Several non-antimicrobial related strategies to prevent recurrent acute uncomplicated UTIs have been published [
2]. Behavioral interventions include abstinence or reduction in frequency of sexual intercourse which is often not very feasible. Contraceptive methods such as spermicides and spermicide-coated condoms alter the vaginal flora and favor the colonization of uropathogens and should be avoided. Urination soon after intercourse, drinking fluids, not routinely delaying urination and wiping front to back have not been shown to be associated with a reduced risk of uncomplicated cystitis in case-control studies, but might be effective in some patients and are not unreasonable strategies to suggest for patients with recurrent cystitis. Cranberry juice, capsule or tablets are widely used by women to prevent UTI recurrences, but they have not been convincingly demonstrated to be effective in preventing such recurrences [
38]. There are some small studies, however, that suggest cranberry is effective and, given that this strategy appears to be benign, it is reasonable that women continue to use cranberry if they think that it has been effective.
Adhesion blockers such as
d-mannose are increasingly being used by women to prevent cystitis, but supportive data are sparse. In a recently published randomized study [
39] of 308 women with recurrent UTIs, investigators allocated patients into three groups: 2 grams of
d-mannose powder in 200 mL of water daily, 50 mg of daily nitrofurantoin or no treatment for 6 months. Patients in the
d-mannose group and nitrofurantoin group had a significantly lower risk of recurrent UTIs during the study compared to patients receiving no prophylaxis (RR 0.239 and 0.335,
p < 0.0001). Of concern, the authors did not present data for the
d-mannose group and the nitrofurantoin group separately, although they mentioned that the difference between the two groups was not significant. Interestingly, the authors noted that the time from starting prophylaxis to onset of symptoms did not differ significantly between the groups (presumably including the no-treatment group). Patients in the
d-mannose group had a significantly lower risk of side effects compared to patients in the nitrofurantoin group (RR 0.276,
p < 0.0001). Porru
et al. [
40], in a recent randomized cross-over pilot trial, evaluated the efficacy of
d-mannose in the treatment and prophylaxis of recurrent UTIs in 60 patients (mean age 42 years). Patients were randomly assigned to treatment and prophylaxis with TMP-SMX or to a regimen of oral
d-mannose 1 g every 8 h for 2 weeks followed by 1 g twice a day for 22 weeks. Patients were crossed over to the other intervention in the second phase of the study, with no further antimicrobial prophylaxis. Mean time to UTI recurrence was 52.7 days with antimicrobial treatment, and 200 days with
d-mannose (
p < 0.0001). Of note, however, the investigators used an unusual and unproven prophylactic regimen of TMP-SMX in the study (one week per month), observed a highly unusual rate of UTI recurrence in the 24-week period on TMP-SMX (91.7% of women had ≥1 recurrence compared with 20% of the
d-mannose women), and the authors do not describe how the data were analyzed for the crossover aspect of the trial. While neither of these studies provide convincing evidence that
d-mannose is effective in preventing cystitis, further studies of
d-mannose are clearly warranted to determine its pharmacokinetic properties and clinical efficacy.
Other non-antimicrobial strategies to reduce the risk of recurrent uncomplicated cystitis include replacement topical estrogen therapy in postmenopausal women, probiotics, oral immunostimulants and vaccination. Replacement topical estrogen normalizes the vaginal flora in postmenopausal women and has been shown to greatly reduce the risk of recurrent UTI in this population [
41]. Probiotics are widely used to prevent recurrent UTI but the published data to date remain unconvincing. Probiotics are touted to protect the vagina from colonization by uropathogens by steric hindrance or blocking potential sites of attachment, production of hydrogen peroxide which is microbicidal to
E. coli and other uropathogens, maintenance of a low pH, and induction of anti-inflammatory cytokine responses in epithelial cells. However, in a review of four randomized controlled trials of lactobacillus probiotics for bacterial genitourinary infections in women, only one demonstrated a significant reduction in rates of UTI recurrence [
42]. Moreover, most of these studies did not determine whether the probiotic led to vaginal colonization with the probiotic strain. While the probiotic approach has a credible scientific basis, additional adequately designed clinical trials need to be performed before its routine use can be recommended. Oral immunostimulants may have a role in UTI prevention. In a systematic review and meta-analysis of four trials that together included 891 participants, OM-89, an extract of 18 different serotypes of heat-killed uropathogenic
E. coli given orally to stimulate innate immunity, decreased the rate of UTI recurrence (RR 0.61, 95% CI 0.48–0.78) [
43]. The agent is commercially available in some European countries but not in the United States. Although there is great interest in developing a safe and effective UTI vaccine, there is no currently available product on the market.
Antimicrobial prevention strategies are highly effective for prevention of recurrent uncomplicated cystitis, but should be considered only as a last resort after non-antimicrobial strategies have been tried or considered and the potential risks of long term antimicrobials have been thoroughly discussed with the patient.