Despite a dramatic decline in mortality due to urinary tract infections (UTI) in the last 20 years, UTI’s remain very common in people with spinal cord injury (SCI) and particularly those with indwelling catheters (Biering-Sorenson, et al., 2001) and older individuals (High, 2001). Use of prophylactic antibiotics, particularly for asymptomatic cases of bacteriuria is controversial and discouraged. Thus, many people have been searching for alternative approaches. Cranberry juice has long been reported to prevent Urinary Tract Infection (Papas, et al., 1966; Kahn, et al. 1967). Much folklore and science support the use of cranberries to prevent urinary tract infections. As many as 40% of people with SCI take cranberry concentrates daily to prevent UTI’s. Are there any bases for this practice?
Avorn, et al. (1994) did a double-blind randomized clinical trial of 153 elderly woman who consumed 300 ml per day of a commercially available cranberry beverage or a synthetic placebo drink that was similar tasting and had vitamin C but lacked cranberry content. When they sampled the urine of these women, they found that those that drank the cranberry juice had only 27% incidence of bacteria in the urine, compared to 42% in those drinking the placebo (p=0.004). This led to some clinicians to recommend drinking 300-500 ml of cranberry juice cocktail each day (Fleet, 1994).
Foxman, et al. (1995) studied first-time UTI’s in young unmarried women using a university health service and who had engaged in sexual intercourse at least once. Compared against the general population of students, the study found that intercourse significantly increased the risk of UTI’s by 43% but that cranberry juice drinking reduced the risk by 52% and carbonated soft drinks increased the risk by 237%.
In 1999, Schlager, et al. did a double-blind placebo-controlled crossover trial that compared cranberry or placebo for three months and vice versa for three months in children with neurogenic bladders treated with Intermittent Catheterization. They found that 75% of 151 cultures indicated bacteriuria at both time intervals. It did not differ when the children were drinking cranberry or placebo concentrate.
Jepson, et al. (2000) recently did Cochrane Reviews of clinical trials on the use of cranberries for preventing or treating UTI’s. They found five trials that met the inclusion criterion of randomized and controlled trials to assess cranberry prevention of UTI. Two of the five trials indicated that cranberry therapy was effective in preventing symptomatic or asymptomatic UTI’s. They found no randomized trials that tested the efficacy of cranberry once the UTI has occurred. They pointed to the high dropout rates in all the trials, the small samples sizes, and called for more clinical trials.
Several clinical trials were reported in 2001 and were not covered by the Jepson (2000) review. The recent clinical trials again suggest opposing results. Two studies indicate beneficial preventative effects of cranberry and two studies suggest that cranberries do not differ from other juices and do not reduce bacteriuria. Nevertheless, the best designed trials with the most patients suggest that the cranberry intake reduces the incidence of UTI’s.
In Russia, Kirchhoff, et al. (2001) compared urine tract infection rates in two geriatric units. One unit drank cranberry juice while the other drank the usual mixed berry juice over a 4-week period. In all cases of suspected UTI, urine samples were cultured. In 140/338 cases, urine cultures revealed bacteriuria in 54% of the cases and antibiotic therapy of 44%. There was no difference in the rates of infections in the two units, suggesting no effect of cranberry juice intake on UTI rate.
In Finland, Kontiokari, et al. (2001) randomized 150 women with UTI’s due to E. coli to 50 ml of cranberry-ligonberry juice concentrate daily for 6 months, 100 ml of lactobacillus drink 5 days a week for a year, or no intervention. At 6 months, 16% of the women in the cranberry group, 39% in the lactobacillus group, and 36% in the control group had UTI’s.
Morris & Stickler (2001) studied volunteers who were inoculated with Proteus mirabilis (a common urinary tract bacteria) for 24-48 hours and then examined for the extent of Catheter encrustation. Volunteers who drank 500 ml of cranberry juice did not differ significantly from those who drank 500 ml of water. Note that volunteers who drank either cranberry juice or water had less encrustation than volunteers who did not supplement their normal fluid intake.
