No abstract - Introduction: Cranberry is among the most commonly used natural health products in North America. Commercial cranberry products commonly are derived from the Vaccinium oxycoccos and V macrocarpon species, which are cultivated widely across the Northern hemisphere. Seventy percent of the cranberry crop in North America is controlled by a single manufacturer. Historically, cranberry fruits and leaves have been used for wound dressings, urinary disorders, diabetes, blood poisoning, diarrhea, and liver problems. More recently, cranberry has been used to prevent urinary tract infections (UTIs) and dental plaque. The scientific evidence regarding medicinal uses of cranberry in pediatric populations is presented in this article.

BACKGROUND: Cranberries have been used widely for several decades for the prevention and treatment of urinary tract infections (UTIs).

OBJECTIVES: To assess the effectiveness of cranberry products in preventing UTIs in susceptible populations.

SEARCH STRATEGY: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library) and the Internet. We contacted companies involved with the promotion and distribution of cranberry preparations and checked reference lists of review articles and relevant studies. Date of last search: January 2007.

SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-RCTs of cranberry products for the prevention of UTIs in all populations.

DATA COLLECTION AND ANALYSIS: Two authors independently assessed and extracted information. Information was collected on methods, participants, interventions and outcomes (UTIs - symptomatic and asymptomatic, side effects, adherence to therapy). Relative risk (RR) were calculated where appropriate, otherwise a narrative synthesis was undertaken. Quality was assessed using the Cochrane criteria.

MAIN RESULTS: Ten studies (n = 1049, five cross-over, five parallel group) were included. Cranberry/cranberry-lingonberry juice versus placebo, juice or water was evaluated in seven studies, and cranberries tablets versus placebo in four studies (one study evaluated both juice and tablets). Cranberry products significantly reduced the incidence of UTIs at 12 months (RR 0.65, 95% CI 0.46 to 0.90) compared with placebo/control. Cranberry products were more effective reducing the incidence of UTIs in women with recurrent UTIs, than elderly men and women or people requiring catheterisation. Six studies were not included in the meta-analyses due to methodological issues or lack of available data. However, only one reported a significant result for the outcome of symptomatic UTIs. Side effects were common in all studies, and dropouts/withdrawals in several of the studies were high.

AUTHORS' CONCLUSIONS: There is some evidence that cranberry juice may decrease the number of symptomatic UTIs over a 12 month period, particularly for women with recurrent UTIs. It's effectiveness for other groups is less certain. The large number of dropouts/withdrawals indicates that cranberry juice may not be acceptable over long periods of time. It is not clear what is the optimum dosage or method of administration (e.g. juice, tablets or capsules). Further properly designed studies with relevant outcomes are needed.

