Content uploaded by Christina Khoo
Author content
All content in this area was uploaded by Christina Khoo on Jul 15, 2016
Content may be subject to copyright.
Consumption of a cranberry juice beverage lowered the number of
clinical urinary tract infection episodes in women with a recent history
of urinary tract infection
1
Kevin C Maki,
2,3
* Kerrie L Kaspar,
4
Christina Khoo,
4
Linda H Derrig,
2
Arianne L Schild,
2
and Kalpana Gupta
5,6
2
Biofortis Clinical Research, Addison, IL;
3
MB Clinical Research, Glen Ellyn, IL;
4
Ocean Spray Cranberries, Lakeville-Middleboro, MA;
5
Department of
Medicine, Boston University School of Medicine, Boston, MA; and
6
VA Boston Healthcare System, Boston, MA
ABSTRACT
Background: Urinary tract infections (UTIs) are among the most
common bacterial infections and are often treated with antibiotics.
Concerns about multidrug-resistant uropathogens have pointed to
the need for safe and effective UTI-prevention strategies such as
cranberry consumption.
Objective: We assessed the effects of the consumption of a cran-
berry beverage on episodes of clinical UTIs.
Design: In this randomized, double-blind, placebo-controlled, mul-
ticenter clinical trial, women with a history of a recent UTI were
assigned to consume one 240-mL serving of cranberry beverage/
d(n= 185) or a placebo (n= 188) beverage for 24 wk. The primary
outcome was the clinical UTI incidence density, which was defined
as the total number of clinical UTI events (including multiple events
per subject when applicable) per unit of observation time.
Results: The dates of the random assignment of the first subject and
the last subject’s final visit were February 2013 and March 2015,
respectively. The mean age was 40.9 y, and characteristics were
similar in both groups. Compliance with study product consumption
was 98%, and 86% of subjects completed the treatment period in
both groups. There were 39 investigator-diagnosed episodes of clin-
ical UTI in the cranberry group compared with 67 episodes in the
placebo group (antibiotic use–adjusted incidence rate ratio: 0.61; 95%
CI: 0.41, 0.91; P= 0.016). Clinical UTI with pyuria was also signif-
icantly reduced (incidence rate ratio: 0.63; 95% CI: 0.40, 0.97; P=
0.037). One clinical UTI event was prevented for every 3.2 woman-
years (95% CI: 2.0, 13.1 woman-years) of the cranberry intervention.
The time to UTI with culture positivity did not differ significantly
between groups (HR: 0.97; 95% CI: 0.56, 1.67; P=0.914).
Conclusion: The consumption of a cranberry juice beverage lowered
the number of clinical UTI episodes in women with a recent
history of UTI. This study was registered at clinicaltrials.gov
as NCT01776021. Am J Clin Nutr 2016;103:1434–42.
Keywords: antibiotics, bacteria, cranberry, inflammation,
proanthocyanidin, urinary tract infection, women
INTRODUCTION
A urinary tract infection (UTI) is common and increasingly
difficult to treat because of the rising rates of antibiotic resis-
tance (1, 2). Approximately 60% of women will experience $1
UTI in their lifetimes, and UTIs are responsible for w10.5
million physician office and emergency department visits an-
nually in the United States (3, 4). The costs attributable to UTIs
include those for antibiotic therapy, visits to health care pro-
viders, laboratory testing, and lost productivity (1). It has been
estimated that 25–35% of women diagnosed with a UTI will
suffer a recurrence within 6 mo (1, 5). The prevention of a UTI
is most effectively achieved with antibiotic prophylaxis (6), al-
though it has been recommended that, in women with recurrent
cystitis, prophylactic antimicrobial therapy should be used only
when nonantimicrobial therapy is not effective (7, 8). Increasing
rates of antibiotic resistance (9–12) and other adverse effects from
antibiotic exposure make this approach important to consider.
Cranberry consumption has been evaluated as a strategy for
reducing clinical UTI recurrence in women with a recent history
of a UTI (5, 13). Results from randomized clinical trials have
been generally suggestive of a benefit but have often lacked
sufficient statistical power to provide definitive results (14). The
current study was conducted to compare the effects of the
consumption of a cranberry beverage with that of a placebo
beverage on the clinical (symptomatic) UTI incidence density in
healthy women with a recent history of a UTI.
