Abstract
Antibiotic resistance, and in particular, multidrug resistance are public health concerns. Yet, there has been little theoretical work on the evolutionary dynamics of multidrug resistance (MDR). Here, we present a generic model of MDR inspired by two pervasive trends in resistance dynamics. The first trend is the robust coexistence of antibiotic sensitivity and resistance in multiple bacterial species and for numerous antibiotics. The second is that resistance to different antibiotics tends to be concentrated on the same strains, giving rise to high MDR frequencies. We argue that these two observations are linked: mechanisms that maintain coexistence also promote high MDR frequencies. This argument is based on the recognition that, in many of the most plausible models of coexistence, the coexistence-maintaining mechanism is fundamentally similar: either strain or host population structure stratifies the pathogen population into sub-populations and introduces variation in the fitness effect of resistance between these sub-populations. We show that this model structure also gives rise to high MDR frequencies, because resistance against all antibiotics is concentrated in the sub-populations where the fitness advantage gained from resistance is high. We test predictions from this model on two pneumococcal datasets and find predicted trends are qualitatively consistent with those observed in data. This model provides a parsimonious explanation for the pervasiveness of high MDR frequencies and allows us to reconcile this trend with observed long-term stability in the prevalence of resistance.
