Project Summary Enterobacterales are increasingly resistant to multiple antibiotics, making them a global epidemic public health threat. Multi-drug resistant Enterobacterales (MDR Ent) infections were historically limited to healthcare settings, but over the past two decades there have been significant increases in infections occurring in otherwise healthy children and adults without prior healthcare contact. These community-acquired (CA) MDR Ent strains are epidemiologically and genetically distinct from healthcare-acquired strains, yet similarly associated with severe infections, high costs, long hospital stays, subsequent nosocomial spread, and poor outcomes. Importantly, MDR Ent strains have been recovered from multiple environmental and animal reservoirs, yet the contribution of these sources to community-acquired human infection is unclear. We recently discovered that children residing in the South and Southwest regions of Chicago had a striking 5-fold greater odds of CA-MDR Ent infection than children living in the West region. Children residing in Central and Northwest Chicago had a >80% decreased odds of such infections. Surprisingly, MDR Ent infections were 4-34x more likely to be community-acquired than were infections with susceptible strains. This seeming paradox highlights critical gaps in knowledge of transmission dynamics, reservoirs, sources, and origins of antibiotic resistance genes (ARGs) in CA-MDR Ent. Such information is needed to inform strategies to interrupt community transmission. The clustering of CA-MDR Ent infections in the South and Southwest Chicago “high-risk” regions makes it an ideal setting to investigate environmental reservoirs of MDR Ent. The proposed studies will integrate genomic and epidemiologic data to help define transmission pathways of MDR Ent. The proposal has two aims: 1) Profile MDR Ent and mobile ARGs in Greater Chicago Area waterways and identify environmental reservoirs associated with community acquisition of MDR Ent; 2) Assess risk factors for colonization with CA-MDR Ent and transmission dynamics of CA-MDR Ent among community members located in established regions with high risk of infection. This will be accomplished by: (1) sampling waterways and evaluating the relative contributions of key sources of contamination (e.g., wastewater treatment plants, farms, and waterfowl) within the high-risk region relative to the control (low-risk) region, (2) surveying the households of waterway users and residents in the high-risk region for risk factors and MDR Ent colonization, (3) comprehensive multi-dimensional culture-, metagenomic (MGS)-, and whole genome sequence (WGS)-based characterization of bacteria and ARGs within environmental, animal, and human reservoirs to comprehensively track dissemination patterns of resistant genotypes. MGS and WGS data will be compared across aims to identify sources of CA-MDR Ent. With knowledge generated through this rigorous research, we can identify targeted interventions for reducing exposure to MDR Ent in healthy persons, thereby decreasing infections, hospital admissions, healthcare costs and community spread of MDR Ent.

Project Narrative Infections due to antibiotic-resistant bacteria known as Enterobacterales are occurring increasingly in the community in otherwise healthy persons without significant prior health care contact. Our goal is to identify community-based exposures to resistant bacteria by examining potential environmental, animal, and household sources. Our results will lead to ways to control the sources that we find and to decrease the risk of antibiotic- resistant bacterial infections in the community.