Mechanisms that maintain coexistence of antibiotic sensitivity and resistance also promote high frequencies of multidrug resistance

Abstract

Resistance against different antibiotics appears on the same bacterial strains more often than expected by chance, leading to high frequencies of multidrug resistance. There are multiple explanations for this observation, but these tend to be specific to subsets of antibiotics and/or bacterial species, whereas the trend is pervasive. Here, we consider the question in terms of strain ecology: explaining why resistance to different antibiotics is often seen on the same strain requires an understanding of the competition between strains with different resistance profiles. This work builds on models originally proposed to explain another aspect of strain competition: the stable coexistence of antibiotic sensitivity and resistance observed in a number of bacterial species. We first demonstrate a partial structural similarity in these models of coexistence. We then generalise this unified underlying model to multidrug resistance and show that models with this structure predict high levels of association between resistance to different drugs and high multidrug resistance frequencies. We test predictions from this model in six bacterial datasets and find them to be qualitatively consistent with observed trends. The higher than expected frequencies of multidrug resistance are often interpreted as evidence that these strains are out-competing strains with lower resistance multiplicity. Our work provides an alternative explanation that is compatible with long-term stability in resistance frequencies.\n\nAuthor summaryAntibiotic resistance is a serious public health concern, yet the ecology and evolution of drug resistance are not fully understood. This impacts our ability to design effective interventions to combat resistance. From a public health point of view, multidrug resistance is particularly problematic because resistance to different antibiotics is often seen on the same bacterial strains, which leads to high frequencies of multidrug resistance and limits treatment options. This work seeks to explain this trend in terms of strain ecology and the competition between strains with different resistance profiles. Building on recent work exploring why resistant bacteria are not out-competing sensitive bacteria, we show that models originally proposed to explain this observation also predict high multidrug resistance frequencies. These models are therefore a unifying explanation for two pervasive trends in resistance dynamics. In terms of public health, the implication of our results is that new resistances are likeliest to be found on already multidrug resistant strains and that changing patterns of prescription may not be enough to combat multidrug resistance.