METHODS
Study design
The study was a 24-wk multicenter, double-blind, randomized,
placebo-controlled trial that was designed to assess the effects of
the consumption of a cranberry beverage on episodes of clinical
(symptomatic) UTI in healthy women. The study was conducted
at 17 clinical research sites in the United States and at one clinical
1
Supported by Ocean Spray Cranberries Inc. Beverages were provided by
Ocean Spray Cranberries Inc. This is a free access article, distributed under
terms (http://www.nutrition.org/publications/guidelines-and-policies/license/)
that permit unrestricted noncommercial use, distribution, and reproduction
in any medium, provided the original work is properly cited.
*To whom correspondence should be addressed. E-mail: kmaki@
mbclinicalresearch.com.
Received January 11, 2016. Accepted for publication March 17, 2016.
doi: 10.3945/ajcn.116.130542.
1434 Am J Clin Nutr 2016;103:1434–42. Printed in USA. Ó2016 American Society for Nutrition
by guest on June 1, 2016ajcn.nutrition.orgDownloaded from
research site in France between February 2013 and March 2015.
The protocol was approved by an institutional review board in the
United States (Quorum Review IRB, Seattle, Washington) and by
the National Security Agency for Medicines and Health Products
and an Ethical Research Committee (Committee for Personal
Protection) in France. Procedures were followed in accordance
with the Declaration of Helsinki of 1975 as revised in 1983.
Written informed consent was obtained from all subjects.
Subjects
Eligible subjects included women who were 20–70 y of age
with BMI (in kg/m
2
),40.0 and a recent history of a UTI, which
was defined as $2 episodes of a UTI that were treated by
a health care professional in the past year (self-report) of which
$1 UTI had been treated #6 mo of the screening visit. Women
who were using prophylactic antibiotics for a UTI were not
enrolled, but a 2-wk washout period from antibiotic use was
allowed before screening. Individuals with an active infection or
signs or symptoms of a UTI or other active infection were ex-
cluded. If a clean-catch urine sample at screening was positive
for asymptomatic bacteriuria ($10
5
CFU for a uropathogen), the
woman was rescreened $2 wk later.
Subjects agreed to avoid the consumption of Vaccinium
products (blueberries, cranberry juice, cranberries, dried cran-
berries, and cranberry or blueberry powders, pills, or supple-
ments) and probiotic dietary supplements and to limit the
consumption of all probiotic-containing foods or yogurt, soda,
and energy drinks within 2 wk before screening and through
week 24. The daily consumption of carbonated beverages and
fermented milk products has been associated with a reduced risk
of recurrent UTI in some studies, although this finding has not
been universal (15–18). In the current study, subjects were al-
lowed to consume carbonated beverages, energy drinks, and
yogurt but were asked to avoid intakes that were far above mean
US intakes to allow the results to be generalizable while mini-
mizing the potential for confounding by extreme intakes of these
products. Subjects received a stipend for their participation in
the study, which included 5 clinic visits (screening and baseline
visits at weeks 21 and 0, respectively, and 3 treatment visits at
weeks 8, 16, and 24) and 9 telephone contacts at weeks 2, 4, 6,
10, 12, 14, 18, 20, and 22 to improve study compliance by re-
minding subjects to record data in their daily diaries.
Individuals were excluded from participation in the study if
they used a bladder catheter or had polycystic disease, interstitial
cystitis, previous urologic surgery, stones, anatomical abnor-
malities of the urinary tract, a spinal cord injury, conditions that
produce immunocompromise, severe renal impairment, or
multiple sclerosis. Additional exclusionary conditions included
diabetes mellitus with glycated hemoglobin $8.0%, diabetes
mellitus treated with insulin, a history or presence of cancer in
the previous 2 y (except nonmelanoma skin cancer), a recent
(within the past 3 mo) major trauma or surgical event, or the use
of oral anticoagulants #4 wk before screening. Women were
also excluded from participation if they had an abnormal labo-
ratory test of clinical importance. Women who were pregnant,
planning to be pregnant during the study, or lactating were ex-
cluded from the study, and women of childbearing potential had
to commit to the use of a medically approved form of con-
traception throughout the study.
