Intravesical Bacteriophages for Treating Urinary Tract Infections: A Randomised, Placebo-Controlled, Double-Blind Clinical Trial

Abstract

Background: Urinary tract infections (UTIs) are among the most prevalent microbial diseases and their financial burden on the society is substantial. Moreover, the continuing increase of antibiotic resistance worldwide is alarming. We aimed to determine whether intravesical bacteriophage therapy is effective to treat UTI. Methods: In this randomised, placebo-controlled, double-blind clinical trial 97 patients presenting with UTI were enrolled to receive intravesical Pyo bacteriophage (n=28), intravesical placebo solution (n=32), or oral antibiotic therapy (n=37). The primary outcome included clinical and microbiological treatment response. Secondary outcomes included safety parameters and quantitative microbiological urine assessments. Findings: At day seven, the treatment success rates were statistically similar between the three groups: Compared to the Pyo bacteriophage (5/28 (18%)) group, the placebo group had 9/32 (28%) (Odds Ratio (OR) 1.8, 95% confidence interval (CI) 0.52-6.2; p=0.352) and the antibiotic group had 13/37 (35%) (OR 2.49, 95% CI 0.77-8.1; p=0.129) successes. Also, adverse events were statistically similar between the three groups. They were seen in 6/28 patients (21%) in the Pyo bacteriophage group, in 13/32 (41%) in the placebo group (OR 0.4, 95% CI 0.13-1.25; p=0.116) and in 11/37 (30%) in the antibiotic group (OR 0.65, 95% CI 0.21-2.03; p=0.452). Interpretation: Beside antibiotics, bacteriophages and bladder irrigation appear to have specific but limited beneficial effects on UTI control. Moreover, the bacteriophage safety profile seems to be favourable. Although bacteriophages are not yet a valuable treatment option for UTIs, this randomized controlled trial provides new insights to optimize the setting for further large-scale clinical studies to define the role of bacteriophages for treating UTIs. Trial Registration: Trial registration number: ClinicalTrials.gov, number NCT03140085. Funding Statement: Swiss Continence Foundation (www.swisscontinencefoundation.ch) The Swiss National Science Foundation (www.snsf.ch) and the Swiss Agency for Development and Cooperation in the framework of the program SCOPES (Scientific cooperation between Eastern Europe and Switzerland, grant number 152304). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study protocol was approved by the institutional review board and ethical committee at TNCU (TNCU-02/283; Tbilisi, Georgia), complied with International Conference on Harmonization Guideline for Good Clinical Practice and the Declaration of Helsinki.