Cranberries and Urinary Tract Infections
April 1, 2003
Cranberries and Urinary Tract Infections
By Lynn Keegan, RN, PhD, HNC, FAAN
There is a substantial gap between the viewpoints of urologists and lay people regarding urinary tract infections (UTI). Urologists spend some time thinking about UTIs, but little compared to the millions of women who consider UTI a major issue in their lives. There is substantial concern about the growing interest in "natural compounds" and probiotics that allow women to take charge of their health care. It is easy to understand this concern because UTIs are common, costly, and cause considerable morbidity.1
Prevelance
Infections of the urinary tract are common—only respiratory infections occur more often. Women are especially prone to UTIs for reasons that are poorly understood. One woman in five develops a UTI during her lifetime. UTIs in men are less common, but they can be very serious when they do occur. Nearly 20% of women who have a UTI will have another, and 30% of those will have yet another. Of the last group, 80% will have recurrences. Women who have had three UTIs are likely to continue having them. Four out of five such women get another within 18 months of the last UTI. Many women have them even more often.2
Most infections arise from one type of bacteria, Escherichia coli (E. coli), which normally lives in the colon. Often, recurrent infections stem from a strain or type of bacteria that is different from the infection before it, indicating a separate infection. Even when several UTIs in a row are caused by E. coli, slight differences in the bacteria indicate distinct infections.2
Cranberry Use
Women frequently use the juice or extract of cranberry (Vaccinium macrocarpon) to prevent and treat UTIs. The majority of women referred to specialists are prescribed long-term, low-dose antibiotics, but these are expensive, can have side effects, and may lead to resistance. Given the magnitude of this problem, it is safe to state that large numbers of women are experimenting with alternative remedies such as drinking cranberry juice or ingesting herbal remedies to enhance their immune response.
Although cranberry juice is the form of cranberries most widely used, other cranberry products include cranberry powder in hard or soft gelatin capsules. Cranberry has been ranked as No. 10 among top-selling herbs in the United States. This represents a 1.7% dollar share of the herb market.3
Canadian researchers believe that several forces are driving an expanded use of nutraceuticals, particularly functional foods and probiotics, as instruments of the restoration and maintenance of well-being. These include consumer desire to use natural rather than pharmaceutical products, the mounting scientific evidence that shows efficacy of certain nutraceutical products, and the increasing cost and continued failure of drugs to cure or prevent disease.4
Mechanism of Action
Cranberry extracts and juices contain quinic acid, which causes hippuric acid to be excreted in the urine; since bacteria prefer an alkaline pH for growth, acidification is thought to be the mechanism of action.5 Traditionally, the juice was thought to cause acidification of the urine resulting in a bacteriostatic effect. However, recent research has demonstrated that cranberry prevents adhesion of bacteria to uroepithelial cells. Proanthocyanidins with unique molecular structures and that exhibit potent bacterial antiadhesion activity have been isolated from cranberry fruit. Little is known about the bioavailability and structure-activity relationships of cranberry proanthocyanidins.6 Two different constituents of cranberries inhibit E. coli adhesion: Fructose inhibits the type 1 fimbrial adhesion and proanthocyanidins seem to inhibit the P fimbrial adhesion of uropathogenic strains.7
There is also a mechanistic basis and clinical support for use of Lactobacillus strains such as L. rhamnosus GR-1 and L. fermentum RC-14 to colonize the intestine and vagina and reduce the risk of intestinal and urogenital infections. For such alternative approaches to be successful, scientific rigor must be backed by public education and physician acceptance. Given the emergence of virulent and multidrug-resistant pathogens, it is important to be timely and move forward quickly to explore these treatment alternatives.4
Clinical Trials
The Cochrane Renal Group, a subset of the Cochrane Database System Review Company in Edinburgh, UK, developed a search strategy to assess the effectiveness of cranberries for the treatment of UTIs.5 Companies involved with the promotion and distribution of cranberry preparations were contacted; electronic databases and the Internet were searched using English and non-English language terms; and reference lists of review articles and relevant trials also were searched. The selection criteria included all randomized or quasi-randomized controlled trials of cranberry juice or cranberry products for the treatment of UTIs. Trials of men, women, and children were included. Reviewers independently assessed whether the studies met the inclusion criteria. Further information was sought from the authors of papers containing insufficient information to make a decision about eligibility. The reviewers’ found no trials that fulfilled all of the inclusion criteria and concluded that no well-designed randomized trials assessing the effectiveness of cranberry juice for the treatment of UTIs have been conducted.
In a second Cochrane investigation on UTI prevention, a small number of poor quality trials gave no reliable evidence of the effectiveness of cranberry juice and other cranberry products.8 The large number of dropouts/withdrawals indicated that cranberry juice may not be acceptable long term. Other cranberry products, such as cranberry capsules, may be more acceptable. On the basis of the available evidence, the researchers could not recommend cranberry juice for the prevention of UTIs in susceptible populations.
The use of cranberries also has been tried in other groups. One study examined the effect of cranberry prophylaxis on rates of bacteriuria and symptomatic UTI in children with neurogenic bladder receiving clean intermittent catheterization.9 The double-blind, placebo-controlled, crossover study included 15 children who received cranberry concentrate or placebo concentrate for six months (three months receiving one concentrate, followed by three months of the other). During each weekly home visit, a sample of bladder urine was obtained by intermittent catheterization. Signs and symptoms of UTI, medication usage, and juice consumption were recorded. During consumption of cranberry concentrate, the frequency of bacteriuria remained high. Of the 151 samples obtained during consumption of placebo, 75% (114) were positive for a pathogen compared with 75% (120) of the 160 samples obtained during consumption of cranberry concentrate. E. coli remained the most common pathogen during placebo and cranberry periods. Three symptomatic infections each occurred during the placebo and cranberry periods. No significant difference was observed in the acidification of urine in the placebo group vs. the cranberry group (median, 5.5 and 6.0, respectively). The frequency of bacteriuria in patients with neurogenic bladder receiving intermittent catheterization was 70% and cranberry concentrate had no effect on bacteriuria in this population.
