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Background: Antimicrobial use (AU) of antipseudomonal β-lactams (APBL) has significantly increased over the past decade in US hospitals. This retrospective cohort study compares 2 common antimicrobial stewardship strategies, syndrome-specific interventions and antimicrobial postprescription prospective audit and feedback (PAF), in reducing AU of APBL at a large community-teaching hospital., Methods: Four antimicrobial stewardship interventions targeting APBL were serially introduced, including 2 syndrome-specific interventions (bloodstream and intra-abdominal infections) and 2 PAF interventions (carbapenems and piperacillin/tazobactam). Multivariable linear regression was used to examine overall AU of APBL and audited antimicrobial agents., Results: Overall AU of APBL declined from 92.4-69.1 days of therapy (DOT) per 1,000 patient-days between February 2013 and July 2017 (P < .001). Both syndrome-specific interventions were associated with significant reduction in AU of APBL (-7.7 [95% confidence interval (CI): -11.5, -4.0] and -6.0 [95% CI: -9.7, -2.3] DOT per 1,000 patient-days) for bloodstream and intra-abdominal infections, respectively). No significant change in overall AU of APBL was observed after implementation of PAF interventions for carbapenems (-1.4 [95% CI: -7.4, 4.6] DOT per 1,000 patient-days) or piperacillin/tazobactam (0.9 [95% CI: -3.7, 5.4] DOT per 1,000 patient-days)., Conclusions: Implementation of syndrome-specific interventions was followed by significant reduction in AU of APBL in this population. Despite reducing AU of targeted agents, neither PAF intervention contributed to overall observed decline in APBL use, likely due to compensatory increase in using other APBL., (Copyright © 2019 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)