Real-World Effectiveness of Intravenous and Oral Antibiotic Stepdown Strategies for Gram-Negative Complicated Urinary Tract Infection With Bacteremia

Abstract

Background Robust data are lacking regarding the optimal route, duration, and antibiotic choice for Gram-negative bloodstream infections from a complicated urinary tract infection source (GN-BSI/cUTI). Methods In this multicenter observational cohort study, we simulated a four-arm registry trial using causal inference methodology to compare effectiveness of the following regimens for GN-BSI/cUTI: complete course of an intravenous beta-lactam (IVBL) or oral stepdown therapy within 7 days using fluoroquinolones (FQs), trimethoprim-sulfamethoxazole (TMP-SMX), or high-bioavailability beta-lactams (HBBLs). Adults treated between 1/2016-12/2022 for E. coli or Klebsiella species GN-BSI/cUTI were included. Propensity weighting was used to balance characteristics between groups. Sixty-day recurrence was compared using a multinomial Cox proportional hazards model with probability of treatment weighting. Results Of 2,571 patients screened, 759 (30%) were included. Characteristics were similar between groups. Compared to IVBLs, we did not observe a difference in effectiveness for FQs (adjusted hazard ratio, aHR 1.09 [95% CI, 0.49-2.43]) or TMP-SMX (aHR 1.44 [95% CI, 0.54-3.87]), and effectiveness of TMP-SMX/FQ appeared to be optimal at durations longer than 10 days. HBBLs were associated with nearly 4-fold higher risk of recurrence (aHR 3.83 [95% CI, 1.76-8.33]), which was not mitigated by longer treatment durations. Most HBBLs (67%) were not optimally dosed for bacteremia. Results were robust to multiple sensitivity analyses. Conclusions These real-world data suggest that oral stepdown therapy with FQs or TMP-SMX have similar effectiveness as IVBLs. HBBLs were associated with higher recurrence rates, but dosing was suboptimal. Further data are needed to define optimal dosing and duration to mitigate treatment failures.