A Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparum

Pengxing Cao; Nectarios Klonis; Sophie Zaloumis; Con Dogovski; Stanley C Xie; Sompob Saralamba; Lisa J White; Freya JI Fowkes; Leann Tilley; Julie A Simpson; James M McCaw

Journal article

A Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparum

Pengxing Cao, Nectarios Klonis, Sophie Zaloumis, Con Dogovski, Stanley C Xie, Sompob Saralamba, Lisa J White, Freya JI Fowkes, Leann Tilley, Julie A Simpson, James M McCaw

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | AMER SOC MICROBIOLOGY | Published : 2017

DOI: 10.1128/AAC.00618-17

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Abstract

Artemisinin resistance constitutes a major threat to the continued success of control programs for malaria, particularly in light of developing resistance to partner drugs. Improving our understanding of how artemisinin-based drugs act and how resistance manifests is essential for the optimization of dosing regimens and the development of strategies to prolong the life span of current first-line treatment options. Recent short-drug-pulse in vitro experiments have shown that the parasite killing rate depends not only on drug concentration but also the exposure time, challenging the standard pharmacokinetic-pharmacodynamic (PK-PD) paradigm in which the killing rate depends only on drug concent..

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University of Melbourne Researchers

Pengxing Cao Author Mathematics and Statistics

Freya Fowkes Author Melbourne School of Population and Global Health

Leann Tilley Author Biochemistry and Pharmacology

James McCaw Author Mathematics and Statistics

Stanley Xie Author Biochemistry and Pharmacology

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Grants

Awarded by National Health and Medical Research Centre of Australia (NHMRC)

Awarded by Centre for Research Excellence VicBioStat

Awarded by Centre for Research Excellence PRISM2

Awarded by Australian Research Council

Funding Acknowledgements

The work was supported by the National Health and Medical Research Centre of Australia (NHMRC) through project grants 1100394 and 1060357, the Centre for Research Excellence VicBioStat (1035261), the Centre for Research Excellence PRISM<SUP>2</SUP> (1078068), and the Australian Research Council Discovery project (DP170103076). The Mahidol-Oxford Tropical Medicine Research Unit is supported by the Wellcome Trust of Great Britain. J.M.M. and F.F. were supported by Australian Research Council (ARC) Future Fellowships. L.T. was supported by an ARC Professorial Fellowship. J.A.S. was supported by an NHMRC Senior Research Fellowship.We acknowledge many useful conversations with David S. Khoury, Deborah Cromer, and Miles P. Davenport (Kirby Institute, UNSW, Australia), as well as Joel Tarning and Nicholas J. White (Mahidol University, Bangkok, Thailand). P.C. also thanks TDModNet for providing a traveling fellowship to enable collaboration on this project.