Cranberry (Vaccinium macrocarpon) and Urinary Tract Infection
By Marjorie Alschuler, PhD, and Melinda Ring, MD
Since the early 20th century, the health benefit most attributed to the cranberry is its role in maintaining urinary tract health. The International Food Information Council surveyed consumers in 1998 and found that 47% associated cranberry juice with urinary tract health.
Some physicians suggest drinking cranberry juice to avoid urinary tract infection (UTI).1 However, Cochrane reviews of studies of the use of cranberry juice or products in the prevention or treatment of UTI consistently have found no evidence of their effectiveness.2
Medicinal History
According to legend and accounts by early explorers, the American cranberry was used for both food and medicine by Native Americans in what was to become New England. They passed their recipes and cures on to the early colonists. From the 1600s to the 1800s, cranberries reportedly were used for a variety of complaints, including blood disorders, stomach ailments, liver problems, and fevers. In the 1800s, cranberries were used by seamen to prevent scurvy.
Epidemiology
UTI is a significant health problem, affecting millions of people each year. Only respiratory infections occur more often. Nearly 20% of women who have a UTI will have another, and 30% of those will have yet another. UTI is not as common in men, but can have serious sequellae if prostate and renal infections develop.3
Pathophysiology
Normal urine is sterile. Infection occurs when bacteria from the digestive tract, usually Escherichia coli, cling to the opening of the urethra and multiply.3 Women are especially prone to UTI, most likely because a woman’s urethral opening is near sources of bacteria from the anus and vagina. For many women, sexual intercourse seems to trigger an infection. Several factors that disrupt the normal microbial ecology of the vagina promote the development of a uropathogen-predominant vaginal flora as well as a propensity to recurrent UTI (see Table 1, below). Such factors include the use of spermicides for contraception, the recent use of b-lactam antimicrobials, and the postmenopausal state (when not supplemented by exogenous estrogen).4
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Table 1 |
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Risk factors for urinary tract infection |
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Urinary Tract Abnormalities
Catheterized Patients
Suppressed Immune System
Alteration of the Vaginal Flora
Pregnancy
Adapted from: Urinary Infections in Adults. National Kidney and Urologic Diseases Information Clearing-house, NIH Publication No. 01-2097, January 1999; and Stapleton A. Prevention of recurrent urinary-tract infection in women. Lancet 1999;353:7-8. |
UTI also may result from abnormalities of the urinary tract that obstruct the flow of urine, such as birth anomalies, kidney stones, or prostate hypertrophy. Other high-risk groups include the elderly and persons requiring intermittent or permanent catheterization due to spinal cord injuries or other nervous system disorders.3
Traditionally UTI is treated with antibacterial drugs, but these are expensive, can have side effects, and may lead to resistance. Therefore, physicians often suggest additional steps that patients can take on their own to avoid infection, including drinking cranberry juice.3 (See Table 2).
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Table 2 |
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Recommendations to patients for the prevention of recurrent urinary tract infection |
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• Drink plenty of water every day. • Drink cranberry juice every day.
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Urinate when you feel the need; don’t resist the urge
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Wipe from front to back to prevent bacteria around • Take showers instead of tub baths.
•
Cleanse the genital area before and after sexual • Avoid using feminine hygiene sprays and scented douches which may irritate the urethra.
Adapted from: Urinary Infections in Adults. National |
Pharmacology
Pharmacologically active ingredients include: pro-anthocyanidins, which are polymeric, high-molecular weight compounds that also are found in blueberries; acids (benzoic, citric, malic, and quinic), which pro-duce hippuric acid in the urine; and fructose.5 The single-strength juice is highly acidic (pH 2.5) and quite astringent, making the fruit juice unpalatable at full strength.1
Mechanism of Action
At one time, the bacteriostatic effect of cranberry juice was thought to result from acidification of the urine by generating high levels of benzoic acid. But cranberry does not acidify the urine and current belief is that cranberry juice works by preventing adhesion of bacteria to uroepithelial cells.
Proanthocyanidin inhibits the adherence of p-fimbriated E. coli and fructose inhibits the adherence of type-1 fimbriated E. coli to uroepithelial cells (fimbriae are proteinaceous fibers on the bacterial cell wall that produce adhesions that attach to receptors on uroepithelial cells). Proanthocyanidin is thought to be the prevailing inhibitor since other fructose-containing fruit juices do not exhibit extensive anti-adhesion properties. When unable to adhere, the causative bacteria are flushed, preventing their colonization of the urinary tract. Cranberry juice also may weaken attachment of E. coli to inert surfaces, thus controlling biofilm formation (colonization) on urinary catheters.6
Laboratory Studies
Lee et al tested cranberry juice in vitro to reassess whether it has true broad-spectrum direct antibacterial activity.7 They diluted a five-fold concentrate of the juice with a trypticase soy broth and adjusted the pH to 7.0 to ensure that results would not be confounded by the acidity of the medium. The antibacterial activity of this mixture was compared to that of plain broth when inoculated with quality-control strains of seven different bacteria: E. coli, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, Klebsiella pneumoniae, Proteus mirabilis, and Salmonella enteridis, and incubated at 35° C.
