D-Mannose for Recurrent Urinary Tract Infection Prevention in Postmenopausal Women Using Vaginal Estrogen: A Randomized Controlled Trial

Up to 25% of women experience recurring urinary tract infections, which are typically managed through long-term antibiotic prophylaxis intended for common urogenital pathogens. Unfortunately, prolonged use of antibiotics can lead to several adverse effects such as allergic reactions, sequelae from microbiome alterations, drug interactions/toxicities, and antibiotic resistance. One commonly prescribed prophylactic therapy, vaginal estrogen therapy (VET), is used as a first-line nonantibiotic therapy for rUTIs. Although this approach does avoid antibiotic adverse effects, it also fails to eliminate the risk of rUTIs. The simple sugar of D-mannose has the ability to bind to bacterial-type 1 fimH adhesins, possibly preventing Enterobacteriaceae such as Escherichia coli from bonding to mannose-rich urothelium. Although evidence does support the efficacy of Dmannose in premenopausal women, there remains an absence of studies in postmenopausal women, as well as little evidence for its use in conjunction with VET. Because of this, the authors conducted this randomized controlled trial (RCT) named the NUTI (nutraceutical efficacy for recurrent UTI) for determining the efficacy of D-mannose for rUTI prevention in postmenopausal women with uncomplicated UTIs already using VET. Recruitment of NUTI participants occurred from March 1, 2018, to January 18, 2020 at the tertiary care center of the authors. Inclusion criteria were (1) postmenopausal women with rUTIs, (2) >= 1 prior uropathogen with susceptibility to D-mannose, and (3) VET use for at least 4 weeks before the initiation of the study. Exclusion criteria were (1) complicated UTIs, (2) incomplete bladder emptying, (3) current daily antibiotic UTI prophylaxis, (4) interstitial cystitis/painful bladder syndrome, (5) urothelial cancer, (6) known contraindication to VET, (7) non-English speaking, and (8) other clinical trial enrollment for UTI. Randomization of patients occurred following enrollment, to either the D-mannose or control (VET only) arm of the study. From 545 patients with rUTI, a total of 71 qualified, with 44 enrolling in the study. Of these, only 32 completed the 3-month trial. CONSORT details are clearly described. This small and randomized trial regarding the efficacy of D-mannose found it to be a well-tolerated medication with high adherence levels for daily use. Adverse events, even those related to gastrointestinal function, were mild and not significantly different between groups. Although the results indicated a slightly lower rate of rUTIs in the D-mannose group for postmenopausal women already using VET for prophylaxis, this difference was not statistically significant. Furthermore, the authors did not reproduce the significant level of protection from D-mannose previously published in premenopausal women with rUTIs. This further compromised their ability to detect a difference between groups and was not consistent with their predetermined power assumptions. The study was thereby halted early due to futility. The authors determined that D-mannose exhibited an ease of daily use, was well-tolerated, and (for women already using VET) had a possible association with a modest, nonstatistically significant reduction in rUTI incidence. However, future trials are also essential for determining D-mannose in combination with VET, and it bears a beneficial effect more significant than solitary usage of VET for postmenopausal women with rUTIs. The preliminary estimates of safety, efficacy, and adherence of D-mannose of this study can inform these future trials.