J Infect Chemother (2013) 19:112117

DOI 10.1007/s10156-012-0467-7

ORIGINAL ARTICLE

A randomized clinical trial to evaluate the preventive effect

of cranberry juice (UR65) for patients with recurrent urinary
tract infection
Satoshi Takahashi Ryoichi Hamasuna Mitsuru Yasuda Soichi Arakawa

Kazushi Tanaka Kiyohito Ishikawa Hiroshi Kiyota Hiroshi Hayami

Shingo Yamamoto Tatsuhiko Kubo Tetsuro Matsumoto

Received: 4 July 2012 / Accepted: 8 August 2012 / Published online: 8 September 2012
Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2012

Abstract We examined the rate of relapse, as a variable
index, in patients with urinary tract infection (UTI) who
suffered from multiple relapses when using cranberry juice
(UR65). A randomized, placebo-controlled, double-blind
study was conducted from October 2007 to September
2009 in Japan. The subjects were outpatients aged 20 to
79 years who were randomly divided into two groups. One
group received cranberry juice (group A) and the other a
placebo beverage (group P). To keep the conditions blind,
the color and taste of the beverages were adjusted. The
subjects drank 1 bottle (125 mL) of cranberry juice or the
placebo beverage once daily, before going to sleep, for
24 weeks. The primary endpoint was relapse of UTI. In the
group of females aged 50 years or more, there was a sig-
nicant difference in the rate of relapse of UTI between
groups A and P (log-rank test; p = 0.0425). In this
subgroup analysis, relapse of UTI was observed in 16 of 55
(29.1 %) patients in group A and 31 of 63 (49.2 %) in
group P. In this study, cranberry juice prevented the
recurrence of UTI in a limited female population with
24-week intake of the beverage.
Keywords Recurrent urinary tract infection
Cranberry

Prevention
Introduction
Recurrent cystitis, especially in females, is likely to develop
in a not negligible female population worldwide. In this
situation, unplanned antimicrobial agents are administered
repeatedly to the patients and this can be generally

S. Takahashi (&) K. Ishikawa

Department of Urology, Sapporo Medical University School
of Medicine, S1, W16, Chuo-ku, Sapporo 0608543, Japan
e-mail: stakahas@sapmed.ac.jp
S. Takahashi
R. Hamasuna
M. Yasuda
S. Arakawa

K. Tanaka
K. Ishikawa
H. Kiyota
H. Hayami

S. Yamamoto
T. Kubo
T. Matsumoto
Japanese UTI Research Group, Kitakyushu, Japan
R. Hamasuna
T. Matsumoto
Department of Urology, University of Occupational
and Environmental Health, Kitakyushu, Japan
M. Yasuda
Department of Urology, Graduate School of Medicine,
Gifu University, Gifu, Japan
S. Arakawa
K. Tanaka
Division of Urology, Department of Surgery Related
Faculty of Medicine, Kobe University Graduate School
of Medicine, Kobe, Japan
Department of Urology, School of Medicine,
Fujita Health University, Toyoake, Japan
H. Kiyota
Department of Urology, The Jikei University Katsushika
Medical Center, Tokyo, Japan
H. Hayami
Department of Urology, Graduate School of Medical
and Dental Sciences, Kagoshima University, Kagoshima, Japan
S. Yamamoto
Department of Urology, Hyogo College of Medicine,
Nishinomiya, Japan
T. Kubo
Department of Public Health, University of Occupational
and Environmental Health, Kitakyushu, Japan