Urinary tract infection (UTI) refers to the presence of clinical signs and symptoms arising from the genitourinary tract plus the presence of one or more micro-organisms in the urine exceeding a threshold value for significance (ranges from 102 to 103 colony-forming units/mL). Infections are localized to the bladder (cystitis), renal parenchyma (pyelonephritis) or prostate (acute or chronic bacterial prostatitis). Single UTI episodes are very common, especially in adult women where there is a 50-fold predominance compared with adult men. In addition, recurrent UTIs are also common, occurring in up to one-third of women after first-episode UTIs. Recurrences requiring intervention are usually defined as two or more episodes over 6 months or three or more episodes over 1 year (this definition applies only to young women with acute uncomplicated UTIs). A cornerstone of prevention of UTI recurrence has been the use of low-dose once-daily or post-coital antimicrobials; however, much interest has surrounded non-antimicrobial-based approaches undergoing investigation such as use of probiotics, vaccines, oligosaccharide inhibitors of bacterial adherence and colonization, and bacterial interference with immunoreactive extracts of Escherichia coli. Local (intravaginal) estrogen therapy has had mixed results to date. Cranberry products in a variety of formulations have also undergone extensive evaluation over several decades in the management of UTIs. At present, there is no evidence that cranberry can be used to treat UTIs. Hence, the focus has been on its use as a preventative strategy. Cranberry has been effective in vitro and in vivo in animals for the prevention of UTI. Cranberry appears to work by inhibiting the adhesion of type I and P-fimbriated uropathogens (e.g. uropathogenic E. coli) to the uroepithelium, thus impairing colonization and subsequent infection. The isolation of the component(s) of cranberry with this activity has been a daunting task, considering the hundreds of compounds found in the fruit and its juice derivatives. Reasonable evidence suggests that the anthocyanidin/proanthocyanidin moieties are potent antiadhesion compounds. However, problems still exist with standardization of cranberry products, which makes it extremely difficult to compare products or extrapolate results. Unfortunately, most clinical trials have had design deficiencies and none have evaluated specific key cranberry-derived compounds considered likely to be active moieties (e.g. proanthocyanidins). In general, the preventive efficacy of cranberry has been variable and modest at best. Meta-analyses have established that recurrence rates over 1 year are reduced approximately 35% in young to middle-aged women. The efficacy of cranberry in other groups (i.e. elderly, paediatric patients, those with neurogenic bladder, those with chronic indwelling urinary catheters) is questionable. Withdrawal rates have been quite high (up to 55%), suggesting that these products may not be acceptable over long periods. Adverse events include gastrointestinal intolerance, weight gain (due to the excessive calorie load) and drug-cranberry interactions (due to the inhibitory effect of flavonoids on cytochrome P450-mediated drug metabolism). The findings of the Cochrane Collaboration support the potential use of cranberry products in the prophylaxis of recurrent UTIs in young and middle-aged women. However, in light of the heterogeneity of clinical study designs and the lack of consensus regarding the dosage regimen and formulation to use, cranberry products cannot be recommended for the prophylaxis of recurrent UTIs at this time.

Catheter associated urinary tract infections (CAUTI) linked with the uropathogens Escherichia coli (E. coli) and Enterococcus faecalis (E. faecalis) account for the majority of nosocomial infections acquired in the clinical environment. Because these infections develop following initial adhesion of the bacterial pathogens to the catheter surface, there is increased interest in developing effective methods to inhibit attachment of cells to biomaterials used in the manufacture of indwelling devices. High molecular weight proanthocyanidins (PAC) extracted from the North American cranberry (Vaccinium macrocarpon) were examined for their potential to reduce the initial adhesion of uropathogenic bacteria (E. coli CFT073 and E. faecalis 29212) to two model biomaterials, poly(vinyl chloride) (PVC) and polytetrafluoroethylene (PTFE). Well-controlled experiments conducted in a parallel-plate flow chamber (PPFC) demonstrated decreased attachment of both bacteria to PVC and PTFE when either the bacteria, biomaterial or both surfaces were treated with PAC. Most significant inhibition of bacterial adhesion was observed for the condition where both the bacteria and biomaterial surfaces were coated with PAC. Additional experiments conducted with nonbiological model particles demonstrate comparable extents of adhesion inhibition, supporting a nonbiospecific mechanism of PAC action. The results of this study are promising for the implementation of PAC in the clinical milieu for prevention of device associated infection as the proposed functional modification is independent of antibacterial mechanisms that may give rise to resistant strains.

Matrix metalloproteinases (MMPs) produced by resident and inflammatory cells in response to periodontopathogens play a major role in periodontal tissue destruction. Our aim was to investigate the effects of A-type cranberry proanthocyanidins (AC-PACs) on: (i) the production of various MMPs by human monocyte-derived macrophages stimulated with Aggregatibacter actinomycetemcomitans lipopolysaccharide (LPS), and (ii) the catalytic activity of recombinant MMP-1 and MMP-9. The effects of AC-PACs on the expression of 5 protein kinases and the activity of nuclear factor-kappa B (NF-kappaB) p65 in macrophages stimulated with LPS were also monitored. Our results indicated that AC-PACs inhibited the production of MMPs in a concentration-dependent manner. Furthermore, the catalytic activity of MMP-1 and MMP-9 was also inhibited. The inhibition of MMP production was associated with reduced phosphorylation of key intracellular kinases and the inhibition of NF-kappaB p65 activity. AC-PACs thus show potential for the development of novel host-modulating strategies to inhibit MMP-mediated tissue destruction during periodontitis.

