Stepdown strategies for complicated gram-negative UTI with bacteremia

One of the hottest areas of debate in antimicrobial stewardship centers around duration and choice of therapy for gram-negative bacteremia. Shortening therapy from traditionally used 14-day regimens has been advocated, but just how short a course can be and how oral beta-lactams are best utilized in completing the course remain controversial issues. A recent study published in Open Forum Infectious Diseases provides insight.

Authors affiliated with Intermountain Health used patient data from 2016 to 2022 to simulate a trial in which patients with complicated urinary tract infection (i.e., structural or functional urologic abnormalities) with matching blood and urine cultures for Escherichia coli and Klebsiella species were classified into four groups based on antibiotics received once clinical stability was achieved: intravenous beta-lactams, oral fluoroquinolones, oral trimethoprim-sulfamethoxazole or high-bioavailability oral beta-lactams (amoxicillin, amoxicillin-clavulanate or cephalexin). Analyses centered on recurrence of infection up to day 60. In the study, 759 patients met inclusion criteria: 108 in the IVBL group, 289 in the FQ group, 73 in the TMP-SMX group and 214 in the HBBL group. Propensity for inclusion in groups was fitted according to patient demographics, infection severity, comorbidities, allergies and hospital size. Median time to oral switch was 3 days, and median total duration of antimicrobial therapy was 14 days.

As compared to the IVBL group, no difference was seen in recurrence in the FQ group (adjusted hazard ratio, 1.09; 95% confidence interval, 0.49-2.43) or the TMP-SMX group (aHR, 1.44; 95% CI, 0.54-3.87), but recurrence was significantly higher in the HBBL group (aHR, 3.83; 95% CI, 1.76-8.33). However, HBBLs were not optimally dosed for bacteremia in 57% (1,000 mg every 8 hours for amoxicillin; 875/125 mg every 8 hours for amoxicillin-clavulanate; 1 g every 6 hours for cephalexin) Short (≤ 10 days) duration of TMP-SMX stepdown therapy was also associated with recurrence (aHR, 5.26; 95% CI, 1.36-20.46), though, notably, patients receiving TMP-SMX were dosed 5 mg/kg every 12 hours rarely (4%) and tended to have more kidney stones.

While this study is limited by lack of true randomization (but adjustment) to account for imbalances between groups — the IVBL group had more comorbid conditions, urologic abnormalities and extended-spectrum beta-lactamase-producing organisms — it does add fuel to the notion that FQs and TMP-SMX may be preferred stepdown agents in complicated gram-negative urinary tract infection with bacteremia in patients who otherwise do not have relative contraindications to them. More study is needed regarding efficacy of beta-lactams in this context when they are more aggressively dosed. The exact duration of therapy (especially when TMP-SMX is used) also requires more study, but individualization of duration according to patient-specific factors should be considered.

(Veillette et al. Clin Infect Dis. Published online: April 2, 2024.)