Abstract
Background and objectives: The rate of evolution of drug resistance depends on the fitness of resistant pathogens. The fitness of resistant pathogens is reduced by competition with sensitive pathogens in untreated hosts and so enhanced by competitive release in drug-treated hosts. We set out to estimate the magnitude of those effects on a variety of fitness measures, hypothesizing that competitive suppression and competitive release would have larger impacts when resistance was rarer to begin with. Methodology: We infected mice with varying densities of drug-resistant Plasmodium chabaudi malaria parasites in a fixed density of drug-sensitive parasites and followed infection dynamics using strain-specific quantitative PCR. Results: Competition with susceptible parasites reduced the absolute fitness of resistant parasites by 50-100%. Drug treatment increased the absolute fitness from 2- to >10 000-fold. The ecological context and choice of fitness measure was responsible for the wide variation in those estimates. Initial population growth rates poorly predicted parasite abundance and transmission probabilities. Conclusions and implications: (i) The sensitivity of estimates of pathogen fitness to ecological context and choice of fitness measure make it difficult to derive field-relevant estimates of the fitness costs and benefits of resistance from experimental settings. (ii) Competitive suppression can be a key force preventing resistance from emerging when it is rare, as it is when it first arises. (iii) Drug treatment profoundly affects the fitness of resistance. Resistance evolution could be slowed by developing drug use policies that consider in-host competition.
Highlights
A core aspiration of evolutionary medicine is to prolong the useful lifespan of antimicrobial drugs by slowing or even stopping the evolution of drug resistance [1]
Drug treatment and inoculating dose had no impact on the density of resistant parasites when grown alone (Supplementary Fig. S1)
The resistant parasites were fully resistant to the drug dosages we used and any effect of treatments in the presence of multi-clonal infections is the consequence of competition with the susceptible strain
Summary
A core aspiration of evolutionary medicine is to prolong the useful lifespan of antimicrobial drugs by slowing or even stopping the evolution of drug resistance [1]. Competition between resistance and sensitive strains can occur when resistance first arises in a drug-sensitive infection, and in situations where hosts can become infected with several strains at the same time (co- or superinfections). Such co-infections are common in many disease systems, such as malaria Conclusions and implications: (i) The sensitivity of estimates of pathogen fitness to ecological context and choice of fitness measure make it difficult to derive field-relevant estimates of the fitness costs and benefits of resistance from experimental settings. Resistance evolution could be slowed by developing drug use policies that consider in-host competition
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