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- Cranberry (Vaccinium macrocarpon)
- Urinary Tract Infections
| Date:
11-15-2012 | HC# 101231-460
|
Re: Cranberry Juice Intake Prevented Recurrent Urinary Tract Infections in Women 50 Years of Age and Older
Takahashi
S, Hamasuna R, Yasuda M, et al. A randomized clinical trial to evaluate the
preventive effect of cranberry juice (UR65) for patients with recurrent urinary
tract infection. J Infect Chemother.
September 8, 2012; [epub ahead of print]. doi: 10.1007/s10156-012-0467-7.
Recurrent
cystitis in women is often treated with prophylactic antimicrobial agents.
Associated with this treatment are high costs, the potential development of
resistant uropathogens, and adverse events. Cranberry (Vaccinium macrocarpon) juice is an attractive alternative; it is
significantly less expensive, does not induce bacterial resistance, and adverse
effects are rare (other than complaints about the taste). However, clinical
evaluations of its efficacy in treating recurrent urinary tract infections (UTIs)
have produced mixed results. These Japanese authors conducted a randomized,
placebo-controlled, double-blinded trial to examine the effect of cranberry
juice (UR65) or a placebo beverage on the rate of relapse in patients with UTIs
who had suffered multiple relapses.
The
24-week study was conducted at 40 urology clinics in Japan from October 2007 to
September 2009. Eligible subjects were outpatients aged 20 to 79 years with
exacerbation of acute uncomplicated cystitis or chronic complicated cystitis
with a history of multiple UTIs in the past year and in whom the efficacy of antimicrobial
agents was confirmed. Exclusion criteria were comorbid urological or systemic
disease, severe medical complications, cranberry allergy, and subjects
otherwise deemed ineligible by the clinic doctor.
Of
the 213 female subjects included in the study, 107 were randomly assigned to
Group A to receive cranberry juice (UR65) and 106 to Group P to receive the
placebo beverage. The color and taste of the drinks were adjusted to maintain
adequate blinding.
UR65
contained more than 40 mg of proanthocyanidins per 125 mL (Kikkoman Food
Products and The Nisshin Oillio Group; Tokyo, Japan). Subjects drank 1 bottle
(125 mL) of cranberry juice or the placebo beverage once daily at bedtime for
24 weeks. They visited a clinic every 4 weeks, during which time they were
interviewed about their symptoms and any adverse events.
The
primary endpoint was a UTI requiring antibiotic treatment. Upon being diagnosed
with a relapse, subjects discontinued the study beverage and were withdrawn
from the study. Only 1 subject reported an adverse event—a strong burning
sensation after drinking the study beverage for the first time. The beverage
was discontinued and the symptom was resolved by the next day.
The
authors report no significant difference in the UTI relapse rates between the 2
groups. Relapse was observed in 32 of 107 subjects (19.9%) in Group A and 38 of
106 subjects (35.8%) in group P. A subset of 170 subjects with acute
uncomplicated cystitis was analyzed separately, but again, no significant
difference between the 2 groups was found.
Further
analysis of the acute cystitis subset identified 52 subjects <50 years, and
118 subjects aged ≥50 years. No significant difference in relapse rate was seen
in the younger group; however, in the older subjects, a significant difference
in UTI relapse rates was seen in 16 of 55 subjects (29.1%) in Group A and 31 of
63 subjects (49.2%) in Group P (log-rank test, P=0.0425).
To
identify the factors responsible for UTI relapse in the ≥50-year-old subjects, a
multivariate analysis using Cox's proportional hazards model was conducted. The
results revealed that drinking cranberry juice had a marginally significant
effect in the prevention of UTIs (hazard ratio [HR], 0.545); that aging was
significantly associated with relapse (HR, 1.037); and that a history of recurrent
UTIs during the preceding year was not associated with relapse (HR, 0.909).
The
scientific literature contains conflicting reports regarding the efficacy of
cranberry products in preventing recurrent UTIs. Its prophylactic effect is supported
by experimental evidence. Cranberry inhibits the adherence of Escherichia coli to bladder cells,1
and this effect is proportional to the proanthocyanidin concentration in the
juice.2
The metabolism of the constituent quinic acid produces hippuric acid, which
acidifies the urine and exerts a strong bacteriostatic effect. However,
evidence that cranberry ingestion results in therapeutic concentrations of
these compounds is lacking.
A 2008 Cochrane
review3
concluded that over a 12-month period, cranberry juice may decrease the number
of recurrent UTIs, especially in the female sub-population (mostly
pre-menopausal or sexually active women). However, a 2011 placebo-controlled
study involving 319 college women reported there was no significant difference
in relapse rates.4
A systematic review analyzing 10 clinical trials published prior to November
2011 concluded that cranberry-containing products are associated with a protective
effect against UTIs but the reviewers cautioned that this finding should be
interpreted in the context of substantial heterogeneity across trials.5
The results of this Takahashi et al. study support the heterogeneity proviso,
as a clinical effect was only seen once the data set was restricted to the more
homogeneous acute cystitis sub-population.
A
key challenge in prevention studies is statistical power; the lower the
recurrence rate of the disorder, the more participants are required to detect a
significant difference. The ≥50-year-old group had a higher risk of UTI
recurrence (HR, 1.037). Conversely, the <50-year-old cohort was much smaller
and had a much lower risk of recurrent UTI (the relapse rate was only 12% in
the placebo group). The authors suggest that the lack of statistical
significance in the overall results may be due to those factors (and they may
also explain why some previous studies failed to detect any significant
differences).
Compliance
is also a substantial challenge in prevention trials. This study required
participants to drink the beverage every night for 168 nights. The authors
state that doctors "strictly confirmed the regular intake of the beverage,"
but with no other checks in place, protocol compliance must be questioned.
In
order to obtain more definitive results, future trials should enroll more
homogeneous high-risk subject pools, use more conservative estimates of relapse
rates to ensure sufficient statistical power, and employ more robust compliance
protocols such as random urine analysis.
―Shari
Henson
References
1Gupta K, Chou MY,
Howell A, Wobbe C, Grady R, Stapleton AE. Cranberry products inhibit adherence
of p-fimbriated Escherichia coli to
primary cultured bladder and vaginal epithelial cells. J Urol. 2007;177(6):2357-2360.
2Gupta A, Dwivedi M,
Mahdi AA, Nagana Gowda GA, Khetrapal CL, Bhandari M. Inhibition of adherence of
multi-drug resistant E. coli by
proanthocyanidin. Urol Res.
2012;40(2):143-150.
3Jepson RG, Craig JC. Cranberries for preventing urinary tract
infections. Cochrane Database Syst Rev.
2008;(1):CD001321. doi: 10.1002/14651858.CD001321.pub4.
4Barbosa-Cesnik C, Brown MB, Buxton M, Zhang L, DeBusscher J, Foxman B.
Cranberry juice fails to prevent recurrent urinary tract infection: results
from a randomized placebo-controlled trial. Clin
Infect Dis. 2011;52(1):23-30. 5Wang CH, Fang CC, Chen NC, et al. Cranberry-containing products for prevention of urinary tract infections in susceptible populations: a systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172(13):988-996.
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