123
J Infect Chemother (2013) 19:112117
unfavorable from the aspects of medical cost, potential
development of resistant uropathogens, and unexpected
adverse events. Planned continuous antimicrobial prophy-
laxis for 612 months for patients with recurrent urinary
tract infection (UTI) can prevent recurrence more effec-
tively than a placebo [1, 2]. However, the efcacy of such
antimicrobial prophylaxis is limited to the period during
which the prophylaxis is carried out. In addition, the ade-
quate duration of the prophylaxis and the appropriate anti-
microbial dose have not been clearly established [3].
Therefore, the prevention of recurrent UTI by means other
than antimicrobial chemotherapy is an important healthcare
measure, and various preventive options for patients with
recurrent UTI have been suggested worldwide.
The potential effect of cranberry juice has been noted in
previous reports [47] and the preventive effect of cran-
berry juice against recurrent UTI has been discussed [8]. In
some randomized controlled trials [4, 5], the results
showed that cranberry juice or a cranberry product could
reduce the rate of recurrence in patients with recurrent UTI.
However, the results of other research showed that there
was no statistically signicant difference between the
cranberry product and placebo with regard the recurrence
rate of UTI [9]. Whether there is a signicant preventive
effect of cranberry products for patients with recurrent UTI
thus remains controversial. In addition, no studies have
ever tried to clarify the preventive effect of cranberry
products in Japan. The purpose of this clinical study was to
examine the rate of relapse, as a variable index, in patients
with UTI who suffered from multiple relapses when
cranberry juice (UR65) or a placebo beverage was taken
continuously for 24 weeks.
Subjects, materials, and methods
This was a randomized, placebo-controlled, double-blind
study with a target sample size of 150 participants in each
group. It was conducted at 40 urology clinics in Japan from
October 2007 to September 2009. The subjects were out-
patients aged 20 to 79 years with acute exacerbation of
acute uncomplicated cystitis or chronic complicated cys-
titis (including self-catheterization) who had a past history
of multiple relapses of UTI and in whom healing by anti-
microbial agents had been conrmed by expert urologists.
The exclusion criteria were as follows: (1) a current or past
history of uric acid stone disease in the urinary tract or
hyperuricemia that (2) required urological manipulation for
urinary tract stone disease, urinary tract obstruction, or
urinary tract malignant disease; (3) an indwelling urinary
catheter; (4) concomitant urogenital infection such as
urethritis, acute or chronic bacterial prostatitis, or acute
epididymitis; (5) systemic diseases or severe complications
113
such as uncontrolled diabetes, collagen disease, leukemia,
advanced cancer, congenital heart failure, or severe hepatic
or renal dysfunction; (6) a past history of allergic reaction
to cranberry products; and (7) non-eligibility for this trial
as judged by the doctor in the clinic.
The participants were randomly divided into two groups.
One group received cranberry juice (UR65) (group A) and
the other a placebo beverage (group P). To keep the con-
ditions blind, the color and taste of the beverages were
adjusted. The UR65 contained more than 40 mg of pro-
anthocyanidin per 125 mL (Kikkoman Food Products and
The Nisshin Oillio Group, Tokyo, Japan). The subjects
drank 1 bottle (125 mL) of cranberry juice or the placebo
beverage once daily, before going to sleep, for 24 weeks.
The participants visited the clinics every 4 weeks and an
interview on symptoms, including adverse events, was
done at each visit. All participants were interviewed about
the frequency of relapse of UTI in the past year. The
doctors also strictly conrmed the regular intake of the
beverage. The primary endpoint was relapse of UTI. This
was dened as the point when antibiotics were adminis-
tered after the diagnosis of UTI. Immediately after a
relapse of UTI was diagnosed, the participants stopped
taking the beverage and were withdrawn from this study.
In the statistical analysis, we used the log-rank test, and its
conditions were as follows: bilateral 5 % (a = 0.05); power
80 % (b = 0.2). The KaplanMeier method was employed
for calculation of the cumulative relapse-free rate at the onset
of each event. This method can include the data for censored
cases/censoring cases (dropped out/discontinued patients).
Multivariate analysis to identify the factors for the relapse of
UTI was done using Coxs proportional hazards model. The
statistical package SPSS version 12.0J (SPSS, Chicago, IL,
USA) was used for the statistical analysis.
This study was approved by the Institutional Review
Board in the Clinical Research Collaboration Network
(http://www1.bbiq.jp/asia.rinsho) (Nos. I19-36, I20-40, E20-
01, and E21-03) and Sapporo Medical University Hospital
(Nos. 19-17 and 20-3136), and written informed consent was
obtained from each subject. This study was registered in the
University Hospital Medical Information Network Clinical
Trials Registry (UMIN-CTR) (http://www.umin.ac.jp/
ctr/index.htm) (UMIN ID: UMIN00007232).
Results
At rst, 237 participants were screened; however, 10 par-
ticipants were excluded from participating in this study
after the study was explained to them. A total of 227
participants were registered in this study. The male par-
ticipants were excluded from analysis because only 5 men
were registered. Similarly, female participants with self-
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114 J Infect Chemother (2013) 19:112117

