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Cranberry Juice

It always somewhat surprises me how some interventions never seem to die. Theophylline seems to have disappeared in the medical pantheon, but what comes around, goes around.  I predict a resurgence of theophylline this century.  Despite the recent study that shows, yet again, echinacea has no effect on colds, I predict the study will neither decrease the sales of echinacea nor prevent further funds being spent on clinical trials on its efficacy.  Hear that JREF?  I made predictions.  I will await my million dollar check. Make it out to Mark Crislip.

Another therapy that refuses to be put to rest, or even to be clarified, is the use of cranberry juice for urinary tract infections.  Pubmed references go back to 1962, and there are over 100 references.  Firm conclusions are still lacking.

There is a reasonable, but incomplete,  basic science behind the use of the cranberry juice for urinary tract infections.E. coli , the most common cause of urinary tract infections, causes infection in the bladder by binding to the uroepithelial cells.  To do this, they make  fimbriae,  proteinaceous fibers on the bacterial cell wall. Fimbriae are adhesins that attach to specific sugar based receptors on uroepithelial cells.  Think Velcro.  Being able to stick to cells is an important virulence factor for bacteria, but not a critical one; it is not the sine qua non of bladder infections.

Are all E. coli causing UTI’s fimbriated?  No.  It is the minority of E. coli that cause UTI that have fimbria, and the presence of fimbriae may be more important for the development of pyelonephritis (kidney infection) than cystitis (bladder infection).

The prevalence of uropathogenic Escherichia coli bearing type 1 and/or p fimbriae was assessed in 179 adult women with urinary tract infections, and the presence of specific fimbriae types was correlated with results of localization studies. E. coli with p fimbriae occurred more frequently in patients with clinically defined pyelonephritis (13 of 23 [57%]) than in women with cystitis (22 of 116 [19%]; P = .0004) or asymptomatic bacteriuria (6 of 40 [15%]; P = .0008), whereas organisms with type 1 fimbriae were equally distributed in these three patient groups. In contrast, the presence of p-fimbriated strains was not correlated with infection localized to the upper urinary tract by either the antibody-coated bacteria technique (among symptomatic women) or ureteral catheterization (among asymptomatic women). Thus although p fimbriation seems to be an important virulence factor associated with development of acute pyelonephritis in adult women, its detection appears not to be a useful localization test per se, and efforts to prevent these infections should not be directed against this factor alone.

and in children

P-fimbriae were present in 91% (33/35) of the urinary strains causing acute pyelonephritis. Among strains causing cystitis and asymptomatic bacteriuria P-fimbriae were found in 19% and 14% of cases, respectively.

So fimbriated E. coli account for a distinct minority of urinary tract infections.

What is the alleged mechanism by which cranberry juice is  beneficial in preventing urinary tract infections?   Cranberry juice, and some other fruits, contain  proanthocyanidins.  There is reasonable data that demonstrates that proanthocyanidins block adherence, usually of p fimbriated E. coli , to uroepithelial cells.  But not all E. coli:

Interestingly, proanthocyanidin shows a very strong inhibitory activity against mannose-resistant adhesins produced by urinary isolates of E. coli  but shows only moderate anti adherent activity against fecal E. coli isolates.

So the theory is that by taking cranberry juice, or cranberry pills, you will block the E. coli sticking to bladder cells and that will decrease the number of UTI’s.  The use of cranberry should be more beneficial as a preventative than as a treatment of cystitis and should be effective for a minority of patients.

There have been a variety of clinical trials, in different populations, to see if cranberry products are of benefit in the prevention of UTI’s and there has been variable efficacy.

There are, I am shocked, shocked to find,  problems with the studies.

First, no one has ever done basic pharmacokinetics on proanthocyanidins to see if there is, indeed, proanthocyanidins in the urine of patients who take cranberry products.

The closest they have come is that the urine of patients who consume cranberry juice  inhibits E coli binding to bladder epithelial cells.  Close.  But it may be something else in the urine that is leading to the decreased E. coli adherence.  I may complain about the pharmaceutical companies and the spin they put on their clinical studies, but at least they are nice (1) and methodical in elucidating the basic pharmacokinetics of their preparations.

Doing clinical trials without determining first if there is sufficient material that  CAN be effective, before showing that it IS effective,  is the homeopathic, and most SCAM, method of research.  No one has been methodical in their evaluation of cranberry juice, so we are left with a hodgepodge of incomplete  studies.

Imagine doing an antibiotic study where you neither tested the susceptibility of the organisms to the antibiotic before nor after you treated an infection.  It would be stupid.  You would have no idea if the therapy should or could have been effective.

Some populations where cranberry prodcuts has been tried, the neurogenic bladder, spinal cord injury and the elderly, have a radically different microbiology and epidemiology and one wonders if the basic principals behind the rationale for cranberry juice are even remotely applicable.  Fimbriated E. coli are the least of the reasons why these patients get cystitis.  It would have been nice if they had done the groundwork first.  It is the usual throw the feces at the wall, uncertain if feces are even the correct projectile,  see if anything sticks, and then trying to draw a target around it.

