KEYWORDS: Hippuric acid, Cranberry, Urinary tract infections

JAMA Disses the Cranberry

By Alan R. Gaby, M.D.

Cranberry juice and cranberry extract have been used for many years to prevent and treat urinary tract infections (UTIs). There are several different mechanisms by which cranberry juice could be beneficial. First, cranberry extracts have been shown to prevent the adherence of uropathogenic strains of E. coli to human uroepithelial cells.¹ This inhibitory effect has been demonstrated both in vitro and in the urine of mice and humans after ingestion of cranberry juice.² The compounds in cranberries that are responsible for preventing bacterial adherence have been identified as proanthocyanidins (condensed tannins).³ Both cranberry juice and urine obtained after drinking cranberry juice have also demonstrated anti-adherence activity against Proteus spp. and Pseudomonas spp.⁴ Second, ingestion of cranberry juice produced a slight acidification of the urine in some, but not all, studies. Acidification of the urine may inhibit the growth of some uropathogenic bacteria. Third, cranberry juice has demonstrated potent antibacterial activity against E. coli and several other urinary pathogens in vitro.⁵ This effect may be due in part to hippuric acid, an antibacterial compound found in cranberry juice.⁶ While the concentration of hippuric acid in urine after consumption of cranberry juice is usually not sufficient by itself to inhibit bacterial growth,⁷ it is possible that the presence of hippuric acid enhances some of the other antibacterial actions of cranberry juice.

Numerous clinical trials have investigated the efficacy of cranberry juice or cranberry concentrate in tablets or capsules for preventing UTIs. Most,^{8, 9,10, 11,12,13,14,15,16,17,18} but not all,¹⁹ of the results have been positive, although cranberry juice was ineffective in children with neurogenic bladder.²⁰

Against this backdrop, a recent study published in the Journal of the American Medical Association (JAMA) concluded that administration of cranberry capsules daily for one year had no significant effect on the presence of bacteriuria plus pyuria in elderly women living in nursing homes.²¹ In actuality, the study was not entirely negative (as discussed below), and the authors did comment on some, though not all, of the limitations of their research. What prompted me to write this editorial was not the study itself, but the biased editorial that accompanied it.²² Here are some of the quotes from this editorial: “Any continued promotion of the use of cranberry products seems to go beyond available scientific evidence and rational reasoning. . . . The evidence . . . is convincing that cranberry products should not be recommended as a medical intervention for the prevention of UTI. A person may, of course, choose to use cranberry juice or capsules for whatever reason he or she wishes. However, clinicians should not be promoting cranberry use by suggesting that there is proven, or even possible, benefit. Clinicians who encourage such use are doing their patients a disservice. . . . It is time to move on from cranberries.”

Before commenting on the editorial, let’s first look at the study that prompted it. One hundred eighty-five women (mean age, 86.4 years) living in a nursing home were randomly assigned to receive, in double-blind fashion, two oral cranberry capsules (equivalent to 20 ounces of cranberry juice) or placebo once a day for one year. Bacteriuria was defined as at least 10⁵ colony-forming units per ml of one or two microorganisms in urine culture, and pyuria was defined as any number of white blood cells on urinalysis. The presence of bacteriuria plus pyuria was assessed every two months. The proportion of bimonthly evaluations that were positive for bacteriuria plus pyuria was nonsignificantly lower by 13.6% in the cranberry group than in the placebo group (25.5% vs. 29.5%). The number of symptomatic UTIs (10 vs. 12; 17% reduction), the incidence of bacteriuria associated with multidrug-resistant gram-negative bacilli (10.8 vs. 28.6 episodes per 100 person-years; 62% reduction), and the number of days of antibiotic administration for suspected UTIs (8.3 vs. 10.8 days per person per year; 23% reduction) was nonsignificantly lower in the cranberry group than in the placebo group.

Although not statistically significant, the results were consistent with a possible beneficial effect of cranberry. The lack of statistical significance may have been due to the study being underpowered. According to the authors’ calculations, a sample size of 180 (they actually enrolled 185) would have an 80% probability of detecting a 33% reduction in bacteriuria plus pyuria, assuming an overall bacteriuria plus pyuria rate of 45% in the control group and 20% attrition. A less-than-33% reduction in bacteriuria plus pyuria would have a less-than-80% chance of being statistically significant. Moreover, since the actual rate of bacteriuria plus pyuria in the control group was only 29.5%, a larger sample size would likely have been needed for there to be an 80% probability that a 33% reduction would be statistically significant.

Another potential weakness of the study was that the participants were not advised to consume liquid with the cranberry capsules. As the authors of the study suggested, it is possible that a fluid load is needed for cranberry capsules to be effective. In a previous study in which cranberry capsules decreased UTI incidence by 50%, participants were instructed to drink eight ounces of water twice a day along with the capsules.¹⁸

In addition, it is not clear whether the study participants were taking the cranberry capsules frequently enough for them to be beneficial. The overall adherence rate (determined by counting the unused capsules) was reported to be only 77.5%. This relatively low rate suggests that the nursing home staff that dispensed medications was not fully paying attention to the study protocol. One cannot rule out the possibility that staff members surreptitiously discarded some of the unused capsules in order to avoid the embarrassment of an even lower adherence rate. It has previously been reported that deception is common among noncompliers in clinical trials.²³

While the results of the new study were equivocal, they certainly do not negate the many studies showing a beneficial effect of cranberry products.

The author of the editorial cited several other studies to support her thesis that cranberry is ineffective for UTI prophylaxis. In one of these studies, the incidence of UTIs was 49% lower in patients given cranberry juice than in those given placebo.¹⁴ Although the results did not reach statistical significance (p = 0.12), a 49% improvement is hardly strong evidence that the treatment was ineffective. Another purportedly negative study was a small trial that was not designed to determine whether cranberry capsules are effective; rather, its goal was to determine whether it is feasible to administer cranberry capsules and to do clean catch urine collections among nursing home residents.²⁴ A third study compared cranberry capsules with antibiotic prophylaxis (trimethoprim-sulfamethoxazole) in women with recurrent UTIs. The editorial writer emphasized the fact that cranberry capsules were less effective than antibiotics but ignored the fact that cranberry capsules reduced the UTI recurrence rate by at least 43% compared with baseline.²⁵

One can reasonably question the quality of the evidence that supports the efficacy of cranberries, but to assert that cranberries have been proven to be ineffective is ridiculous. The editors of JAMA erred in allowing such a biased editorial to be published. Perhaps they need to take a vacation – at the beach, of course, where they can experience the joy of the ocean spray.