Cranberries and Urinary Tract Infections

By Lynn Keegan, RN, PhD, AHN-BC, FAAN, Dr. Keegan is Director, Holistic Nursing Consultants, Port Angeles, WA; she reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.

Urinary Tract Infection (UTI) is one of the most common bacterial infections in women and has significant financial implications. About 60% of women experience at least one UTI during their lifetime, and up to 20% will experience recurrence.1

Various risk factors predispose women of different age groups to recurrence. These factors include sexual intercourse, use of contraception, antimicrobials, estrogen, genetics, and the distance of the urethra from the anus.

Of the different pathogens, Escherichia coli is the organism most commonly isolated. 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

A variety of treatment options has been proposed, including long-term or post-intercourse prophylaxis and patient-initiated therapy. Estrogen and cranberry juice have also been used as prophylactic treatment adjuncts. At present, these and other therapeutic and preventive modalities are being investigated, including the development of vaccines to treat those most severely affected.3

Cranberry Use

Until recently, antibiotics have commonly been used to decrease the frequency of acute episodes. Indeed, the majority of women referred to specialists for chronic UTI are prescribed long-term, low-dose antibiotic prophylaxis, but this can be 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 the immune response.

Food supplements based on cranberries are said to prevent recurrent urinary tract infections.4 Cranberries (particularly in the form of cranberry juice) have been used widely for several decades for the prevention and treatment of UTIs.5 A recent study has shown the juice or extract of cranberry (Vaccinium macrocarpon) should be used to prevent and treat UTIs.6

Although cranberry juice is the form of cranberries most widely used, other cranberry products include cranberry powder in hard or soft gelatin capsules. For additional information see the National Center for Complementary and Alternative Medicine's web page specifically for information about cranberries (available at: http://nccam.nih.gov/health/cranberry/).

Mechanism of Action

Cranberry, which is rich in polyphenols, including anthocyanins and proanthocyanidins, has been found to have various effects beneficial to human health, including prevention of UTIs. These effects have been associated with polyphenols in the fruit.7 The cranberry produces antimicrobial compounds as well, such as proanthocyanidins in response to microbial invasion.

In vitro, cranberry is able to prevent growth, adhesion, or biofilm formation of a large number of bacteria; clinically, cranberry juice has been shown to prevent UTI in women.8

Cranberry extracts and juices also contain quinic acid, which causes hippuric acid to be excreted in the urine. Because bacteria prefer an alkaline pH for growth, acidification was thought to be the mechanism of action.9 Traditionally, the juice was thought to cause acidification of the urine resulting in a bacteriostatic effect. However, more recent data have pointed researchers in a different direction.

It is now understood that the most important steps in the pathogenesis of UTIs are the colonization and adherence of uropathogens. Cranberries interfere with the adherence of uropathogens to uroepithelial cells. Therefore, cranberries are potential alternatives in the prophylaxis of UTIs.10

Summary of Past Research

Many of the clinical studies reported in the literature, and reported previously in this publication, have suffered 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 indicate 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, rate of bacteriuria, biofilm load, and urinary white and red blood cells, rather than UTI.

The National Center for Complementary and Alternative Medicine (NCCAM) developed a cranberry research initiative in 2003 to encourage quality research, both basic and clinical research, on the role of cranberry in the prevention and treatment of UTIs (see Table 1 for a summary of ongoing NCCAM-sponsored clinical trials).

Recent Clinical Trials

Two randomized controlled trials involving a total of about 300 young women showed that daily use of cranberry juice or tablets reduced the relapse rate for acute cystitis: On average, treating 100 women for one year prevented at least one urinary tract infection in 15-33 women.4 The daily doses were 7.5 g of concentrate in 50 mL of water, 750 mL of juice, or two tablets of concentrate. In elderly patients, two trials of cranberry-based products in hospitals or nursing homes showed a small reduction in the frequency of relapses.4

A Cochrane database search retrieved all randomized or quasi-randomized controlled trials (RCT) of cranberry juice/products for the prevention of UTI in susceptible populations.5 Information was collected on methods, participants, interventions, and outcomes (UTIs, symptomatic and asymptomatic, side effects, and adherence to therapy). Quality was assessed using the Cochrane criteria. Seven trials met the inclusion criteria.

The effectiveness of cranberry juice (or cranberry-lingonberry juice) vs. placebo juice or water was evaluated in six trials, and the effectiveness of cranberries tablets vs. placebo was evaluated in two trials (one study evaluated both juice and tablets). In two good quality RCTs, cranberry products significantly reduced the incidence of UTI at 12 months compared with placebo/control in women. One trial gave 7.5 g cranberry concentrate daily (in 50 mL), the other gave 1:30 concentrate in either 250 mL juice or in tablet form. There was no significant difference in the incidence of UTIs between cranberry juice vs. cranberry capsules.

A Japanese team investigated the excretion of anthocyanins in human urine after ingesting cranberry juice to determine how much is absorbed by the body.7 Eleven healthy volunteers consumed 200 mL of cranberry juice containing 650.8 mg total anthocyanins. Urine samples were collected within 24 hours before and after consumption. Six of 12 anthocyanins identified in cranberry were quantified in human urine by high-performance liquid chromatography coupled with electrospray ionization and tandem mass spectrometry. Among these, peonidin 3-O-galactoside, the second most plentiful anthocyanin in the juice, was found to be most abundant in urine within 24 hours, corresponding to 41.5 nmol (56.1% of total anthocyanins). The urinary levels of anthocyanins reached a maximum 3-6 hours after ingestion, and the recovery of total anthocyanins in the urine over 24 hours was estimated to be 5.0% of the amount consumed. This study found high absorption and excretion of cranberry anthocyanins in human urine.