One study found  trimethoprim and cranberry juice equivalent in preventing recurrent UTI.  There was no placebo wing and  at best chronic antibiotics has only modest efficacy in preventing UTI’s, depending on the population studied.

So when the Cochrane review says

Cranberries (usually as cranberry juice) have been used to try and prevent urinary tract infections (UTIs). Cranberries contain a substance that can prevent bacteria from sticking on the walls of the bladder. This may help prevent bladder and other urinary tract infections. This review identified 10 studies (1049 participants) comparing cranberry products with placebo, juice or water. There was some evidence to show that cranberries (juice and capsules) can prevent recurrent infections in women. However, the evidence for elderly men and women was less clear, and there is evidence that is not effective in people who need catheterization. Many people in the trials stopped drinking the juice, suggesting it may not be a popular intervention. In addition it is not clear how long cranberry juice needs to be taken to be effective or what the required dose might be.

I think, well, the studies are so fundamentally flawed who knows what can really be said about the efficacy of cranberry juice.

As noted in the 2004 CID review,

Furthermore, results of the reviewed studies should not be viewed as conclusive because many of the trials suffer from various limitations, including lack of randomization, no or improper blinding, small number of subjects, short trial duration, large number of dropouts, and no reported intent-to-treat analysis. Perhaps the single most consistent limitation of these trials is the lack of uniformity regarding the intervention, including the particular cranberry product evaluated (juice, sweetened cocktail, or capsules/tablets), concentration, dosing regimen, and duration of the intervention, which greatly differed from study to study.

What good is a meta-analysis on crap?  If you collect individual cow pies into a larger pile, it does not transmogrify into gold.  Can you make any conclusions under those circumstances?  GIGO. Garbage in, garbage out, which, I am starting to think, should be the motto for some of the Cochrane reviews.

Which brings us to the most recent cranberry juice study,  Cranberry Juice Fails to Prevent Recurrent Urinary Tract Infection: Results From a Randomized Placebo-Controlled Trial, which has all the SBM words: prospective, randomized, double-blind comparison of the therapeutic efficacy of 8 oz of CJC drunk twice daily in preventing recurring UTI.

The cranberry juice “consisted of one 8-oz bottle (240 mL) containing a mean proanthocyanidin concentration of 112 mg per dose (range, 83–136 mg; standard deviation, ±14.1 mg),” but we have no idea there was any product in the urine.

At the end of the 6 month study period, there was no difference in relapsing UTI  between those who consumed cranberry juice and placebo.

We report results of a double-blind, randomized, placebo controlled trial of the effects of drinking cranberry juice on risk of recurring UTI among college-aged women. The trial was developed to detect a 2-fold difference in incidence of recurring UTI with alpha of .05 and power of 99%. The power was estimated assuming we would observe a 30% recurrence rate among controls, consistent with that reported in observational studies. Contrary to expectation, we found that drinking an 8-oz dosage of cranberry juice twice per day gave no protection against the risk of recurring UTI among college-aged women.

Does this put the issue to rest?  No.

You do not know if the formulation led to active drug in the urine and you do not know if the E. coli that predominated  as a cause of the UTI could have been prevented.  Were there recurrent infections the same E. coli ?  Or a new E. coli .  Were any of the E. coli fimbriated?  Given that the minority of E. coli should be inhibited by cranberry juice, it would be nice to know if the pre-study bacteria were fimbriated and if the post-therapy infections were also fimbriated.

And to complicated matters, ascorbic acid is found in both products which has been associated with decreased in UTI’s, although the studies have even less rigor than the cranberry juice studies.

But I would predict that the use of cranberry juice will have little effect on either the treatment or prevention of cystitis.  When it comes to infection prevention, targeting the bacteria rather that the underlying predisposing cause, is doomed to failure.  If you target the bacteria with an antibiotic, the organisms rapidly evolve resistance and you end up with the same infections rates, only with resistant organisms.

People get UTI’s for a reason: catheters, sex (not both at once), and/or genetics.  The bacteria take advantage of the underlying pathology  to infect people.  Even if the use of cranberry juice may decrease the number of UTI’s due to fimbriated E. coli, if the underlying reason for the cystitis is not addressed, then there will only be a substitution in the species of  bacteria causing infections, not a decrease in the rates of infection.

In the end, I would conclude that cranberry juice probably does not prevent UTI, and any effects are likely of little clinical value, given the relative rarity of organisms for which it could be effective. It would require a much larger study to prove or disprove efficacy, and not having proper microbiology renders all the studies to date probably worthless for coming up with worthwhile conclusions.

Forty years of evaluation and we are still left wanting. Still, I am sticking with the cranberry juice in my Cosmopolitan, but not for its UTI prevention.

Clarifications

(1) Nice as in The Nice and Accurate Prophecies of Agnes Nutter, Witch.

Posted in: Herbs & Supplements

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