Reid, et al. (2001) examined 15 spinal injured patients, to see if cranberry juice altered bacterial biofilm load in the bladder. They found that cranberry juice significantly reduced biofilm load, with reduction in adhesion of both gram-positive and gram-negative bacteria to cells. Water intake did not change bacterial adhesions. [Note that Ocean Spray Cranberries funded this study.
Possible Mechanisms of Cranberry Effects on Infections
Direct antibacterial and anti-fungal effects of cranberry juice have long been reported (Swartz & Medrek, 1968; Borukh, et al. 1972; Ibragimov & Kazanskaia, 1981) although the mechanisms were not well understood. Early studies focused on the ability of cranberry juice to reduce urinary pH, i.e. Kinney & Blount (1979; Jackson & Hicks, 1997). Hippuric acid in cranberry juice reduces pH and may suppress infections (Nahata, et al. 1982; Simpson & Khajawall, 1983; Walsh, 1992) and enhance antibiotic activity (Chernomordik & Vasilenko, 1981.
Over 16 years ago, Sobota, et al. (1984) reported that cranberry juice inhibited bacterial adherence to the bladder surface in mice. They tested over 77 clinical isolates of the bacteria Escherichia coli (E. coli) and cranberry juice inhibited adhesion to the bladder by more that 75% for over 60% of the strains of bacteria. Schmidt & Sobota (1988) showed that this was true of many other bacteria besides E. coli, including Proteus, Klebsiella, Enterobacter, and Pseudomonas.
In 1989, in Israel, Zafriri, et al. confirmed that cranberry juice reduced expression of various surface lectins on E. coli isolated from bladder infections. Some of this effect apparently was due to the fructose (sugar) present in the juices but there was something else in cranberry juice that orange and pineapple juice did not. In 1991, Ofek, et al. reported a similar antiadhesion activity of cranberry and blueberry juice on E. coli adhesin activity. Ahuja, et al. (1998) reported that cranberry juice inhibited formation of fimbria that E. coli uses to attach to cellular surfaces and proposed that cranberry juice prevents expression of molecules in the bacteria that prevents fimbria formation and attachment. Cranberry extracts also reduce E. coli adhesion to glass (Allison, et al., 2000).
In 1999, Habash, et al. (1999) studied the effects of supplemental water, ascorbic acid, or cranberry concentrations on urine and bacterial adhesions to silicone rubber. Urine from people taking ascorbic acid and cranberry juice inhibited E. coli and enterococcus faecalis adhesion to silicone rubber but not pseudomonas, staphylococcus epidermidis, or Candida albicans. Interesting, people with increased water intake had “vastly increased” initial deposition rates and numbers of adherent E. coli and E. faecalis, suggesting that dilution of urine increased bacterial adhesion and that something in urine may inhibit such adhesion.
Cranberry have antioxidants that can scavenge free radicals. Of berries, blackberries, blueberries, cranberries, and raspberries have the higest antioxidant capacity (Wang & Jiao, 2000). Wilson, et al. (1998) showed that cranberry extracts reduce oxidation of low density of lipoprotein. Perderson, et al. (2000) studied the effects of blueberry and cranberry consumption of the plasma antioxidant capacity of healthy female volunteers. Daily ingestion of 500 ml of cranberry juice increased plasma phenolic content and antioxidant capacity. Consumption of a similar amount of blueberry did not have this effect, perhaps due to the higher vitamin C contents of cranberry.
Foo, et al. (2000) isolated the some chemicals from cranberry juice that might be responsible for its anti-infective traits. Three proanthocyanidin trimers, in particular, inhibited adhesion of E coli to cellular surfaces. Weiss, et al. (1998) likewise found a high-molecular weight molecule in cranberries that prevent aggregation of bacteria in the mouth. Burger, et al. (2000) isolated a high molecular weight constituent of cranberry juice which inhibited sialic acid specific adhesions of Helibacter pylori to mucus.
