After menopause only 25% to 30% of women have lactobacilli in the vagina. With estrogen replacement therapy this percentage may increase to 60% to 100% [15]. In a placebo-controlled study with intravaginal estrogens in postmenopausal women with recurrent UTIs, no intravaginal lactobacilli were present at baseline. After one month of treatment, in 22 out of 36 women in the estrogen group intravaginal lactobacilli were present, compared with zero of the 24 women in the placebo group (difference 61%, 95% confidence interval (CI) 45% to 77%). In the estrogen group the vaginal pH decreased from 5.5 to 3.8 (p < 0.001), while there was no change in the placebo group. The percentage of women with vaginal colonization with Enterobacteriaceae in the estrogen group decreased from 67% to 31%, but was virtually unchanged in the placebo group. The incidence of UTIs was lower in the estrogen group compared to the placebo group: 0.5 versus 5.9 episodes per patient year (p < 0.001) [16]. In another trial in which women received either an estradiol-releasing ring or no treatment, the vaginal estrogens reduced the proportion of women with a UTI by about one third [17]. Although vaginal estrogens reduced the number of UTIs, oral estrogens did not. In addition, oral estrogens are associated with coronary heart disease, venous thromboembolism, stroke, and breast cancer. Therefore, oral estrogens are not recommended in postmenopausal women to prevent recurrent UTIs [18].

The precise interaction of lactobacilli with the commensal flora and the host, and the mechanism of action by which they exert their beneficial effects are still largely unknown. However, specific lactobacilli strains seem to have the ability to interfere with the adherence, growth, and colonization of uropathogenic bacteria [19].

In the study by Baerheim et al. [20], 48 women were randomized to vaginal suppositories containing L. casei v rhamnosus, twice weekly for 26 weeks, or placebo. The study from Kontiokari et al. [21] was an open randomized trial in 150 women who had UTIs caused by E. coli. After being treated with antimicrobial agents for the UTI, they were randomly allocated to one of three groups. The first group received 50 mL of cranberry lingonberry juice per day, the second group took 100 mL of a Lactobacillus GG (4 × 10 ¹⁰ cfu) drink five days per week, and a third group received no further treatment. In both studies lactobacilli prophylaxis did not show an advantage in terms of UTI prevention compared to placebo or no treatment. Baerheim reported a monthly incidence of symptomatic UTI of 0.21 in the L. casei group and 0.15 in the placebo group (incidence rate ratio 1.41; 95% CI 0.88–1.98). Kontiokari also did not show a difference between Lactobacillus GG drink and no treatment. At 12 months 21 (42.9%) and 19 (38.0%) women in the lactobacillus and control groups, respectively, had a UTI. The mean number of UTIs experienced during the 12-months follow-up was 0.80 UTIs/patient in the lactobacilli-treated women compared to 0.76 UTI/patient in the control group.

In another double-blind placebo-controlled trial, 100 premenopausal women with at least one prior UTI in the last year were randomized to receive Lactobacillus crispatus containing intravaginal suppositories or placebo following antimicrobial treatment for an acute UTI. Recurrent UTI occurred in seven of 48 women (15%) receiving Lactin-V compared to 13 out of 48 women (27%) receiving placebo (Relative Risk (RR) 0.5; 95% CI 0.2–1.2). High-level vaginal colonization with L. crispatus (≥10⁶ throughout follow-up) was associated with a significant reduction in recurrent UTI only for Lactin-V (RR for Lactin-V 0.07; RR for placebo 1.1; p < 0.01) [22].

A trial of antibiotic prophylaxis and lactobacillus prophylaxis was undertaken in 252 postmenopausal women with recurrent UTIs. They were randomized to receive 12 months of prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX), 480 mg once daily or oral capsules containing 10⁹ colony-forming units of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 twice daily. The mean number of symptomatic UTIs in the year preceding randomization was 7.0 in the TMP-SMX group and 6.8 in the lactobacilli group. In the intention-to-treat analysis, after 12 months of prophylaxis, these numbers were 2.9 and 3.3, respectively. The between-treatment difference of 0.4 UTIs per year (95% CI, −0.4 to 1.5) was outside the non-inferiority margin of 10%. After one month of TMP-SMX prophylaxis, resistance to TMP-SMX, trimethoprim, and amoxicillin had increased from 20%–40% to 80%–95% in E. coli from the feces and urine of asymptomatic women, and among E. coli causing a UTI. During the three months after TMP-SMX discontinuation, resistance levels gradually decreased. Resistance did not increase during lactobacilli prophylaxis [23].

Many women use vitamin C to prevent UTIs, but only two trials, with contradictory results, have been reported. In the first study the effect of ascorbic acid on urine pH was studied in spinal cord injury patients. The study was designed to compare the baseline urine pH after the administration of placebo or 500 mg ascorbic acid four times daily. Of the 38 patients who began the study, only 13 completed it. A significant decrease in urine pH value was not observed. There was no clinical benefit from the use of ascorbic acid; two patients in the ascorbic acid and one patient in the placebo group developed a UTI between the sixth and eighth day after initiating the study [24].