Recent studies brought evidence regarding the potential beneficial effects of cranberry polyphenols for periodontal infections. In this study, we evaluated the capacity of a proanthocyanidin-rich cranberry fraction to protect macrophages and oral epithelial cells against cytotoxicity induced by bacterial components. U937 cells, differentiated into adherent macrophage-like cells, as well as oral epithelial cells were treated with cell wall or lipopolysaccharide preparations from periodontopathogens. Cell viability was monitored using a commercial MTT (3-[4,5-diethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. The cytoprotective effect was evaluated by pre-incubating human cells with a proanthocyanidin-rich cranberry fraction prior to treatment with the bacterial components at toxic concentrations. Among the various bacterial components tested, Peptostreptotoccus micros cell wall was found to be the most toxic for macrophages and epithelial cells and was thus selected for further analyses. Treatment of monocyte-derived macrophages with cell wall of P. micros (20 microg/ml) decreased the cell viability by approximately 50%. Adding the cranberry fraction prior to treating cells with P. micros cell wall dose-dependently protected monocyte-derived macrophages from the toxic effect. A dose-dependent cytoprotective effect of the cranberry fraction was also observed with oral epithelial cells treated with P. micros cell wall. This study suggests that cranberry polyphenols may exert a protective effect for host cells against the toxicity induced by bacterial components

OBJECTIVE: Bacteriuria is a usual complication of enterocystoplasty following cystectomy. Cranberry products may decrease the number of urinary tract infections because of a non-dialysable compound, a condensed tannin, the proanthocyanidin (PAC) type A. This study determined the effectiveness of treatment with a cranberry preparation highly dosed in proanthocyanidin A in prevention of repeated bacteriuria in patients with an ileal enterocystoplasty.

MATERIAL AND METHODS: Between November 2004 and November 2009, a controlled study was open to patients seen in consultation for follow-up after a radical cystectomy and ileal cystoplasty. Patients had a history of repeated urinary infection and/or bacteriuria during the pretreatment phase. During the treatment phase, patients received a cranberry (Vaccinium macrocarpon) preparation highly dosed in proanthocyanidin A (36 mg measured by the dimethylaminocinnamaldehyde method), one capsule a day. The primary endpoint was the absence of bacteria in urine culture. The secondary endpoints were the presence or absence of symptoms (pain, fever), continence status and upper excretory tract enlargement. Each patient was his or her own historical control.

RESULTS: Fifteen patients were included. The median duration of the period without treatment with cranberry compound was 18.5 (1-93) months. The median duration of the period with treatment with cranberry compound was 32.8 (13-60) months. There was a significant decrease in the number of positive urine cultures during cranberry compound treatment.

CONCLUSIONS: Treatment with a cranberry compound seems to be effective in reducing asymptomatic bacteriuria in patients with an ileal enterocystoplasty. These results need to be validated by further double-blind randomized studies.

STUDY DESIGN: Randomized, double blind, placebo-controlled trial with a crossover design.

OBJECTIVE: To evaluate cranberry tablets for the prevention of urinary tract infection (UTI) in spinal cord injured (SCI) patients.

SETTING: Spinal Cord Injury Unit of a Veterans Administration Hospital, MA, USA.

METHODS: Subjects with spinal cord injury and documentation of neurogenic bladder were randomized to receive 6 months of cranberry extract tablet or placebo, followed by the alternate preparation for an additional 6 months. The primary outcome was the incidence of UTI.

