Explaining the stable coexistence of drug-resistant and -susceptible pathogens: the resistance acquisition purifying selection model

Drug resistance is a problem in many pathogens. While overall, levels of resistance have risen in recent decades, there are many examples where after an initial rise, levels of resistance have stabilized. The stable coexistence of resistance and susceptibility has proven hard to explain – in most evolutionary models, either resistance or susceptibility ultimately “wins” and takes over the population. Here, we show that a simple model, mathematically akin to mutation-selection balance theory, can explain several key observations about drug resistance: (1) the stable coexistence of resistant and susceptible strains (2) at levels that depend on population-level drug usage and (3) with resistance often due to many different strains (resistance is present on many different genetic backgrounds). The model is applicable to resistance due to both mutations and horizontal gene transfer (HGT). It predicts that new resistant strains should continuously appear (through mutation or HGT and positive selection within treated hosts) and disappear (due to a fitness cost of resistance). The result is that while resistance is stable, which strains carry resistance is constantly changing. We used data from a longitudinal genomic study on E. coli in Norway to test this prediction for resistance to five different drugs and found that, consistent with the model, most resistant strains indeed disappear quickly after they appear in the dataset. Having a model that explains the dynamics of drug resistance will allow us to plan science-backed interventions to reduce the burden of drug resistance.