Outpatient antibiotic stewardship interventions: geographic scale and associations between antibiotic use and resistance

Abstract

Antibiotic use is a key driver of antibiotic resistance. Understanding the quantitative association between antibiotic use and resulting resistance is important for predicting future rates of antibiotic resistance and for designing antibiotic stewardship policy. However, the use-resistance association is complicated by "spillover", in which one populations level of antibiotic use affects another populations level of resistance via the transmission of bacteria between those populations. Spillover is known to have effects at the level of families and hospitals, but it is unclear if spillover is relevant at larger scales. We used mathematical modeling and analysis of observational data to address this question. First, we used dynamical models of antibiotic resistance to predict the effects of spillover. Whereas populations completely isolated from one another do not experience any spillover, we found that if even 1% of interactions are between populations, then spillover may have large consequences: the effect of a change in antibiotic use in one population on antibiotic resistance in that population could be reduced by as much as 50%. Then, we quantified spillover in observational antibiotic use and resistance data from US states and European countries for 3 pathogen-antibiotic combinations, finding that increased interactions between populations were associated with smaller differences in antibiotic resistance between those populations. Thus, spillover may have an important impact at the level of states and countries, which has ramifications for predicting the future of antibiotic resistance, designing antibiotic resistance stewardship policy, and interpreting stewardship interventions.