Temporal Trends in Antibiotic Resistance in Europe, 1998-2019

The emergence of resistant phenotypes following the introduction of new antibiotics is well documented. However, the subsequent dynamics of resistance frequencies over long time periods are less well understood: the extent to which resistance frequencies increase, the rate at which resistance frequencies change, and how this depends on antibiotic consumption remain open questions. Here, we systematically analyse the resistance trajectories emerging from 3,375,774 hospital bacterial isolates sampled from infections in Europe over 1998-2019, representing 887 bug-drug-country combinations. Our analyses support a model in which, after an initial increase, resistance frequencies reach a stable intermediate equilibrium. The plurality (37%) of analysed trajectories were best described as stable (neither increasing nor decreasing). The second largest category of trajectories (21%) was those best described as stabilising - i.e. showing a transition from increasing frequency to a stable plateau. The antibiotic consumption in a country predicts both the equilibrium frequency of the corresponding resistance and the speed at which this equilibrium is reached. Moreover, we find weak evidence that temporal fluctuations in resistance frequency are driven by temporal fluctuations in hospital antibiotic consumption. Overall, our results indicate that ever increasing antibiotic resistance frequencies are not inevitable and that antibiotic management limits resistance spread. A large fraction of the variability in the speed of increase and the equilibrium level of resistance remains unexplained by antibiotic use, suggesting other factors also drive resistance dynamics.