats:italic>responses to artesunate (parasite clearance time [<jats:italic>r</jats:italic>= 0.44,<jats:italic>P</jats:italic>= 0.001] and parasite clearance half-life [<jats:italic>r</jats:italic>= 0.46,<jats:italic>P</jats:italic>= 0.001]), whereas the standard 48-h test values did not. On continuous culture of two resistant isolates, the artemisinin-resistant phenotype was lost after 6 weeks (IC<jats:sub>50</jats:sub>s fell from 10 and 12 ng/ml to 2.7 and 3 ng/ml, respectively). Slow parasite clearance in falciparum malaria in western Cambodia results from reduced ring-stage susceptibility.</jats:p>

Original publication

DOI

10.1128/aac.01924-13

Type

Journal

Antimicrobial Agents and Chemotherapy

Publisher

American Society for Microbiology

Publication Date

06/2014

Volume

58

Pages

3157 - 3161