With an average incidence ranging between 0.5% and 1% of the population, bacterial cystitis is undoubtedly one of the most frequent infections in humans. The frequency of cystitis increases with advancing age, and is favored by a host of factors, including functional or anatomic alterations in the urinary tract, congenital malformations, prostate disorders, bladder surgery, urinary incontinence, catheterization, hindered urinary outflow, presence of bladder stones, diabetes, acquired immune deficiency syndrome, and bone marrow lesions. Approximately 90% of bladder infections are caused by Gram-negative bacteria, with a clear prevalence of germs of fecal origin. More than half of urinary infections are caused by E. coli
, with contributions from Enterococcus fecalis
, Pseudomonas aeruginosa
, Enterobacter cloacae
, Klebsiella pneumoniae
, and Proteus mirabilis
being less frequent.30
Notwithstanding the use of antibiotics, LUTIs are plagued by a high frequency of relapse (20%), especially in certain populations, including menopausal women, where the short length of the urethra combines with unfavorable changes in the vaginal microenvironment caused by decreased estrogen.30
Another population at increased risk of urinary infections is patients with cancer treated using pelvic radiotherapy, with an incidence ranging from 14% to 33%, depending on the type of cancer and radiation technique used.33
Consumption of cranberry juice and its extracts has been related to a decreased incidence of LUTIs.2
The mechanism of this effect has been widely debated but is still largely unknown. The older belief that acidification of urine underlies this action has been dispelled, mainly because of the observation that several bacterial strains sensitive to the action of cranberry extract actually develop well at low pH values. The activity of cranberry products has been consistently associated with their procyanidin content but, given that these compounds are not absorbed to a significant extent, a direct action seems unlikely, and various alternative theories have been proposed, including stimulation of secretion of an hitherto unidentified endogenous antibacterial agent.37
In in-vitro assays, cranberry procyanidins can significantly inhibit adhesion of pathogenic bacteria to the mucous membrane, preventing progression of infection.38
Without adhesion, bacteria cannot proliferate in the urinary tract and are eventually excreted. Inhibition of bacterial adhesion to the bladder wall has, in turn, been related to dose-dependent inhibition of specific structurally complementary carbohydrates on the surface of membranes and mucous cells.1
After intake of cranberry-based products, only procyanidin A2, a dimeric compound, has been detected in urine, while higher oligomers do not appear to be absorbed at all. Nevertheless, antiadhesive properties are maintained in the urine,42
an action that would be difficult to trace to the presence of procyanidin A2 alone.
The results of this study demonstrate that the beneficial effects of cranberry extract in prevention of LUTIs can be observed also in nonphysiologic situations, such as the acute bladder damage associated with high-dose irradiation. Pelvic radiotherapy is well known to induce inflammatory damage to and partial de-epithelization of the bladder mucosa, easily triggering bacterial infections and decreasing compliance with treatment. The data on coliform bacteria infecting 5/184 patients in the treatment group and 21/186 patients in the control group seems to be of special relevance, and an even more statistically significant result is observed when recurrent infections are also considered. Therefore, it seems surprising that use of cranberry extract in supportive care cancer had been largely overlooked in the clinical literature, with only two studies having been reported. The first was by Cowan et al,43
and was a placebo-controlled, double-blind study conducted in 128 female patients treated with radiotherapy or a combination of radiotherapy and chemotherapy for uterine cancer, with only a tendency towards reduction of the frequency of LUTI observed in the treatment group (82.5% versus 89.3% in the placebo group), with the difference failing to reach statistical significance. A limitation of that study was the use of cranberry juice as a nonstandardized preparation, so it is therefore unclear what dosage of proanthocyanidin was actually administered, the optimal dosage of which appears to be 36 mg/day.44
A second limitation was the reduced compliance observed in the treatment group, due to poor palatability of the cranberry juice, the strong acidity of which is generally buffered by addition of sugar.
The second study by Campbell et al also used cranberry juice for prevention (or at least attenuation) of bladder symptoms in patients undergoing pelvic radiotherapy, and had a negative outcome,45
with no significant difference observed between the cranberry-treated group and controls. In this study, the endpoint did not include the incidence of urinary infections, with only urinary symptoms being considered, and the 120 patients enrolled were randomly sorted into two equivalent groups treated with cranberry juice or apple juice. In addition to having the drawbacks discussed by Cowan et al, use of apple juice, which contains significant amounts of polyphenols, seems questionable. These design limitations were addressed in our study by using an enteric-coated and highly standardized cranberry extract and including a combination of objective (LUTI) and subjective (urinary discomfort) endpoints.
There were several reasons for using an enteric-coated cranberry extract. Proanthocyanidins are polyphenols and, as such, are strongly antioxidant. Like all antioxidants, they are rather unstable during processing and storage.28
Moreover, proanthocyanidins do interact with bacteria that colonize the stomach, like H. pylori
The possible presence of this strain in the stomachs of patients promptly reduces the proanthocyanidin content available to counteract E. coli
and other colonic pathogen bacteria in the gut. Enteric coating provides a solution to these potential problems. Therefore, enteric coating protects the active agents from environmental instability and prevents dissolution, but at pH values of about 6.0–6.8, as found in the duodenum, solving the potential problem created by the possible presence of H. pylori
. Last, but not least, enteric coating also minimizes loss of proanthocyanidins as a result of possible binding with proline-rich proteins in saliva and with biologic membranes on portions of enteric mucosa where proanthocyanidins are not absorbed in significant amounts.46
Despite the lack of randomization in this study, a clear-cut reduction in the LUTIs and bladder discomfort associated with pelvic irradiation was observed, with statistically significant differences in terms of dysuria, nocturia, and urinary frequency. It is possible that, because of its strong antioxidant properties, cranberry could attenuate actinic damage to the bladder mucosa, reducing the inflammatory process and, as a consequence, its symptoms. Full evaluation of this issue will require a further ad hoc study.