ABSTRACT Background Rising resistance and toxicity concerns with fluoroquinolones (FQs) and trimethoprim/sulfamethoxazole (TMP/SMX) have prompted interest in oral β‐lactams as alternatives for complicated urinary tract infections (cUTIs). This review evaluates the effectiveness, safety, and pharmacokinetic (PK) considerations of oral β‐lactams compared to FQs and TMP/SMX in these clinical contexts. A structured point‐counterpoint discussion explores their role in antimicrobial stewardship and patient‐centered therapy. Methods A systematic PubMed search identified studies published between January 2000 and December 2025. Eligible studies included randomized trials and observational cohort studies evaluating clinical effectiveness, microbiological outcomes, or safety of oral β‐lactams for cUTIs or bacteremic UTI compared with FQs or TMP/SMX. Outcomes of interest included treatment success, recurrence, adverse events, and PK considerations. Excluded studies involved special populations, nontraditional agents, or infections outside the scope of cUTI. Data were synthesized narratively due to heterogeneity in study design and outcome reporting. Results Seventeen observational studies met the inclusion criteria. Oral β‐lactams demonstrated comparable effectiveness to FQs and TMP/SMX for cUTIs, including bacteremic UTI, when dosed appropriately. Oral β‐lactams with high oral bioavailability (e.g., cephalexin, cefpodoxime, cefuroxime, amoxicillin/clavulanate), showed success rates exceeding 90%, but recurrence was higher when underdosed. Oral β‐lactams had lower adverse event rates (1.3%) compared to FQs (2.3%) and TMP/SMX (5.7%), but may carry limitations including frequent dosing, variable bioavailability, and susceptibility testing challenges. Conclusions Although not traditionally recognized as first‐line therapy, select oral β‐lactams demonstrated effectiveness comparable to FQs or TMP/SMX for cUTIs and bacteremic UTI and can serve as effective alternatives in appropriately selected patients. When optimally dosed, these β‐lactams achieve comparable outcomes with favorable safety profiles and antimicrobial stewardship advantages. Randomized trials are needed to confirm these observational findings and to better define optimal dosing strategies and shorter treatment durations.
Coyne et al. (2026) studied this question.