Resistance Patterns and Optimization of Empirical Therapy for Urinary Tract Infections in Patients on Trimethoprim-Sulfamethoxazole Prophylaxis Against <i>Pneumocystis jirovecii</i>

<b><i>Background:</i></b> Trimethoprim-sulfamethoxazole (SXT) is widely used for <i>Pneumocystis</i> pneumonia prophylaxis. However, prolonged use may induce antimicrobial resistance, potentially compromising empirical therapy for urinary tract infections (UTIs). <b><i>Methods:</i></b> We retrospectively analyzed 3,525 patients with positive urine cultures at Shizuoka General Hospital (2018-2023). Among them, 149 received SXT prophylaxis. Antimicrobial susceptibility and the relationship between prophylaxis duration and resistance were evaluated. <b><i>Results:</i></b> <i>Escherichia coli</i> and <i>Klebsiella pneumoniae</i> were the most common pathogens. In the SXT prophylaxis group, <i>E. coli</i> susceptibility to SXT was significantly reduced (21.2% vs. 87.4%). Susceptibility to other antibiotics also declined, including ampicillin (31.2% vs. 71.6%), piperacillin (32.5% vs. 74.8%), levofloxacin (57.5% vs. 74.7%), and ciprofloxacin (56.2% vs. 74.1%). Susceptibility to expanded-spectrum cephalosporins, including second-, third-, and fourth-generation agents remained preserved. Receiver operating characteristic analysis identified a prophylaxis duration >406 days as predictive of SXT resistance (area under the curve 0.82, sensitivity 94%, and specificity 60%). Short-term prophylaxis (≤30 days) mitigated resistance, although <i>E. coli</i> susceptibility to SXT was still limited (47.8%). <b><i>Conclusions:</i></b> Prophylactic SXT use markedly reduces susceptibility to multiple antibiotics, especially penicillins and fluoroquinolones. Resistance correlates with prophylaxis duration. For empirical UTI therapy, intravenous expanded-spectrum cephalosporins may be preferable.