Estimating the proportion of bystander selection for antibiotic resistance in the US

Abstract Bystander selection -- the selective pressures exerted by antibiotics on microbial flora that are not the target pathogen of treatment -- is critical to understanding the total impact of broad-spectrum antibiotic use; however, to our knowledge, this effect has never been quantified. Using the 2010-2011 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (NAMCS/NHAMCS), the Human Microbiome Project, and additional carriage and etiological data from existing literature, we estimate the magnitude of bystander selection for a range of clinically relevant antibiotic-species pairs as the proportion of all exposures of an antibiotic experienced by a species for conditions in which that species was not the causative pathogen (“proportion of bystander exposures”). For outpatient prescribing in the United States, we find that this proportion over all included antibiotics is over 80% for 8 out of 9 organisms of interest. Low proportions of bystander exposure are often associated with infrequent bacterial carriage or a high proportion of antibiotic prescribing focused on conditions caused by the species of interest. Using the proportion of bystander exposures, we roughly estimate that S. aureus and E. coli may benefit from 90.7% and 99.7%, respectively, of the estimated reduction in antibiotic use due to pneumococcal conjugate vaccination, despite not being the pathogen targeted by the vaccine. These results underscore the importance of considering antibiotic exposures to bystanders, in addition to the targeted pathogen, in measuring the impact of antibiotic resistance interventions. Significance Statement The forces that contribute to changing population prevalence of antibiotic resistance are not well understood. Bystander selection -- the inadvertent pressures imposed by antibiotics on the microbial flora other than the pathogen targeted by treatment -- is hypothesized to be a major factor in the propagation of antibiotic resistance, but its extent has not been characterized. We estimate the proportion of bystander exposures across a range of antibiotics and organisms and describe factors driving variability of these proportions. Impact estimates for antibiotic resistance interventions, including vaccination, are often limited to effects on a target pathogen. However, the reduction of antibiotic treatment for illnesses caused by the target pathogen may have the broader potential to decrease bystander selection pressures for resistance on many other organisms.