Background and Rationale
Recurrent cystitis is common after menopause and burdens quality of life and healthcare use. Antibiotic prophylaxis is effective but may promote antimicrobial resistance with long-term use. Vaginal Lactobacillus with ultra-low-dose estriol can restore urogenital flora and potentially reduce rUTI and lower urinary tract symptoms. Comparative data versus nightly antibiotic prophylaxis-and effects on the urinary microbiome-remain limited. This trial directly evaluates clinical recurrence and microbiome modulation with nitrofurantoin versus a Lactobacillus/estriol vaginal tablet over 6 months.
Objectives
Primary objective: Compare the 6-month rUTI recurrence proportion between nitrofurantoin and Gynoflor.
Key secondary objectives: (a) time to first recurrence; (b) antimicrobial resistance patterns in breakthrough infections; (c) change in Thai RUTISS score; (d) Lactobacillus dominance and within-sample diversity of the urinary microbiome.
Key Endpoint Definitions
rUTI recurrence (primary): ≥1 symptomatic episode meeting clinical criteria with urine culture growth of a uropathogen during the 6-month follow-up (episodes during temporary treatment holds still count toward the endpoint).
Time to first recurrence: days from randomization to first qualifying rUTI.
Antibiotic resistance: susceptibility profile of cultured uropathogens from breakthrough infections, categorized per local laboratory standards.
Microbiome metrics: quantitative Lactobacillus abundance (qPCR) and alpha diversity indices from 16S rRNA profiling.
Design Overview
Open-label, two-arm, parallel RCT with 1:1 allocation by concealed, computer-generated block randomization. Follow-up is 6 months. Masking is not feasible due to intervention routes; laboratory personnel for microbiome and culture testing are shielded from allocation where practicable.
Interventions (Summary)
Nitrofurantoin arm: 100 mg orally once nightly through month 6.
Gynoflor arm: one vaginal tablet nightly for 14 days, then twice weekly (e.g., Monday/Friday) through month 6.
(Rescue treatment for symptomatic UTI follows standard of care; study prophylaxis resumes afterward to complete 6 months.)
Study Procedures (Selected)
Baseline (Day 0): consent, randomization, Thai RUTISS, urinalysis, urine culture, urinary microbiome sampling, BUN/creatinine.
Follow-up (Months 0-6): twice-weekly phone/Line check-ins to reinforce adherence and capture symptoms/adverse events; prompt clinical evaluation if UTI symptoms arise.
Month 6: repeat Thai RUTISS, urinalysis/culture, urinary microbiome sampling, BUN/creatinine.
Specimen handling: midstream clean-catch urine; UA \~20 mL, culture 5-10 mL, microbiome \~50 mL. Samples processed promptly or refrigerated at 4 °C ≤24 h if needed.
Laboratory Methods (Overview)
Urinary microbiome assays are performed at the Department of Medical Sciences: (1) qPCR estimating Lactobacillus abundance across time points; (2) 16S rRNA gene sequencing for community profiling and alpha diversity.
Sample Size and Analysis Plan (Pilot)
Approximately 100 participants (50/arm) are planned based on local feasibility for an initial pilot. Analyses will follow intention-to-treat with supportive per-protocol summaries. The primary endpoint will be compared between arms using a risk difference with 95% CIs and a chi-square or Fisher's exact test. Time-to-event data will be presented with Kaplan-Meier estimates and log-rank testing. Continuous outcomes (e.g., Thai RUTISS change) will use t-tests or Wilcoxon rank-sum as appropriate; paired pre/post within-arm changes will use paired tests. Missing outcome data will be handled by complete-case analysis with sensitivity analyses (e.g., worst-case imputation for the primary endpoint) if missingness \>5-10%.
Safety Monitoring and Adherence
Expected risks include nitrofurantoin intolerance (e.g., GI upset, hypersensitivity), local vaginal irritation, minor phlebotomy discomfort, and time burden. Adverse events are solicited during twice-weekly contacts and at visits; serious adverse events are reported per IRB policy. Given the low-risk profile and pilot scope, a formal DSMB is not planned; the PI and study team review safety at regular intervals. Adherence is promoted by structured reminders and documented via participant report during check-ins.
Data Management and Quality
Case report forms are source-verified against electronic medical records and laboratory outputs. Microbiome and culture laboratories follow internal QC procedures; analytical staff are kept unaware of allocation when feasible. Randomization files are access-restricted; analysis is pre-specified prior to database lock.