RESULTS: Forty-seven subjects completed the trial. We found a reduction in the likelihood of UTI and symptoms for any month while receiving the cranberry tablet (P0.05 for all). During the cranberry period, 6 subjects had 7 UTI, compared with 16 subjects and 21 UTI in the placebo period (P0.05 for both number of subjects and incidence). The frequency of UTI was reduced to 0.3 UTI per year vs 1.0 UTI per year while receiving placebo. Subjects with a glomerular filtration rate (GFR) greater than 75 ml min(-1) received the most benefit.

CONCLUSION: Cranberry extract tablets should be considered for the prevention of UTI in SCI patients with neurogenic bladder. Patients with a high GFR may receive the most benefit.

Cranberry juice (CJ) has biological properties that may provide health benefits. In this study, we investigated the influence of CJ (pH 5.5) on several activities in vitro associated with the development of Streptococcus mutans UA159 biofilms. The ability of CJ to influence the adherence of S. mutans to either saliva- (sHA) or glucan-coated hydroxyapatite (gsHA), and to inhibit the glucan production by purified glucosyltransferases adsorbed to sHA was determined. For the adherence assays, we used both uncoated and saliva-coated bacterial cells. Furthermore, we examined whether CJ interferes with the viability, development, polysaccharide composition and acidogenicity of S. mutans biofilms. A solution containing equivalent amounts of glucose, fructose and organic acids at pH 5.5 was used as negative control. The adherence of S. mutans (uncoated and saliva-coated) to either sHA or gsHA treated with 25% CJ (v/v) was remarkably reduced (40-85% inhibition compared to control: p 0.05), indicating that CJ effectively blocked the bacterial adherence to binding sites in salivary pellicle and in glucans. In contrast, when the bacterial cells alone were treated with CJ they adhered to the similar untreated surfaces. Cranberry juice (25%, v/v) also inhibited the activities of surface-adsorbed GTF B and C (70-80% inhibition compared to control, p 0.05). The effect of CJ on the viability of microorganisms in biofilms was not significant. Biofilm formation and accumulation were significantly reduced by topical applications of 25% CJ (v/v) twice daily with 1-min exposures (p 0.05). The biomass and insoluble glucan content of the biofilms in addition to its acidogenicity were significantly reduced by cranberry treatments (p 0.05). Our data show that cranberry juice inhibited glucan-mediated biofilm development and acid production, and holds promise as a natural product to prevent biofilm-related oral diseases.

Cranberry crude extracts, in various vehicles, have shown inhibitory effects on the formation of oral biofilms in vitro. The presence of proanthocyanidins (PAC) in cranberry extracts has been linked to biological activities against specific virulence attributes of Streptococcus mutans, e.g. the inhibition of glucosyltransferase (Gtf) activity. The aim of the present study was to determine the influence of a highly purified and chemically defined cranberry PAC fraction on S. mutans biofilm formation on saliva-coated hydroxyapatite surface, and on dental caries development in Sprague-Dawley rats. In addition, we examined the ability of specific PAC (ranging from low-molecular-weight monomers and dimers to high-molecular-weight oligomers/polymers) to inhibit GtfB activity and glycolytic pH drop by S. mutans cells, in an attempt to identify specific bioactive compounds. Topical applications (60-second exposure, twice daily) with PAC (1.5 mg/ml) during biofilm formation resulted in less biomass and fewer insoluble polysaccharides than the biofilms treated with vehicle control had (10% ethanol, v/v; p 0.05). The incidence of smooth-surface caries in rats was significantly reduced by PAC treatment (twice daily), and resulted in less severe carious lesions compared to the vehicle control group (p 0.05); the animals treated with PAC also showed significantly less caries severity on sulcal surfaces (p 0.05). Furthermore, specific A-type PAC oligomers (dimers to dodecamers; 0.1 mg/ml) effectively diminished the synthesis of insoluble glucans by GtfB adsorbed on a saliva-coated hydroxyapatite surface, and also affected bacterial glycolysis. Our data show that cranberry PAC reduced the formation of biofilms by S. mutans in vitro and dental caries development in vivo, which may be attributed to the presence of specific bioactive A-type dimers and oligomers.