The other, non-randomized, trial in 110 pregnant women reported that daily intake of a vitamin regimen with 100 mg ascorbic acid for three months reduced the incidence of symptomatic UTIs from 29.1% to 12.7% compared to a vitamin regimen without ascorbic acid [25]. However, it is difficult to evaluate these results, as the daily vitamin C dose was very low. In addition, it was unclear if a urine culture was done when the women had symptoms of a UTI.

Cranberries have been used in the prevention of UTIs for many years. The mechanism of action has not been completely elucidated. Based on in vitro studies, cranberries are thought to contain proanthocyanidins (PACs) that can inhibit adherence of P-fimbriated E. coli to the uroepithelial cell receptors [26]. In 2012, Stapleton et al. demonstrated in a placebo controlled trial that women randomized to cranberry juice had a concurrent but non-significant reduction in numbers of P-fimbriated E. coli in urine and in the rate of symptomatic UTIs [27].

The optimal PAC concentration, dosage regimen, and formulation are not known. In early studies with cranberries the chemical composition of available cranberry products was not standardized, and the dose not properly described. In more recent studies PAC standardized cranberry products have been used.

Based on the studies from Stothers [28] and Kontiokari et al. [21] in a Cochrane review from 2008, it was concluded that cranberry products significantly reduced the incidence of UTIs at 12 months (RR 0.65, 95% CI 0.46–0.90) compared with placebo/control in women with recurrent UTIs. However, in a more recent version of this Cochrane review it was concluded that cranberry products did not significantly reduce the occurrence of symptomatic UTI in women with recurrent UTIs. This difference is due to the inclusion of two additional trials in their meta-analysis. However, one of these studies was in women with an acute (not recurrent) UTI [29], and the other study [30] determined the effect of cranberry consumption on the amelioration of symptoms rather than on the incidence of recurrences.

In two studies, the effectiveness of cranberry extract was compared with low-dose antibiotic prophylaxis. In a study with 137 older women with two or more antibiotic-treated UTIs in the previous 12 months, the authors concluded that TMP had a limited advantage over cranberry extract in the prevention of recurrent UTIs in older women [31]. In a more recent study, it was shown that cranberry capsules are less effective than low-dose (480 mg) TMP-SMX in the prevention of recurrent UTIs in premenopausal women. However, in contrast to low-dose TMP-SMX, cranberries did not result in an increase in resistant micro-organisms in the commensal flora [32].

In vitro and in vivo animal studies have shown that d-mannose can inhibit the adhesion of Type 1 fimbria of uropathogenic bacteria to the uroepithelial cells [33]. Recently, the first randomized clinical trial that evaluated its effectiveness was published [34]. Three hundred and eight women with recurrent UTIs were randomized to receive daily 2 grams of d-mannose prophylaxis for six months, continuous antibiotic prophylaxis with nitrofurantoin, or no prophylaxis. The rate of recurrent UTI in the d-mannose group was 15%, compared to 20% in the nitrofurantoin group, and 60% in the group without prophylaxis. These initial findings are promising, but further clinical trials are needed.

The oral immunostimulant OM-89, an extract of 18 different serotypes of heat-killed uropathogenic E. coli, stimulates innate immunity by increasing neutrophils, macrophage phagocytosis, and the upregulation of dendritic cells. Four placebo-controlled studies [36,37,38,39], with a total of 891 patients with recurrent UTIs, evaluating the oral immunostimulant OM-89 have been reported. During the intervention period women used one capsule daily. The risk ratio for developing at least one UTI was significantly lower in the active treatment group (RR 0.61, 95% CI 0.48–0.78) and the mean number of UTIs was about half compared to placebo. Despite these initial promising findings, a recent trial did not demonstrate a preventive effect of OM-89 compared to placebo. Remarkably, in the same trial a preventive effect of nitrofurantoin was also not observed. Since the preventive effect of nitrofurantion is well-established [1], the lack of effect of nitrofurantoin and OM-89 might be due to the low number of UTIs that occurred during the study [40].

Urovac^® is a vaginal vaccine that contains 10 heat-killed uropathogenic bacterial species, including six different serotypes of uropathogenic E. coli, Proteus vulgaris, Klebsiella pneumoniae, Morganella morganii, and Enterococcus faecalis. This vaccine induces primarily immunoglobulin G and immunoglobulin A in the urogenital tract, thereby reducing potential colonization of the vagina and bladder with uropathogens [41]. In three trials comprising 220 women, all by the same group of investigators, placebo was compared with primary immunization [42], or with primary immunization with booster immunizations [41,43]. Primary immunization consisted of three vaginal vaccine suppositories at weekly intervals. Booster immunization consisted of three additional vaccine suppositories at monthly intervals. Primary immunization alone did not reduce UTI recurrence. However, following the booster immunizations there was a prolonged time to the first recurrence of UTI, compared to primary immunization only or placebo.