Reference
Beerepoot M, ter Riet G, Nys S, et al. Lactobacilli vs antibiotics to prevent urinary tract infections: a randomized, double-blind, noninferiority trial in postmenopausal women. Arch Intern Med. 2012;172(9):704-712.
Study Design
Randomized, double-blind trial of 15 months duration
Participants and Study Design
Postmenopausal women with recurring urinary tract infections (UTIs). A total of 252 women who had reported at least 3 symptomatic UTIs in the preceding year were randomized to a 12-month regimen of either trimethoprim-sulfamethoxazole 480 mg once daily (n=125), or a probiotic capsule of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 twice daily (n=127). Each capsule of probiotics contained at least 1 billion colony-forming units of the combination rhamnosus/reuteri.
The women were evaluated at baseline, monthly for 12 months, and then until 3 months after discontinuation of the study medication. Women recorded symptoms and collected urine, feces, and a vaginal swab once monthly.
Outcome Measures
Two primary outcomes and 2 secondary outcomes were evaluated. Primary outcomes included:
- average number of symptomatic UTIs over the course of the 12 months, and
- number of patients with a documented clinical recurrence and the average time from baseline until the first clinical UTI.
A clinical recurrence of UTI was defined as a UTI from the participant’s symptomatic report of dysuria, frequency, and/or urgency. Secondary outcomes included:
- average number of symptomatic UTIs confirmed by microbiology over the course of the 12 months of prophylaxis and the 3 months following discontinuation, which were called microbiological recurrences and were defined as a UTI based on both clinical symptoms and bacteriuria (> 103 DVU/mL bacteria); and
- number of women with serious adverse events.
Additionally, the effect of treatment on vaginal microflora and shifts in the Nugent score at baseline and at month 12 were compared. Development of resistance to the antibiotic was evaluated by measuring trimethoprim-sulfamethoxazole-resistant E. coli isolates from feces and urine at 1 month and 12 months after initiating treatment. The researchers also analyzed susceptibility of the E. coli isolates to other antibiotics.
Key Findings
After the 12 months of prophylaxis, the average number of recurrent symptomatic UTIs was 7.0 in the antibiotic group and 6.8 in the lactobacilli group. In the intention-to-treat analysis, this was 2.9 vs. 3.3, respectively. The between-group difference in the average number of UTIs per year was 0.4, equaling a 13.8% difference. At least 1 symptomatic UTI occurred in 69.3% of the antibiotic users and 79.1% of the lactobacilli users. Average time to the first UTI was 6 months for the antibiotic and 3 months for the lactobacilli group. After the first month of antibiotic prophylaxis, resistance to the study drug trimethoprim-sulfamethoxazole, as well as trimethoprim and amoxicillin, increased from a 20% to 40% range to about 80% to 95% in the feces and urine of women who were asymptomatic.
After the 12 months of antibiotic use, all the urinary isolates of E. coli in asymptomatic women were resistant to the study medication and trimethoprim. The resistance rates for other antibiotics such as ciprofloxacin and norfloxacin increased from 16% to 18% at baseline to 34% at month 13, which was 1 month after discontinuation of the antibiotic. There was no increase in E. coli resistance during lactobacilli use.
Secondary Outcome Results
The average number of microbiology recurrences was 1.2 in the antibiotic group and 1.8 in the lactobacilli group. Patients with at least 1 microbiology recurrence were 49.4% in the antibiotic group and 62.9% in the lactobacilli group. The average time to the first microbiology recurrence was 12+ months in the antibiotic group and 6+ months in the lactobacilli group.
E. coli was the most common organism cultured in both groups (76.0% for the antibiotic group, 69.1% for the lactobacilli group). After 1 month, 39.6% of the women in the antibiotic group had asymptomatic bacteriuria vs 44.7% in the lactobacilli group. After 12 months, it was 38.5% and 53.2% respectively.