In another study, seven juices (cranberry, blueberry, grapefruit, guava, mango, orange, and pineapple) were examined; only cranberry and blueberry prevented bacterial bladder adhesion.10 Although blueberries have not been studied as thoroughly as cranberries, they also may prove to be an alternative treatment for UTI.
A recent small, Canadian, pilot study of 15 patients with spinal cord injuries was done to determine whether alteration of fluid intake and use of cranberry juice altered the bacterial biofilm load in the bladder. Urine samples were collected at the start of study, on day 7 following each patient taking one glass of water tid in addition to normal diet, and on day 15 following each patient taking one glass of cranberry juice tid. The results showed that cranberry juice intake significantly reduced the biofilm load compared to baseline (P = 0.013). This was due to a reduction in adhesion of Gram-negative (P = 0.054) and Gram-positive (P = 0.022) bacteria to cells. Water intake did not significantly reduce the bacterial adhesion or biofilm presence. The 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. This study was funded by Ocean Spray Cranberries.11 It is also noteworthy that the U.S. Department of Agriculture sponsors ongoing studies to better understand the therapeutic effects of cranberries.12
Summary of Past Research
Many of the clinical studies reported in the literature suffer from major limitations, even those included in the Cochrane Library reviews. Many trials have not been controlled or randomized, and randomization procedures have not always been described. Crossover designs used in some studies may not be appropriate for studies of UTI. Other limitations include no blinding or failed blinding, lack of controlled diets or dietary assessment, use of convenience samples, and small number of subjects. Sample sizes have ranged from as few as 10 to as many as 192. Trials have been faulted for the large number of dropouts/withdrawals which may be indicative that cranberry juice is not acceptable over longer periods. Intention-to-treat analyses often were not applied. Most studies have been conducted in older or elderly patients. Very few have been in younger patients, with or without comorbidities. Primary outcomes have differed and often have been urinary pH, as well as rate of bacteriuria, biofilm load, and urinary white and red blood cells, rather than UTI.3
Upcoming Research
To assess the effectiveness of cranberry juice in treating UTIs, well-designed, parallel-group, double-blind trials comparing cranberry juice and other cranberry products vs. placebo are needed. Outcomes should include reduction in symptoms, sterilization of the urine, side effects, and adherence to therapy. Dosage (amount and concentration) and duration of therapy also should be assessed.
For aspiring researchers, the National Center for Complementary and Alternative Medicine has developed a recent cranberry research initiative (see Table 1) to support basic and clinical research on the role of cranberry in the prevention and treatment of UTIs. The funding mechanisms proposed for this initiative are R21 and R01 projects. Objectives include:
- 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 product(s) as well as production of clinical grade materials for testing in NIH-sponsored clinical trials.
Conclusion and Recommendations
Cranberry juice and extract have biologic effects against bacterial adhesion in the bladder. No significant adverse effects have been noted in this long-used folk remedy that is both safe and well tolerated. For those concerned about the high sugar content of cranberry juice, oral capsule extracts are an available option.
This area is ripe for more investigation. Studies could relate to dose intake, use of cranberry products in control and experimental groups combined with antibiotics, or contrasting and comparing the effects of cranberry in children, adults, and the elderly.
Table 2 describes conventional steps that one can take to avoid an infection.
| Table 1 |
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NCCAM suggested research topics for federal funding3
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| Table 2 |
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Conventional steps that a patient can take to avoid an infection
Source: National Kidney and Urologic Diseases Information Clearinghouse, NIH Publication No. 02-2097, July 2002. Available at: www.niddk.nih.gov/health/urolog/pubs/utiadult/utiadult.htm. Accessed Feb. 12, 2003. |
Dr. Keegan is Director, Holistic Nursing Consultants in Port Angeles, WA.
References
1. Miller JL, Krieger JN. Urinary tract infections cranberry juice, underwear, and probiotics in the 21st century. Urol Clin North Am 2002;29:695-699.
2. Urinary Infections in Adults. National Kidney and Urologic Diseases Information Clearinghouse, NIH Publication No. 02-2097, July 2002. Available at: www.niddk.nih.gov/health/urolog/pubs/utiadult/utiadult.htm. Accessed Feb. 12, 2003.
3. Klein 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. Accessed Feb. 12, 2003.
4. Reid G. The role of cranberry and probiotics in intestinal and urogenital tract health. Crit Rev Food Sci Nutr 2002;42(3 Suppl):293-300.
5. Jepson RG, et al. Cranberries for treating urinary tract infections. Cochrane Database Syst Rev 2000;2:CD001322.
6. Howell AB. Cranberry proanthocyanidins and the maintenance of urinary tract health. Crit Rev Food Sci Nutr 2002;42(3 Suppl):273-278.
7. Zafriri D, et al. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 1994;271: 751-754.
8. Jepson RG, et al. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2000; 2:CD001321.
9. Schlager TA, et al. Effect of cranberry juice on bacteriuria in children with neurogenic bladder receiving intermittent catheterization. J Peds 1999;135:698-702.
10. Ofek I, et al. Anti-Escherichia coli adhesion activity of cranberry and blueberry juices. N Engl J Med 1991; 324:1599.
11. 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.
12. Zheng W, Wang SY. Oxygen radical absorbing capacity of phenolics in blueberries, cranberries, chokeberries, and lingonberries. J Agric Food Chem 2003;51:502-509.