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Antibiotic exposure can lead to unintended outcomes, including drug-drug interactions, adverse drug events, and healthcare-associated infections like Clostridioides difficile infection (CDI). Improving antibiotic use is critical to reduce an individual's CDI risk. Antibiotic stewardship initiatives can reduce inappropriate antibiotic prescribing (e.g., unnecessary antibiotic prescribing, inappropriate antibiotic selection), impacting both hospital (healthcare)-onset (HO)-CDI and community-associated (CA)-CDI. Previous computational and mathematical modeling studies have demonstrated a reduction in CDI incidence associated with antibiotic stewardship initiatives in hospital settings. Although the impact of antibiotic stewardship initiatives in long-term care facilities (LTCFs), including nursing homes, and in outpatient settings have been documented, the effects of specific interventions on CDI incidence are not well understood. We examined the relative effectiveness of antibiotic stewardship interventions on CDI incidence using a geospatially explicit agent-based model of a regional healthcare network in North Carolina. We simulated reductions in unnecessary antibiotic prescribing and inappropriate antibiotic selection with intervention scenarios at individual and network healthcare facilities, including short-term acute care hospitals (STACHs), nursing homes, and outpatient locations. Modeled antibiotic prescription rates were calculated using patient-level data on antibiotic length of therapy for the 10 modeled network STACHs. By simulating a 30% reduction in antibiotics prescribed across all inpatient and outpatient locations, we found the greatest reductions on network CDI incidence among tested scenarios, namely a 17% decrease in HO-CDI incidence and 7% decrease in CA-CDI. Among intervention scenarios of reducing inappropriate antibiotic selection, we found a greater impact on network CDI incidence when modeling this reduction in nursing homes alone compared to the same intervention in STACHs alone. These results support the potential importance of LTCF and outpatient antibiotic stewardship efforts on network CDI burden and add to the evidence that a coordinated approach to antibiotic stewardship across multiple facilities, including inpatient and outpatient settings, within a regional healthcare network could be an effective strategy to reduce network CDI burden. [ABSTRACT FROM AUTHOR]