The Association Between Antibiotic Use and the Incidence of Third-Generation Cephalosporin-Resistance in Escherichia coli Bloodstream Infections: An Ecological Study

<b>Background/Objectives</b>: The COVID-19 period was marked by changes in antibiotic use and in the incidence of bacterial infections. We examined the association between antibiotic use and the proportion of <i>Escherichia coli</i> bloodstream infections (BSI) that were third-generation cephalosporin-resistant (3GC-R), using the COVID-19 period as a natural experiment. <b>Methods</b>: Data for this ecological study came from Israeli national surveillance systems for BSI and antibiotic consumption in 2015-2023. We performed interrupted time series analyses with a 1-year lag to examine the impact of COVID-19 on the proportion of <i>E. coli</i> BSI that were 3GC-R. We used linear regression to test the association between antibiotic use and 3GC resistance. <b>Results</b>: The majority of national antibiotic use was in outpatient settings; it was stable between 2015-2019, dropped by 19.4% in 2020, then increased gradually, but in 2023 remained 10.8% lower than before the pandemic. Incidence of <i>E. coli</i> BSI per 100,000 population increased from 62.6 in 2015 to a peak of 66.0 in 2019, with a small, non-significant change in the proportion of <i>E. coli</i> BSI that were 3GC-R (0.339 in 2015 vs. 0.335 in 2020). In 2020, the incidence of both 3GC-susceptible and 3GC-R <i>E. coli</i> BSI decreased. In 2021, only 3GC-R BSI declined, resulting in the proportion resistant dropping significantly by 0.05 (95% CI: 0.03-0.07). Post-pandemic, BSI incidence rose but remained below the 2019 rate. The proportion resistant after 2021 rose by 0.02 per year relative to the pre-COVID slope (95% CI: 0.02-0.03), such that it was higher in 2023 (0.341) than in 2019 and 2015. There was a significant positive linear relationship between antibiotic use and resistance: the proportion of <i>E. coli</i> BSI that were 3GC-R increased by 0.02 for each increase of one defined daily dose of antibiotic per person (95% CI: 0.001-0.03). <b>Conclusions</b>: Reduced outpatient antibiotic use during COVID-19 was followed by a reduction in the proportion of <i>E. coli</i> BSI that were 3GC-R.