The study also reported on uncomplicated vs complicated UTIs. The average number of clinical recurrences after 12 months in women with uncomplicated UTIs was 1.9 in the antibiotic group and 3.2 in the lactobacilli group but was 4.4 vs 3.4, respectively, in women with complicated UTIs, suggesting that lactobacilli was more effective in prophylaxis of complicated UTIs. The E. coli isolate of the urine of women with a history of complicated UTIs were also more often resistant to the trimethoprim-sulfamethoxazole (study medication), trimethoprim, and amoxicillin than in women with uncomplicated UTIs; after 1 month of using the study antibiotic, these differences disappeared.
There were no significant differences in serious adverse events between the antibiotic and lactobacilli group. Oddly enough, though statistically nonsignificant, a greater number of patients dropped out in the lactobacilli group due to diarrhea. One case of an allergic reaction was reported in the antibiotic group.
L. reuteri was not identified on vaginal swabs in either group at baseline or after the 12 months, and the mean Nugent scores were 6.1 for the antibiotic group and 5.8 for the lactobacilli group at baseline and 6.1 and 6.0, respectively, at the end of 12 months.
Commentary
It can be hard to track the multiple outcomes that were studied and reported on in this study. To make it simple: The women in both the antibiotic combination and the lactobacilli combination groups had a similar number of clinical UTI recurrences (7.0 vs 6.8 respectively with a reduction in recurrences of 2.9 vs. 3.3 respectively). There were slightly more microbiology recurrences in the lactobacilli group, and it took an average of 6 months to have a recurrence with the antibiotic combination vs 3 months with the probiotic. In cases of complicated UTI, women on the antibiotic combination had more episodes (4.4) than did women on the lactobacilli combination (3.4). In addition, women taking the antibiotic combo developed significant resistance to the drug, whereas those taking the lactobacilli combination did not experience an increase in antibiotic resistance.
Antibacterial medications are the mainstay of the conventional medical approach, but the use of longer-term antibiotic prophylaxis is associated with drug resistance and some adverse effects in many women.
When I first read this study, my first thought was, well, the lactobacilli combination didn’t work any better than the antibiotic, and in fact, in some parameters, it did not even work as well. But as I read it again and pondered it some more, I realized that if the lactobacilli combination of rheuteri and rhamnosus worked as well as the antibiotic in any parameter, that would in fact be noteworthy since it would be a possible alternative to the antibiotic. Yes, there were slightly more recurrent UTIs in the probiotic group and a shorter time to a recurrence in the probiotic group, but the lactobacilli were more effective in prophylaxis in women with complicated UTIs. Also, there was a significant rate of E. coli resistance in the antibiotic group that lasted as long as 1 month after discontinuing the antibiotic, and there was no E. coli resistance in the probiotic group.
Recurrent UTIs are common, especially in postmenopausal women and in sexually active reproductive-aged women. Recurrence rates are approximately 25%–30% in adult women. Antibacterial medications are the mainstay of the conventional medical approach, but the use of longer-term antibiotic prophylaxis is associated with drug resistance and some adverse effects in many women. Urogenital (bladder and vaginal)-specific species of lactobacilli present a viable alternative, with several in vitro and in vivo studies supporting the positive effects of select species and strains of lactobacilli on not only the prevention of recurrent UTIs, but also on the restoration of normal vaginal flora and in the management of acute and chronic yeast and bacterial vaginitis.
I gave a lecture at the 2011 AANP convention on vaginal ecology and addressed in detail the studies pointing this out for vaginitis. Most of the studies show that L. rhamnosus GR-1 and L. reuteri RC-14 (formally known as L. fermentum RC-14) when given either orally or intravaginally are quite effective. These species, as well as other select species, including L. crispatus and L. casei shirota have shown efficacy. In addition, L. acidophilus, L. plantarum, and L. salivarius have been shown to colonize and grow in the urogenital epithelium and have the ability to inhibit adherence of pathogens. The current study using L. rhamnosus GR-1 and L. reuteri RC-14 demonstrates an acceptable role for these probiotics in prophylaxis for recurrent UTIs—particularly when considering antibiotic drug resistance, which was significantly lower with the use of this particular combination.
