On the evolutionary ecology of multidrug resistance in bacteria

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 identify a partial structural similarity in these models: either strain or host population structure stratifies the pathogen population into evolutionarily independent sub-populations and introduces variation in the fitness effect of resistance between these sub-populations, thus creating niches for sensitivity and resistance. 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.

Factors favouring the evolution of multidrug resistance in bacteria

“…Combination therapy of course favours MDR, but is comparatively rarer ( figure 1b, table 1). In other words, MDR may evolve even when drugs are never taken in combination in individual hosts (in agreement with previous results from a simpler model [17]). -In a structured host population, alignment in antibiotic use across classes favours MDR (figure 3a, electronic supplementary material, figure S3C).…”

“…Until recently, few theoretical studies had examined these three hypotheses for the proliferation of MDR. Lehtinen et al [17] developed an epidemiological model to describe the evolution of MDR when the host population is structured (e.g. different age classes or geographical regions).…”

Targeted surveillance strategies for efficient detection of novel antibiotic resistance variants

“…Multiple drug resistance is more common in pathogenic bacteria than one would expect from the product of frequencies of resistance to individual drugs 43,44 . This suggests that novel resistance mechanisms might be more likely to arise and spread in bacterial strains that are already resistant to other drugs, a phenomenon that has been documented in N. gonorrhoeae 45 .…”

Mathematical modelling for antibiotic resistance control policy: do we know enough?

“…A number of recent studies have proposed potentially complementary mechanisms — e.g. balancing selection caused by within-host competition [10, 28], variable selection for resistance over heterogeneous genetic backgrounds [29, 30], or population heterogeneity in treatment rates [28, 31] — which may each be capable of explaining this empirically-observed coexistence [13]. The relative importance of these and other mechanisms will vary depending upon the pathogen and setting, but remains to be identified for any one case.…”