catheterization were excluded from analysis because only 9

were registered. Therefore, data for a total of 213 subjects
could be analyzed (Table 1). The evaluation was nally
carried out by per-protocol analysis, because no partici-
pants changed the protocol by themselves. There was no
signicant difference between the backgrounds of groups A
and P. An adverse event was observed in only 1 patient
(0.47 %), who felt a strong burning-like sensation of dis-
comfort after drinking the study beverage (UR65) for the
rst time. The doctor judged that the beverage should be
discontinued and careful observation was done. Fortu-
nately, there were no subjective symptoms or after-effects
on the following morning or thereafter.
There was no signicant difference in the relapse rates
of UTI between groups A and P (log-rank test, p = 0.4209)
(Fig. 1). In this analysis, relapse of UTI was observed in 32
of 107 (29.9 %) subjects in group A and 38 of 106
(35.8 %) in group P. One hundred and seventy participants
with acute uncomplicated cystitis were extracted from the
total of 213 subjects and analyzed similarly. The results
showed that there was no signicant difference in the
relapse rates of UTI between groups A and P (log-rank test, Fig. 1 Difference between cumulative non-relapse rates in group A
p = 0.1300). In this analysis, relapse of UTI was observed (those who received cranberry juice) and group P (placebo group) in
the total of 213 participants (log-rank test, p = 0.4209)
in 22 of 82 subjects (26.8 %) in group A and 34 of 88
(38.6 %) in group P. Then, of these 170 participants with
acute uncomplicated cystitis, 52 who were less than
50 years old and 118 who were aged 50 years and older
were analyzed. In the group aged under 50 years there was
no signicant difference in the relapse rates of UTI
between groups A and P (log-rank test, p = 0.3623); in this
analysis, relapse of UTI was observed in 6 of 27 (22.2 %)

Table 1 Background of the 213 participants and the subpopulation

aged 50 years or more that was analyzed
Total: 213 participants Group A Group P

Factors
Number of subjects 107 106
Age, years (median; range) 55 (2079) 59 (2079)
Recurrence of urinary tract Single 13 12
infection (UTI) during past Multiple 94 94
1 year
Past history of administration No 94 94
of antimicrobial agents for Yes 9 9
the treatment without UTI
Unknown 3 4
Subpopulation aged 50 years or more
Number of subjects 55 63
Fig. 2 Difference between cumulative non-relapse rates in groups A
Age, years (median; range) 66 (5079) 65 (5079)
and P in the participants with acute uncomplicated cystitis who were
Recurrence of UTI Single 6 5 50 years old or older (log-rank test, p = 0.0425)
Multiple 49 58
Past history of administration No 50 57
of antimicrobial agents for subjects in group A and 3 of 25 (12.0 %) in group P. In the
Yes 5 6
the treatment without UTI group aged under 50, the median age in group A was 32
Unknown 0 0
years (range 2048 years) and that in group P was 35 years