Bacterial counts were performed at 90 minutes and 24 hours. In all cases, the bacterial count in the plain broth was 106-108 times as high as that of the cranberry mixture. This group is now studying whether sufficient urinary concentrations of the active ingredients of cranberry juice can be achieved.
Clinical Studies
In 2001, the Cochrane Library published an updated review of the use of cranberries for the prevention and treatment of UTI.2 Selection criteria included all randomized or quasi-randomized controlled trials of cranberry juice/products for the prevention and treatment of UTI in susceptible populations of men, women, or children. Data were collected on methods, participants, interventions, and outcomes: UTI (symptomatic and asymptomatic), side effects, and adherence to therapy. For prevention, five trials met the inclusion criteria (four crossover, one parallel group). Four compared the effectiveness of cranberry juice vs. placebo juice or water, and one compared the effectiveness of cranberry capsules vs. placebo. The five trials were criticized for their poor quality ratings and small sample sizes. No trials met the inclusion criteria for treatment of UTI and no reliable evidence was found for the effectiveness of cranberry juice or products for the prevention or treatment of UTI.
Two small, more recent studies suggest there may be effectiveness. A pilot study (funded by Ocean Spray) of 15 spinal cord injured patients compared the reduction of bacterial biofilms on uroepithelial cells when patients consumed three glasses of cranberry juice per day vs. consumption of three glasses of water per day.8 Cranberry juice intake significantly reduced the biofilm load of Gram-positive and Gram-negative bacteria to cells (P = 0.013) compared to baseline. The authors concluded that these findings provide evidence in support of further, larger clinical trials into the use of functional foods, particularly cranberry juice, to reduce the risk of UTI in a patient population highly susceptible to morbidity and mortality associated with drug-resistant uropathogens.
Kontiokari et al compared the effectiveness of a cranberry-lingonberry juice with Lactobacillus GG drink in preventing the recurrence of UTI in 150 young (mean age 30 years) women with UTI caused by E. coli.9 The subjects had an average of six previous UTIs, and 85% had taken antimicrobials for a UTI in the year before enrollment. Subjects were randomly divided into three groups. Group 1 drank 50 mL of unsweetened cranberry-lingonberry concentrate diluted to 250 mL daily for six months. Group 2 drank 100 mL of 4 x 1010 colony-forming units Lactobacillus GG drink five days a week for one year. Group 3 served as an open control group. The main outcome measure was the first recurrence of symptomatic UTI. At six months, eight (16%) women in the cranberry group, 19 (39%) in the Lactobacillus group, and 18 (36%) in the control group had had at least one recurrence, reflecting a 20% reduction in absolute risk in the cranberry group compared to the other two.
These two later studies indicate positive results, but still suffer from major evidence-based limitations including small sample sizes, no blinding, and different primary outcomes. None have compared cranberry to antibiotics.10
NCCAM Research Initiative
The National Center for Complementary and Alternative Medicine (NCCAM) recently offered to provide funds for the support of basic and clinical research on the role of cranberry in the prevention and treatment of UTI.6
The NCCAM suggested that further research should be undertaken to:
- study the effect of cranberry in the prevention of UTI and as an adjunct to antibiotics in the treatment of UTI;
- demonstrate whether cranberry reduces symptomatic UTI; and
- conduct randomized controlled trials of longer duration in a broad array of patient types, especially younger women with symptomatic cystitis, as well as other patient groups with recurrent UTI.
Specifically, the objectives of this NCCAM initiative are to:
- conduct phase I/II clinical studies to assess dose, pharmacology, feasibility, safety, and biological efficacy of a variety of cranberry products to justify more definitive trials of their safety and efficacy;
- determine pharmacodynamics and pharmacokinetics of cranberry study agents in animal and/or clinical studies;
- conduct laboratory studies to validate mechanistic hypotheses; and
- support the characterization, standardization, and preparation of cranberry products, as well as production of clinical grade materials for testing in clinical trials sponsored by the National Institutes of Health.