In another double-blind, randomized, placebo-controlled, crossover study, each volunteer received at dinner (in addition to normal diet) a single dose of 750 mL of a total drink composed of: 1) 250 mL of the placebo and 500 mL of mineral water, 2) 750 mL of the placebo, 3) 250 mL of the cranberry juice and 500 mL of mineral water, or 4) 750 mL of the cranberry juice.11 Each volunteer took the four regimens successively in random order, with a washout period of at least six days between each change in regimen. The first urine of the morning following cranberry or placebo consumption was collected and used to support bacterial growth. Six uropathogenic E. coli strains, previously isolated from patients with symptomatic urinary tract infections, were grown in urine samples and tested for their ability to adhere to the T24 bladder cell line in vitro. There were no significant differences in the pH or specific gravity between the urine samples collected after cranberry or placebo consumption; however, the investigators reported a dose-dependent significant decrease in bacterial adherence associated with cranberry consumption. The investigators concluded that cranberry juice consumption provides significant anti-adherence activity against different E. coli uropathogenic strains in the urine compared with placebo.

The aim of another study was to determine whether consumption of sweetened dried cranberries elicits urinary anti-adherence properties against E. coli, as previously demonstrated with cranberry juice and/or sweetened cranberry juice cocktail, compared to unsweetened raisins.12 Uropathogenic E. coli isolates were obtained from five women with culture-confirmed UTIs. Four urine samples were collected from each subject. The first urine sample was collected before any study intervention. The second urine sample was collected 2-5 hours after consumption of one box (42.5 g) of raisins. The third urine sample was collected 5-7 days later. The final urine sample was collected 2-5 hours after consumption of approximately 42.5 g of dried cranberries. Of the urine samples collected after dried cranberry consumption, one demonstrated 50% anti-adherence activity, two demonstrated 25% activity, and two did not show any increased activity. None of the control urine samples and none of the post-raisin consumption samples demonstrated any inhibitory activity. Data from this pilot study of only five subjects suggest that consumption of a single serving of sweetened dried cranberries may elicit bacterial anti-adhesion activity in human urine, whereas consumption of a single serving of raisins does not.

Adverse Effects

Adverse effects appear to be negligible. However, several case reports of interactions with warfarin have been published, including one involving severe bleeding. Patients on vitamin K antagonists must be warned about this risk of interactions so that they avoid consuming cranberry-based products without medical supervision.4

Conclusion and Recommendations

Randomized studies have confirmed that the proanthocyanidin contained in cranberries can inhibit E. coli adhesion to the urothelium and could be useful to treat urinary infections. Clinical studies have shown that the incidence of acute cystitis decreased when treated with cranberries, confirming the probable benefit of this fruit as a prophylactic treatment for female cystitis. Cranberry juice and extract have biologic effects against bacterial adhesion in the bladder. Prescription modalities remain to be defined.6

Case reports of bleeding with concomitant warfarin use are the only significant adverse effects noted with this long-used folk remedy. (See Table 2 for practical tips patients can take to avoid a UTI). 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 comparing the effects of cranberry in children, adults, and the elderly.

References

1. No authors listed. Cranberry and urinary tract infection. Drug Ther Bull 2005;43:17-19.

2. Urinary Infections in Adults. National Kidney and Urologic Diseases Information Clearinghouse, NIH Publication No. 02-2097, July 2002. Available at: http://kidney.niddk.nih.gov/kudiseases/pubs/utiadult/index.htm. Accessed Jan. 5, 2007.

3. Franco AV. Recurrent urinary tract infections. Best Pract Res Clin Obstet Gynaecol 2005;19:861-873. Epub 2005 Nov 17.

4. No authors listed. Cranberry and urinary tract infections: Slightly fewer episodes in young women, but watch out for interactions. Prescrire Int 2006;15:145-146.

5. Jepson RG, et al. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2004;(2):CD001321.

6. Bruyere F. Use of cranberry in chronic urinary tract infections. Med Mal Infect 2006;36:358-363. Epub 2006 Jul 18.

7. Ohnishi R, et al. Urinary excretion of anthocyanins in humans after cranberry juice ingestion. Biosci Biotechnol Biochem 2006;70:1681-1687.

8. Kontiokari T, et al. Cranberry juice and bacterial colonization in children—a placebo-controlled randomized trial. Clin Nutr 2005;24:1065-1072. Epub 2005 Sep 27.

9. Jepson RG, et al. Cranberries for treating urinary tract infections. Cochrane Database Syst Rev 2000;(2):CD001322.

10. Beerepoot MA, et al. Non-antibiotic prophylaxis for recurrent urinary-tract infections. Ned Tijdschr Geneeskd 2006;150:541-544.

11. Di Martino P, et al. Reduction of Escherichia coli adherence to uroepithelial bladder cells after consumption of cranberry juice: A double-blind randomized placebo-controlled cross-over trial. World J Urol 2006;24:21-27. Epub 2006 Jan 6.

12. Greenberg JA, et al. Consumption of sweetened dried cranberries versus unsweetened raisins for inhibition of uropathogenic Escherichia coli adhesion in human urine: A pilot study. J Altern Complement Med 2005;11:875-878.