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.