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Table 2 Multivariate analysis to identify factors responsible for the
relapse of UTI in the group aged 50 years or more with acute
uncomplicated cystitis
Signicant Hazard 95 % condence
probability ratio interval
Lower
limit
Cranberry juice 0.050 0.545 0.297
Age C 50 years 0.038 1.037 1.002
Frequency of the relapse 0.857 0.909 0.325
of UTI during the past
1 year
(range 2049 years). There was no signicant difference in
the average age between groups A and P (p = 1.00). In the
group aged 50 years or older, there was a signicant dif-
ference in the relapse rates of UTI between groups A and P
(log-rank test, p = 0.0425) (Fig. 2); in this analysis,
relapse of UTI was observed in 16 of 55 subjects (29.1 %)
in group A and 31 of 63 (49.2 %) in group P. To identify
the factors responsible for the relapse of UTI, multivariate
analysis using Coxs proportional hazard model was done
in the group aged 50 years or more with acute uncompli-
cated cystitis (Table 2). The results revealed that drinking
cranberry juice had a marginally signicant preventive
effect against UTI recurrence. In addition, aging was sig-
nicantly associated with the relapse of UTI; however, a
past history of single or multiple relapses of UTI during the
past 1 year was not associated with the relapse of UTI.
Discussion
In a double-blind, placebo-controlled study, it is very
important to include participants with the proper back-
ground. Barbosa-Cesnik and colleagues [9] reported that
cranberry juice did not help to prevent the recurrence of
UTI among 319 college women. The results were disap-
pointing because the failure rate in the cranberry juice
group was higher than that in the placebo group (20 vs.
14 %). Does cranberry juice really have no protective
effect for patients with recurrent UTI? Afterward, it was
indicated that the above study was underpowered to detect
a difference between the cranberry juice and placebo
groups because the UTI recurrence rate in the placebo arm,
for which the authors estimated a UTI recurrence rate of
30 %, was 14 % [10]. In addition, Eells and colleagues
[10] strongly suggested that a forceful strategy for UTI
prevention could work in populations of women at higher
risk for recurrence. It was suggested that this theory could
be applied to other studies such as that of antibiotic-asso-
ciated diarrhea (AAD). In a study on the prevention of
115
AAD, most trials of probiotics for AAD reported diarrhea
in 1520 % in the placebo group, with 2550 % reduction
in diarrhea with probiotic therapy compared with the pla-
cebo [11]. If a study revealed a low occurrence of diarrhea,
no benet of probiotics for the prevention of AAD could be
Upper shown [12]. In our study, there was a signicant difference
limit in the relapse rates of UTI between the cranberry juice and
1.000
placebo groups in the subgroup of females with acute
uncomplicated cystitis who were 50 years old or older; the
1.073
analysis revealed relapse of UTI in 29.1 % of subjects in
2.547
the cranberry juice group and 49.2 % in the placebo group.
Therefore, it was clearly indicated that cranberry juice
could prevent the recurrence of UTI in that age group. The
background of this specic group must theoretically
include a higher risk of recurrence of UTI [10, 12] and be
appropriate for comparing the relapse rates of UTI between
the two groups selected. However, in the present study,
there was no signicant difference in the relapse rates of
UTI between the cranberry juice and placebo groups as a
whole. In the group of females with acute uncomplicated
cystitis who were under 50 years old, the number of par-
ticipants was relatively small and those participants might
have been a group with a lower risk of recurrence of UTI.
For these subjects, the relapse rate of UTI in the placebo
group was only 12 %. These factors might have affected
the results for the total number of subjects in our study.
A previous review [8] showed that cranberry products
had a preventive effect against recurrent UTI in a female
subpopulation. Most studies have reported that cranberry
products could prevent UTI for premenopausal or sexually
active women [4, 5, 13]. However, there have been few
studies of postmenopausal or elderly women. In elderly
women with a mean age of 78.5 years, in whom Avorn and
colleagues [14] compared cranberry juice with a placebo,
the use of cranberry juice signicantly reduced the fre-
quency of bacteriuria with pyuria. But the duration of that
study was 1 month and the primary outcome was the fre-
quency of bacteriuria, not the prevention of UTI. Another
study, reported by McMurdo et al. [6], compared cranberry
extract with low-dose trimethoprim for women aged
45 years or more, with the primary outcome being recur-
rence of an antibiotic-treated UTI and the time to rst
recurrence. They found that 25 (36.2 %) of 69 women in
the cranberry group and 14 (20.6 %) of 68 in the trimeth-
oprim group had recurrence of an antibiotic-treated UTI,
and the difference between the two groups was not
signicant. A previous randomized, placebo-controlled,
double-blind study reported by McMurdo and colleagues
