Probiotics with prebiotics and cranberry side effects

Koradia P, Kapadia S, Trivedi Y, Chanchu G, Harper A. Probiotic and cranberry supplementation for preventing recurrent uncomplicated urinary tract infections in premenopausal women: a controlled pilot study. Expert Rev Anti Infect Ther. September 2019;17(9):733-740. doi: 10.1080/14787210.2019.1664287.

Urinary tract infections (UTIs) affect more than half of the women at some stage in their lives and a quarter of those often experience recurring UTIs. Bacteria associated with UTIs are most often Escherichia coli, but other species, namely Klebsiella pneumoniae, Proteus mirabilis, Citrobacter spp., and Enterobacter spp. can also cause infections. Current strategies for managing UTIs include lifestyle measures and antibacterial therapy. Women with recurrent UTIs are often treated with too low-dose daily antibiotic therapy as prophylaxis. However, routine use of antibiotics has been associated with the wide-spread emergence of antibiotic-resistant strains. Previous studies indicate that cranberry products delivering at least 36 mg of proanthocyanidins in divided daily doses are effective in preventing UTIs. Other studies indicate a connection between vaginal health, specifically a healthy microbiome, and a reduced incidence of UTIs. The approach of this study was to combine the benefits of cranberry with those of probiotics.

This randomized, double-blind, placebo-controlled, parallel group, pilot clinical trial investigated the efficacy of Bio-Kult Pro-Cyan® (BKPro-Cyan; ADM Protexin, Inc.; Somerset, United Kingdom) and cranberry extract (36 mg of cranberry proanthocyanidin [PAC]) delivered in divided doses for preventing recurrent uncomplicated UTIs in premenopausal adult women.

The study was conducted in four centers in India between August 2016 and June 2018. Premenopausal women between the ages of 18 and 55 years with a history of ≥ 2 episodes of uncomplicated acute UTIs in the previous six months, or ≥ 3 episodes within the previous 12 months were included. Additional inclusion criteria consisted of availability during the trial period, compliance with study protocol, avoidance of supplements/foods containing cranberries or probiotic supplements during the study, and either with an inability to get pregnant or using approved contraceptives during the study period. Women were excluded with active UTIs, use of antibiotics within two weeks of the screening, known allergy to treatment medications, use of natural products one month prior to the beginning the study, a positive pregnancy test, postmenopausal, use of corticosteroids, anticoagulants, antidepressants, other mood-stabilizing medications, and any other medication that could interact with the supplement, and significant illness and/or disease. Women were also excluded who had participated in any clinical trial within one month of this trial. A total of 115 women were screened; 23 did not meet inclusion criteria, and two withdrew prior to randomization. Ninety women were randomly assigned to the BKPro-Cyan (n = 45) and placebo (n = 45) groups. Five were lost to follow-up (n = 2) or withdrew consent (n = 3) in the BKPro-Cyan group, and four were lost to follow-up (n = 2) or withdrew consent (n = 2) in the placebo group.  

BKPro-Cyan contained cranberry extract, probiotics (Lactobacillus acidophilus PXN 35, Lactobacillus plantarum PXN 47), and vitamin A (retinyl acetate; 160 µg/capsule). Each capsule contained a minimum of 18 mg cranberry PACs and >500 million live probiotic microorganisms (>5 x 108 CFU/capsule). The placebo, cellulose with added coloring agent, was matched in color and shape to the intervention. Participants were instructed to take two capsules per day, one in the morning and one at night, with food for 26 weeks. Demographics, medical history, vital signs, hematology, biochemistry, serology, urinalysis, and urine culture were recorded at baseline. Participants were seen on days 45, 90, 135, and 180 (end of the study period). Vital signs, urinalysis, and pregnancy tests were conducted, and diary cards were evaluated. The number and percentage of UTIs were determined in both a full analysis set (FAS), including all randomized participants who received at least one dose of the study drug, and per-protocol population (PP), which included participants who maintained 80% compliance with the treatment protocol.

For both the FAS and PP populations, there were no differences between the two groups at baseline in terms of number of UTIs and demographic data. The majority of the women were either surgically sterile or of non-child-bearing potential. The remaining women used double-barrier contraception during the trial period. Three treatment-emergent adverse events (TEAEs) were reported in the BKPro-Cyan group including abdominal distention (n = 1) and diarrhea (n = 2). All TEAEs were considered related to the study drug; each resolved without treatment.

Following the 26-week study, statistically fewer women experienced UTIs in the BKPro-Cyan group compared to the placebo (P = 0.0053). The majority of the participants that experienced UTIs during the trial period experienced one episode in both treatment groups; however, significantly fewer women in the BKPro-Cyan group experienced UTIs (P < 0.05). The median time to first UTI from baseline was significantly longer in the BKPro-Cyan group compared to the placebo (P = 0.001). In the placebo group, the first UTI was reported four days after beginning the trial compared to 154 days in the BKPro-Cyan group. Mean duration of active UTIs was lower in the BKPro-Cyan group, but the difference was not significant. Fewer women in the BKPro-Cyan group required antibiotic treatment compared to the placebo (P < 0.05). The number of antibiotic courses and duration of antibiotic therapy were less in the BKPro-Cyan group compared to the placebo, but the results were not significant.

Urine culture tests were negative for both treatment groups at baseline. Urine cultures were identified on 18 occasions in the placebo group during the trial period. At the end of the study, four positive urine cultures were identified in 40 participants in the BKPro-Cyan group compared with one in 41 for the placebo groups.    

This study had several limitations including small sample size, inability to determine the ecological impacts of the treatment upon the microbiota of the participants, and inability to evaluate whether the combination of cranberry and probiotics in BKPro-Cyan is more effective than the individual components.

The authors conclude that BKPro-Cyan is safe and effective for preventing recurrent UTIs in premenopausal adult women. The authors suggest that the clinical benefits of oral probiotic and cranberry extract may reduce antibiotic use and further suggest that results of this pilot study should be confirmed.

A Harper is an employee of ADM Protexin International, Ltd. The other authors declare no conflict of interest.

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