Introduction

Top Abstract Introduction Participants and methods Results Discussion References

Up to 60% of women have a urinary tract infection at some point in their life.¹ At least a third of women with urinary tract infection will experience a recurrence during the following year, with recurrence being most common in the age groups 25-9 and over 55 years.²

The bacteria causing urinary tract infection arise from the stools. Dietary changes can alter the balance of faecal bacteria.³ Vaccinium berries and products containing lactobacilli have been shown to act against the coliform bacteria that cause most urinary tract infections. ^{4 5} Cranberry juice prevents bacteriuria in elderly women,⁶ and locally administered lactobacilli prevent recurrences of urinary tract infections.⁷ To evaluate whether these products given orally are effective in preventing symptomatic recurrences of urinary tract infection we conducted an open, randomised, controlled trial.

	Participants and methods

Top Abstract Introduction Participants and methods Results Discussion References

Study population and design
We recruited women during 1993-7 from the Finnish student health service at the University of Oulu and the occupational health centre for the staff of Oulu University Hospital. Women who had a urinary tract infection caused by Escherichia coli (10⁵ colony forming units/ml in clean voided midstream urine) and were not taking antimicrobial prophylaxis were invited to participate. After giving informed consent, they were randomly allocated into three groups.

Sample size
We calculated the sample size based on the assumption that at least 30% of women will experience a recurrence of urinary tract infection within a year.² We considered a reduction in recurrences to 10% as clinically important. To detect such a reduction with a two tailed  of 0.05 and a power of 80%, we needed 70 women in each group. Recruitment had to be stopped prematurely because the cranberry juice supplier stopped producing the juice.

Statistical methods
We used the Kaplan-Meier method to analyse the cumulative first recurrence and the Breslow test to assess the differences in occurrences at the end of the study. We calculated the incidence density by adding the total number of episodes of urinary tract infection and the time at risk in each group and then calculating the rate of episodes per person year at risk.

	Results

Top Abstract Introduction Participants and methods Results Discussion References

A total of 150 women gave their informed consent and were randomly allocated into three groups, 50 in each. One subject in the lactobacillus group who was taking postcoital antimicrobials was excluded from the analysis. The groups were similar in their baseline characteristics with regard to the risk of urinary tract infection (table). Only 13 women dropped out of the study, usually because of moving away.

During the six months, eight (16%) women in the cranberry group, 19 (39%) in the lactobacillus group, and 18 (36%) in the control group had at least one episode of urinary tract infection. This is a 20% reduction in absolute risk in the cranberry group compared with the control group (95% confidence interval 3% to 36%, P=0.023, number needed to treat=5, 95% confidence interval 3 to 34). The numbers who had had a recurrence at 12 months were 12, 21, and 19 in the cranberry, lactobacillus, and control groups respectively. The cumulative first recurrence of urinary tract infection differed significantly between the groups throughout the trial (P=0.048 at 12 months; figure). Recurrence during the study period was significantly lower in the cranberry group than in the control group (P=0.014 at 6 months, P=0.052 at 12 months).

View larger version (18K): [in this window] [in a new window]   Cumulative rate of first recurrence of urinary tract infection during 12 month follow up in women receiving cranberry juice for six months, Lactobacillus GG drink for 12 months, or no intervention. The difference between groups was significant (P=0.023 at 6 months, 0.048 at 12 months). Occurrence of urinary tract infection was significantly lower in cranberry group than in control group (P=0.014 at 6 months, 0.052 at 12 months)

There were 98 episodes of urinary tract infection altogether during follow up, of which 21 (21%) occurred in the cranberry group, 39 (40%) in the lactobacillus group, and 38 (39%) in the control group. The difference of 0.36 in incidence densities per person year between the cranberry and control group was significant (95% confidence interval 0.03 to 0.68).

The causative bacterium was E coli in 80% of the episodes. The proportion of episodes caused by E coli did not differ between the study groups. The number of women with perianal or urethral cultures positive for lactobacilli at any time during follow up was similar in all three groups; there were 32 (71%) in the cranberry group, 33 (67%) in the lactobacillus group, and 37 (82%) in the control group.

No adverse events were reported except occasional complaints about the bitter taste of the cranberry juice.

	Discussion

Top Abstract Introduction Participants and methods Results Discussion References

Our study confirms the common belief that symptomatic recurrences of urinary tract infection can be prevented with cranberry juice. In a recent review, the previous evidence for this was found inconclusive,⁸ although earlier reports had suggested a beneficial effect.⁹ The daily consumption of 300 ml of cranberry juice reduced bacteriuria in postmenopausal women, but no beneficial effect was found among children with neurogenic bladder. ^{6 10} Our study population represented a typical group of women at risk of recurrences of urinary tract infection. Such women are also the most willing and able to take preventive measures. We thus believe that our result is of both medical and practical importance.

In the United States, over 11 million women each year receive antimicrobials for urinary tract infection, costing over $1.6bn (£1100m).¹ Antimicrobial treatment and prophylaxis has resulted in increasing resistance to antimicrobials among uropathogenic bacteria.¹¹ Cranberry juice provides an alternative tool for prevention of urinary tract infection that could result in decreased use of antimicrobials.

Action of cranberry juice
The berries of Vaccinium species such as cranberries and blueberries contain condensed tannins called proanthocyanidins. These can prevent the expression of the P fimbriae of E coli,⁴ which is the most common uropathogenic bacterium; its P fimbriae are thought to be the most important virulence factor in causing urinary tract infection. The blocking of fimbrial adhesion by cranberry juice prevents E coli and other gram negative bacteria from colonising the uroepithelial cells.^12-14 The juice may help to prevent urinary tract infection either by selecting less adhesive bacterial strains in the stool or by directly preventing E coli from adhering to uroepithelial cells, or by both of these mechanisms. ^{15 16} Our finding of no increase in recurrences after stopping cranberry prophylaxis supports the theory of bacterial selection in the stool.

Lactobacillus
The lactobacillus drink had no effect on urinary tract infection, possibly because we were unable to induce lactobacilli colonisation of the periurethral area. Lactobacilli have been shown to colonise the human intestine at doses of 10^8-10 cfu/day and to replace other bacterial species, especially coliform bacteria. ^{5 17} Consumption five times a week may have been too infrequent. Intravaginal administration of lactobacilli has been found to reduce the number of coliform bacteria in the periurethral area and the number of urinary tract infections after antimicrobial treatment.⁷ In postmenopausal women, vaginal lactobacilli are replaced by enterobacteriaceae, increasing the risk of bacteriuria. This process can be reversed by intravaginal administration of oestriol.¹⁸

Validity
We had to stop our trial prematurely because the manufacturer of the cranberry juice stopped producing it. However, the difference in the occurrence of urinary tract infection between the cranberry and control group was clear and constant even in this limited sample size. A compliance follow up sheet was returned by only half of the subjects, but the reports suggested that the compliance was good and the stratified analysis showed no differences between the subjects who did and did not return the follow up sheet.