[15] examined patients aged 60 years and older. The results
of that study revealed that 5.6 % of the patients had UTI
during the study period. Seven (3.7 %) of 187 in the
cranberry juice group and 14 (7.4 %) of 189 in the placebo
group had symptomatic UTI, with no signicant difference
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116
between the two groups. Although cranberry juice tended
to be effective, there was no signicant ascendancy over
the placebo. The authors reported that the actual UTI rate
was lower than anticipated; the low frequency of UTI in
that study might have affected the results on the efcacy of
cranberry juice for the patients. Our randomized, placebo-
controlled, double-blind study, however, clearly showed a
signicant difference between subpopulations of the cran-
berry juice and placebo groups. We believe our study is
valuable for determining the efcacy of cranberry juice for
women aged 50 years or more, because our study popula-
tion were women with a high risk of recurrent UTI, and this
population is strongly t for this kind of study.
Although antibiotics may have an advantage over
cranberry products for the prevention of UTI [3, 6],
potential adverse events can occur, and the development of
resistant microorganisms is inevitable. Cranberry products,
however, never induce antibiotic-resistant bacteria or lose
their efcacy. Of note, intravaginal estriol [16], vaginal
suppositories of a probiotic [17], and intravesical admin-
istration of hyaluronic acid [18] have been evaluated to
clarify their efcacies for the prevention of UTI, and they
induced no resistant microorganisms. One superior char-
acteristic of the cranberry for patients with recurrent UTI is
its oral intake with ease. However, there is one known
unfavorable factor in cranberry products. That is the tol-
erability of consuming cranberry products during a some-
what long period. In one study, in pregnant women [19], 73
(38.8 %) of 188 participants could not complete the course
and withdrew. Forty-four (60.3 %) of the 73 women had
gastrointestinal upsets, including nausea, vomiting, and
diarrhea, and dislike of the taste. Although high rates of
gastrointestinal upset (more than 10 %) were reported in
some studies [6, 13, 19], the rates of adverse events with
gastrointestinal upset were relatively low in other studies.
One report [15] found that only 2 (1.1 %) of 187 partici-
pants had gastrointestinal symptoms and another report [4]
found no adverse events. In our study, only 1 participant
had an adverse event. However, the symptoms disappeared
soon after the withdrawal of cranberry juice. The reason for
the differing rates of adverse events in various studies is
unknown. Although some women may feel the cranberry
taste to be somewhat bitter, it is important for them to
continue the oral intake of cranberry products. There are
various types of cranberry products worldwide and it would
be ideal for patients to select and take the product which
they feel is agreeable for themselves.
The preventive effect of cranberry products against UTI
has been claried by some clinical and experimental
studies. Cranberry products, especially proanthocyanidin,
can inhibit the adherence of Escherichia coli to bladder
cells [20]. This effect on bacterial adherence is enhanced
according to the concentration of proanthocyanidin [21].
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J Infect Chemother (2013) 19:112117
The cranberry juice in the present study had a higher
concentration (65 %) than that in a previous study [14].
Also of note, quinic acid, another cranberry component,
can be converted into a large amount of hippuric acid, and
be excreted into urine [8], and hippuric acid in the urine
can exert a strong bacteriostatic effect and acidify the urine
[22]. Therefore, cranberry products have various pre-
ventive effects against UTI in themselves, and high con-
centrations of the product might be necessary to display
their potential power.
There are some limitations to our study. We intensively
recruited the participants and randomized them; however,
the number who could nally be analyzed was limited. At
rst, we tried to include participants with a wide age range;
however, the number of relatively young women was
small. This made analysis of the younger age group dif-
cult. On the other hand, we were able to obtain valuable
data about women aged 50 years or more. As a result, the
analysis of this subpopulation proved valuable, because
there have been few studies of cranberry juice in prevent-
ing recurrent UTI in the subpopulations of postmenopausal
and elderly women.
In conclusion, although a preventive effect of cranberry
juice against uropathogens has been shown, its clinical
efcacy to prevent recurrent UTI remains controversial. In
this study, cranberry juice prevented the recurrence of UTI
in a limited female population with a 24-week intake of the
beverage.
Acknowledgments This study was partly supported, in regard to
data collection, by Kikkoman Food Products Company and The
Nisshin Oillio Group, Ltd., Tokyo, Japan.
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