Abstract
Background and objectivesThere 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.MethodologyIn 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.ResultsThe 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.Conclusions and implications(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 at the time of treatment, although we did not test the effect of immunity whose influence may have been important in the case of late treatment. (iii) Finding the ‘right’ dose and ‘right’ time to maximize clinical gains and limit resistance emergence can vary depending on biological context and was non-trivial even in our simplified experiments.Lay summaryIn a mouse model of malaria, higher drug doses led to increases in drug resistance. The timing of drug treatment also impacted resistance emergence, likely due to the size of the population at the time of treatment.
Highlights
There is widespread agreement that appropriate antimicrobial use is critical for minimizing the emergence and spread of antimicrobial resistance
De novo resistance contributes to treatment failure, as with cancer [7] and several quickly evolving viral [8,9,10] and bacterial infections [11,12,13]
In experiment 2 (Swiss Webster mice, wider range of drug doses), treatment failure occurred in almost all cases and was unrelated to drug dose, but the failures at higher doses were more likely to be due to resistance evolution (c1,752 = 11.5, p < 0.001, Fig. 2B and 3A)
Summary
There is widespread agreement that appropriate antimicrobial use is critical for minimizing the emergence and spread of antimicrobial resistance. We focus on two of those factors – timing and dose – and ask experimentally how they affect the emergence of de novo drug resistance in an animal model. Resistant sub-populations must expand to densities within their host that trigger symptoms and/or become transmissible Both of these processes are impacted by drug treatment. There is significant interest in identifying clinically effective drug treatment regimens that minimize the de novo evolution of antimicrobial resistance in pathogen populations. In vivo studies that vary treatment regimens and directly measure drug resistance evolution are rare. We experimentally investigate the role of drug dose and treatment timing on resistance evolution in an animal model. Conclusions and implications: (i) Higher doses do not always minimize resistance emergence and can result in competitive release of parasites with high-level resistance. (ii) Altering treatment timing affects the risk of resistance emergence, but not as a simple function of population size at the time of treatment. (iii) Finding the ‘right’ dose and ‘right’ time to maximize clinical gains and limit resistance emergence can vary depending on biological context and was non-trivial even in our simplified experiments
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