The Urgent Need for Antibiotic Stewardship

Antibiotic overuse has led to an alarming rise in multidrug-resistant (MDR) uropathogens, particularly Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. These trends are pronounced not only in patients with neurogenic lower urinary tract dysfunction (NLUTD), many of whom require chronic catheterization and have frequent antibiotic exposures, but also in the nonneurologic population, mainly women with risk factors associated with sexual activity, climacteric, pelvic organ prolapse, and incomplete bladder emptying. Repeated antibiotic courses promote colonization with MDR organisms, often culminating in treatment-resistant infections, hospitalization, and increased morbidity.¹

Guidelines from the AUA; Canadian Urological Association; Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction; and the European Association of Urology emphasize the importance of judicious antibiotic use, especially avoiding prophylactic regimens when evidence does not support benefit.^1-3 Instead, an individualized approach emphasizing preventive strategies and alternative therapies is gaining momentum.

Reframing the Approach: Nonantibiotic Strategies

Behavioral and Mechanical Interventions

First-line strategies to reduce recurrent UTI (rUTI) risk in patients with NLUTD include bladder management optimization, clean intermittent catheterization, and reducing indwelling catheter use.⁴ There is a trend of reduced rates of UTI when hydrophilic catheters are used in clean intermittent catheterization, highlighted by several randomized controlled trials (RCTs) and systematic reviews.^1,2 Overall, the use of hydrophilic catheters appears to be associated with lower rates of UTIs and urethral trauma compared with other catheter types, particularly in individuals with spinal cord injury. Nevertheless, the literature presents mixed findings regarding the effectiveness of hydrophilic catheters in reducing the risk of UTIs among distinct patient populations who manage their bladder through intermittent catheterization. The heterogeneity of study designs and outcomes contributes to the ongoing debate on this topic. Adjunctive measures such as adequate fluid intake and double voiding are frequently recommended, although robust evidence remains limited.¹

Immunoprophylaxis, Vaccines, and Other Oral or Vaginal Nonantibiotic Prophylaxis

Cranberry may be offered as rUTI prophylaxis for women (moderate level of evidence); however, it has been demonstrated that cranberry does not reduce the risk of rUTI in NLUTD patients.^2,3 Methenamine hippurate was shown to be noninferior to antibiotic prophylaxis of rUTI (reduction to 1.38 vs 0.89 UTI events per person per year) and is a promising alternative.⁵ There is not enough evidence to allow recommendation in favor of the use of probiotics and D-mannose for prophylaxis.^1,3 OM-89, an oral immunostimulant derived from E coli extracts, has demonstrated moderate efficacy in reducing UTI recurrence in several randomized trials. A meta-analysis reported a significant reduction in UTI episodes with OM-89 compared with placebo (relative risk, 0.61; 95% CI, 0.48-0.78).⁶ Another recent meta-analysis of studies with substantial heterogeneity comparing 5 types of vaccination (StroVac, OM-89, ExPEC4V, MV140, and Solco-Urovac) showed that patients receiving immunostimulation had an approximately 50% lower risk of UTI compared with placebo (relative risk, 1.52; 95% CI, 1.05-2.20).⁷ Vaccines targeting E coli adhesins, such as FimH, are under investigation and represent a promising avenue.⁸

Intravesical Therapies

Intravesical instillation of hyaluronic acid and chondroitin sulfate aims to restore the glycosaminoglycan layer of the bladder. An RCT demonstrated that monthly intravesical hyaluronic acid–chondroitin sulfate significantly reduced UTI recurrence compared with placebo.⁹ Although data in NLUTD patients are limited, preliminary studies suggest similar benefit.¹⁰ Given the limited development of new antibiotics, there has been growing interest in modifying the route or regimen of existing antibiotics. One promising approach is the use of intravesical antibiotics, which offer enhanced local antibacterial effects while minimizing systemic absorption and, consequently, reducing the risk of systemic side effects. A systematic review about intravesical antibiotics, including gentamicin, neomycin/polymyxin, neomycin, or colistin, showed 78% and 88% reduction in symptomatic UTIs for prophylaxis and treatment groups, respectively.¹¹

Bacteriophage Therapy

Bacteriophages (phages)—viruses that selectively infect bacteria—are re-emerging as viable therapeutic agents, particularly for MDR infections. Phage therapy offers precision targeting, sparing the commensal microbiota and minimizing selective pressure for resistance. A recent RCT demonstrated that intravesical bacteriophage therapy was noninferior to standard-of-care antibiotic treatment with respect to both efficacy and safety in the management of UTIs in patients undergoing transurethral resection of the prostate.¹² Ongoing clinical trials are expected to further elucidate the potential role of this emerging therapeutic strategy in patients with NLUTD and recurrent UTIs.

Old Antibiotics and Novel Strategies

Fosfomycin tromethamine, a broad-spectrum oral agent, has demonstrated efficacy against MDR uropathogens, including extended-spectrum beta-lactamase–producing E coli. In NLUTD patients, repeated fosfomycin use has been well tolerated, with low resistance development.¹³ Pivmecillinam, another narrow-spectrum antibiotic, is also promising. A recent review demonstrated a favorable safety and tolerability profile, associated with low resistance rates. This drug was approved for uncomplicated UTI by the US Food and Drug Administration in April 2024.¹⁴

Conclusions

The management of rUTIs is undergoing a paradigm shift, driven by rising antimicrobial resistance and the need for stewardship. In populations with NLUTD and catheter dependence, tailored multimodal strategies integrating nonantibiotic approaches, immunoprophylaxis, and novel antimicrobials such as bacteriophages offer promising alternatives. Ongoing trials and translational research are expected to clarify optimal protocols and expand the therapeutic arsenal for this clinical challenge.

Conflicts of Interest: Dr Truzzi is a board member of and speaker for Apsen, Biolab, Coloplast, and Zambom. Dr Averbeck is a speaker for Apsen, Astellas, Adium, Coloplast, GSK, Medtronic, and Boston Scientific.