Formulation and Dosage
The most popular cranberry beverage today is cranberry juice cocktail, which is a mixture of single-strength cranberry juice (at least 25% by volume), sweetener (sugar, artificial sweetener, or a fruit juice concentrate, such as grape or pear), water, and vitamin C.1 Recommended dosage is one glass daily, though clinical studies have used varying amounts.
Capsules also are available. Nature’s Herbs® produces 505 mg capsules containing fresh whole dried cranberry juice concentrate and 475 mg capsules containing whole cranberry fruit. Suggested dosage for both is 2-4 capsules three times daily with water, preferably at mealtimes.11 Some brands indicate that they contain proanthocyanidins as the active ingredient, though amounts are not mentioned. Other brands say they have been tested for bacterial "anti-adherence activity."12
Safety
Cranberry taken orally in normal food amounts appears safe, although ingesting large amounts may result in diarrhea and other gastrointestinal symptoms. Currently, there is insufficient reliable information available to assess the interaction of cranberry with dietary supplements, medications, foods, or laboratory tests.6 Cranberries are safe for pregnant and breast-feeding women if used as recommended.5
Conclusion
Centuries of anecdotal evidence and several limited trials point to the efficacy of cranberry products in the prevention of UTIs. A well-conducted in vitro study indicated that concentrated cranberry juice demonstrated antibacterial activity towards E. coli and other bacterial strains. The recent Finnish study of young women with recurrent UTI was the most significant to date, indicating a 20% reduction of recurrence. Some studies (though flawed), as well as anecdotal evidence, have indicated efficacy in reducing the recurrence of UTI in a variety of age groups and in catheterized patients. But the current preponderance of evidence does not demonstrate effectiveness in prophylaxis or treatment. The NCCAM call for research proposals may lead to a series of well-designed studies of dosage, pharmacology, feasibility, safety, and biological efficacy of cranberry products in the prevention and treatment of UTI.
Recommendation
Although prophylactic use of antimicrobial agents is still the cornerstone of pharmaceutical prevention of recurrent UTI, the frequency of side effects and the likelihood of the emergence of resistant bacteria call for the use of a safer option. Cranberry juice has been used as such a preventive. Because it is safe and well-tolerated, patients with a history of recurrent UTI, elderly and institutionalized patients, and those with indwelling catheters are regularly given cranberry juice for this purpose. Folklore, anecdotal evidence, and even some small studies appear to point to its success. But scientific evidence has yet to be produced. Perhaps the NCCAM-funded studies will succeed in accomplishing that. Until then, avoidance of risk factors and antibiotic therapy is recommended.
Dr. Alschuler is Medical Education Specialist, and Dr. Ring is Clinical Training Attending Physician and Coordinator, CAM Curriculum, Internal Medicine Residency Training Program, St. Joseph Hospital, Chicago, IL.
References
1. Henig YS, Leahy MM. Cranberry juice and urinary-tract health: Science supports folklore. Nutrition 2000; 16:684-687.
2. Jepson RG, et al. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2001;(3): CD001321.
3. Urinary Infections in Adults. National Kidney and Urologic Diseases Information Clearinghouse, NIH Publication No. 01-2097, January 1999. Available at: www.niddk.nih.gov/health/urolog/pubs/utiadult/utiadult.htm (last modified April 2001).
4. Stapleton A. Prevention of recurrent urinary-tract infections in women. Lancet 1999;353:7-8.
5. Bascom A. Incorporating Herbal Medicine into Clinical Practice. Philadelphia, PA: Davis Company; 2002.
6. Evans M. Cranberry (Vaccinium macrocarpon) and urinary tract infection. National Center for Complementary and Alternative Medicine Project Concept Review. Available at: http://nccam.nih.gov/research/ concepts/consider/cranberry.htm (last modified May 23, 2002).
7. Lee YL, et al. Does cranberry juice have antibacterial activity? JAMA 2000;283:1691.
8. Reid G, et al. Cranberry juice consumption may reduce biofilms on uroepithelial cells: Pilot study in spinal cord injured patients. Spinal Cord 2001;39:26-30.
9. Kontiokari T, et al. Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ 2001;322:1571.
10. Rand V. Cranberry for the prevention of urinary tract infection. Altern Med Alert 1999;2:116-118.
11. Alive Research Group. Natural Health Products Compendium. Blaire, WA: Natural Life Publishing, Inc.; 1998.
12. Howell A. Tablets may stop UTIs: Do cranberry pills work as well as juice in preventing urinary tract infections? Prevention 2002May:70.
Alschuler M, Ring M. Cranberry (Vaccinium macrocarpon) and urinary tract infection. Altern Med Alert 2002;5(11):125-129.
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