Effect of drug dose and timing of treatment on the emergence of drug resistance in vivo in a malaria model

Evolution, Medicine, and Public Health
Monica M AcostaAndrew F Read

Abstract

There is a significant interest in identifying clinically effective drug treatment regimens that minimize the de novo evolution of antimicrobial resistance in pathogen populations. However, in vivo studies that vary treatment regimens and directly measure drug resistance evolution are rare. Here, we experimentally investigate the role of drug dose and treatment timing on resistance evolution in an animal model. In a series of experiments, we measured the emergence of atovaquone-resistant mutants of Plasmodium chabaudi in laboratory mice, as a function of dose or timing of treatment (day post-infection) with the antimalarial drug atovaquone. The likelihood of high-level resistance emergence increased with atovaquone dose. When varying the timing of treatment, treating either very early or late in infection reduced the risk of resistance. When we varied starting inoculum, resistance was more likely at intermediate inoculum sizes, which correlated with the largest population sizes at time of treatment. (i) Higher doses do not always minimize resistance emergence and can promote the emergence of high-level resistance. (ii) Altering treatment timing affects the risk of resistance emergence, likely due to the size of the population a...Continue Reading

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Citations

Dec 31, 2020·Evolution, Medicine, and Public Health·Erida GjiniVitaly V Ganusov
May 28, 2021·Journal of Asian Natural Products Research·Wang-Yu ZhaoJi-Wen Zhang
Jul 22, 2021·Evolution, Medicine, and Public Health·Alíz T Y OwolabiPetra Schneider

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Methods Mentioned

BETA
PCR

Software Mentioned

RStudio
R
gls
Geneious

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Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.