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Background Urinary tract infections (UTIs), which are usually caused by bacteria in the Enterobacterales family, are a common reason for outpatient visits. Appropriate empiric therapy for UTIs requires an understanding of antibiotic resistance in the community. In this nationwide study, we examined trends in antibiotic resistance in urinary Enterobacterales isolates from ambulatory patients in the United States (US). Methods We analyzed the antimicrobial susceptibility profiles (extended-spectrum beta-lactamase [ESBL]-producing phenotype and not susceptible [NS] to beta-lactams, trimethoprim/sulfamethoxazole [TMP/SMX], fluoroquinolones [FQ], or nitrofurantoin [NFT]) of 30-day non-duplicate Enterobacterales isolates from urine cultures tested at ambulatory centers in the BD Insights Research Database (2011–2020). The outcome of interest was the percentage of resistant isolates by pathogen and year. Multi-variable generalized estimating equation models were used to assess trends in resistance over time and by additional covariates. Results A total of 338 US facilities provided data for &gt; 2.2 million urinary Enterobacterales isolates during the 10-year study. Almost three-quarters (72.8%) of Enterobacterales isolates were  Escherichia coli . Overall unadjusted resistance rates in Enterobacterales isolates were 57.5%, 23.1%, 20.6%, and 20.2% for beta-lactams, TMP/SMX, FQ, and NFT, respectively, and 6.9% had an ESBL-producing phenotype. Resistance to two or more antibiotic classes occurred in 16.4% of isolates and 5.5% were resistant to three or more classes. Among isolates with an ESBL-producing phenotype, 70.1%, 59.9%, and 33.5% were NS to FQ, TMP/SMX, and NFT, respectively. In multivariable models, ESBL-producing and NFT NS Enterobacterales isolates increased significantly (both P &lt; 0.001), while other categories of resistance decreased. High rates (≥ 50%) of beta-lactam and NFT resistance were observed in  Klebsiella  isolates and in non- E. coli , non- Klebsiella  Enterobacterales isolates. Conclusions Antimicrobial resistance was common in urinary Enterobacterales isolates. Isolates with an ESBL-producing phenotype increased by about 30% between 2011 and 2020, and significant increases were also observed in NFT NS Enterobacterales isolates. Resistance rates for all four antibiotic classes were higher than thresholds recommended for use as empiric therapy. Non- E. coli  Enterobacterales isolates showed high levels of resistance to commonly used empiric antibiotics, including NFT. These data may help inform empiric therapy choices for outpatients with UTIs.

A multicenter analysis of trends in resistance in urinary Enterobacterales isolates from ambulatory patients in the United States: 2011–2020