Side-Effects of Cranberries
None of the clinical trials reported significant side-effects of 300-500 ml of cranberry juice consumption. There have been no formal published clinical trials of the popular cranberry concentrates packaged in capsules. One recent study, however, suggest that people should be careful to limit their cranberry intake because it may lead to increased kidney stone formation.
Terris, et al. (2001) reported that dietary supplementation with cranberry concentrates increase blood and urine oxalate levels, and may contribute to more kidney stones. They gave manufacturer-recommended doses to 5 volunteers for 7 days and found a significantly increased level of urinary oxalate levels (p=0.01) by 43% in the cranberry group. Cranberries contain oxalates (2-26 mg per serving) but has much less than spinach (1236 mg), chocolate (126 mg), or tea (66 mg); only spinach has high enough levels to produce significant hyperoxaluria (Brinkley, et al. 1981). Oxalate is a component of the most common type of kidney stone. Cranberry juice may reduce the incidence of calcium stones (Light, et al., 1973).
In addition to ascorbic acid, cranberry juice contains a variety of substances that may be biologically active. For example, cranberries contain flavonoids called procyanidins and other phenolic compounds (Chen, et al., 2001). The levels of procyanidins in cranberry juice (31.9 mg per serving) is higher than red wine (22.0 mg) but lower than chocolates (165 mg) and apples (147 mg). Red delicious apples have the highest level (208 mg) compared with Granny Smiths (183 mg) and McIntosh (105 mg) varieties. Approximately 56% of cranberry juice are flavonoids and 44% are other phenolic compounds. Benzoic acid is the major phenolic compound while the major flavonoids are quercetin and myricetin. Of course, cranberries contain organic acids, including quinic, malic, and citric acid (Coppola, et al. 1978).
In comparison with the risks of antibiotic and other therapies being used to prevent and treat urinary tract infections, however, cranberries seem innocuous (Patel & Daniels, 2000). Cranberries rank in the top four most popular herbal remedies taken by Americans, i.e. garlic, aloe gel, cranberry and echinacea. A recent survey of patients at a large HMO indicate that over 40% of patients take one or more of these herbal remedies (Bennett & Brown, 2000).
Much anecdotal evidence supports the efficacy of cranberry juice in preventing urinary tract infection. Although there is a dearth of formal clinical randomized trials examining the risk of UTI, enough positive studies have been published suggesting that cranberry is better than other kinds of juices for preventing UTI’s. Some evidence suggest that there are special substances in cranberry juice that directly affect bacteria and their attachment to cellular surfaces. In addition, cranberry juice may have other salutory effects, including lowering pH and antioxidant activities.
At least three randomized clinical trials report that this amount of cranberry juice is necessary and sufficient to reduce the risk of UTI. Probably the most influential trial was in 1994, when Avorn, et al. at Brigham and Women’s Hospital in Boston showed that regular intake of 300 ml of cranberry juice more than halved the likelihood of bacteria and urinary infection, compared against a placebo drink with ascorbic acid. A recent trial in Finland (Kontiokari, et al. 2001) likewise showed that cranberry-ligonberry juice more than halved the incidence of urinary tract infections during a 6 month period, compared to a lactobacillus drink 5 days a week.
None of the trials reported significant deleterious side-effects from drinking 300-500 ml of cranberry juice per day. Jepson, et al. (2000) pointed out the high dropout rate of women from all the trials and the need for a rigorously randomized and placebo-controlled clinical trial involving larger populations to answer the efficacy question rigorously. These trials also did not test the most popularly used form of cranberry, i.e. 300-500 mg of cranberry concentrate per day in capsules.
Given the low risk and the potential benefits of a reduction of urinary tract infections, many physicians are encouraging their patients to drink 300-500 ml of cranberry juice per day. Insufficient data is available regarding the cranberry concentrates. A well-organized clinical trial that compares cranberry capsules and ascorbic acid in a large number of patients seems to be in order.
Cranberry Therapy of Urinary Tract Infections
Wise Young PhD MD, Professor II & Director
W M Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey
604 Allison Rd, Piscataway, NJ 08854-8082
tel: 732/445-2061, fax: 732/445-2063