Antimicrobial Resistance and ESBL-Associated Predictors Among Uropathogens: A 2019–2024 Isolate-Level Study

<b>Background/Objectives:</b> Urinary tract infections (UTIs) are among the most common bacterial infections and represent a major source of antimicrobial use. Increasing antimicrobial resistance among uropathogens, particularly the emergence of extended-spectrum beta-lactamase (ESBL)-producing organisms, complicates empiric treatment strategies. ESBL-producing organisms are clinically relevant because they are frequently associated with multidrug resistance and significantly limit empiric antimicrobial treatment options in urinary tract infections. The study period starting in 2019 was selected to reflect contemporary resistance patterns and to ensure consistency with the updated EUCAST antimicrobial susceptibility interpretation criteria introduced at that time. This study aimed to characterize antimicrobial resistance patterns among uropathogens isolated from lower UTIs and to identify independent predictors of antimicrobial resistance using isolate-level analyses. <b>Methods:</b> This retrospective observational study included 1470 patients and isolates with clinically suspected lower UTIs who underwent urine culture and antimicrobial susceptibility testing between 2019 and 2024 at a single clinical center. Antimicrobial susceptibility was interpreted according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria, and ESBL production was assessed among Gram-negative (GN) isolates. Multivariable generalized estimating equation (GEE) logistic regression models accounting for patient clustering were used to identify predictors of resistance. <b>Results:</b> A total of 1470 patients and isolates were included. <i>Escherichia coli</i> was the most frequent uropathogen (66.0%), followed by <i>Klebsiella pneumoniae</i> and <i>Enterococcus faecalis</i>. Among Gram-negative isolates, 17.3% were ESBL-positive. Resistance rates were highest for ciprofloxacin (35.4%) and trimethoprim/sulfamethoxazole (31.7%), while fosfomycin and nitrofurantoin retained high activity against <i>E. coli</i>. In multivariable analyses, ESBL production was the strongest independent predictor of resistance to several antimicrobials, including ciprofloxacin (aOR 9.83), amoxicillin/clavulanic acid (aOR 3.22), trimethoprim/sulfamethoxazole (aOR 2.89), and cefotaxime (aOR 1337). Pathogen identity was also independently associated with resistance. <b>Conclusions:</b> Antimicrobial resistance among uropathogens was heterogeneous and predominantly driven by pathogen identity and ESBL production. ESBL status emerged as the most consistent and powerful predictor of resistance across multiple antimicrobials, underscoring its clinical relevance for empiric treatment decisions and antimicrobial stewardship in urinary tract infections.