Subjects were instructed to maintain a stable body weight, ad-
here to habitual exercise patterns, and avoid the consumption of
foods that are high in polyphenols for the 24 h before and during the
24-h urine collection periods. Cigarette smokers were instructed to
abstain from tobacco products 1 h before and during clinic visits.
Study products
Subjects were randomly assigned (1:1 ratio) to consume one
8-oz (240-mL) bottle of cranberry or placebo study beverage per
day throughout the 24-wk treatment period. The randomization
sequence was generated with SAS for Windows software (version
9.1.3; SAS Institute Inc.) by a blinded statistician with the use of
a seed number and random allocation in blocks by research site.
The randomization module of the DATATRAK Electronic Data
Capture system (DATATRAK ONE UX, versions 13.0.0 to
13.3.5) was used for coded treatment allocation at each research
site by a study coordinator or investigator.
Beverages were provided by Ocean Spray Cranberries Inc. and
were stored at room temperature and refrigerated before con-
sumption. Cranberry and placebo beverages each provided
w35 kcal (w146 kJ)/240-mL serving. The placebo beverage
contained filtered water, fructose, dextrose, citric acid, quinic acid,
malic acid, natural flavors, pectin, potassium citrate, sodium citrate,
red 40, blue 1, acesulfame-potassium, and sucralose. The active
study beverage contained filtered water, cranberry juice from con-
centrate, fructose, natural flavors, pectin, sodium citrate, acesulfame-
potassium, and sucralose. The analytic composition of the study
TABLE 1
Study-product composition
1
Component Cranberry beverage Placebo beverage
Energy,
2
kcal 36 34
Carbohydrates,
3
g98
Sugars,
4
g 6.3 60.1
5
6.9 60.3
Organic acids,
6
g 2.0 60.1 1.9 60.2
Vitamin C,
7
mg ND ND
Proanthocyanidins, mg
DMAC-method I
8
41.1 67.1 ND
DMAC-method II
9
119 616.9 ND
Anthocyanins,
4
mg 1.3 60.8 ND
Phenolic acids,
10
mg 5.4 60.8 ND
Flavanols and flavonols,
10
mg 8.3 63.6 ND
Total phenolics,
11
mg 135 630.7 17.0 65.4
1
DMAC, 4-dimethylaminocinnamaldehyde; ND, not detected.
2
Determined with the use of Atwater factors (Covance Laboratory)
(19).
3
Determined with the use of the carbohydrate by difference method
(20).
4
Measured with the use of HPLC (21).
5
Mean 6SD where applicable per 240-mL serving (all such values).
6
Measured with the use of ion chromatography (21).
7
Measured with the use of an iodiometric titration method (22).
8
Determined with the use of a DMAC colorimetric method with
procyanidin A2 as a standard (23).
9
Determined with the use of a modified DMAC colorimetric method
with the cranberry proanthocyanidin standard isolated and purified from
cranberry juice concentrate (21, 24).
10
Determined with the use of HPLC (25).
11
Determined with the use of the Folin-Ciocalteu reagent colorimetric
method (21).
CRANBERRY JUICE AND CLINICAL UTI 1435
by guest on June 1, 2016ajcn.nutrition.orgDownloaded from
beverages is shown in Table 1 (19–25). The placebo beverage was
designed to look, smell, and taste like the cranberry beverage (27%
juice), and a separate sensory study showed no difference in the
proportions of subjects who correctly guessed if they were randomly
assigned to receive either the cranberry beverage (51%) or the
placebo beverage (40%) (n=167;paralleldesign;P= 0.20). The
cranberry juice cocktail study beverage used was similar to
commercially available low-calorie products in its juice content
(27% cranberry juice) although additional measures were taken
to minimize the variability in the contents of proanthocyanidins
and other bioactives. These additional measures included pro-
duction from a single lot of cranberry concentrate and the use of
a shorter time to expiration than is used for beverages that are
produced for commercial use.
Compliance with study beverage consumption was assessed by
having subjects return all unused bottles of dispensed study
product and empty bottles of study product that had been con-
sumed to the clinic. This information was checked against diary
data, and subjects were queried to evaluate any discrepancies.
Measurements
Subjects completed a validated daily diary in which they recorded
their consumption of the study beverage and captured any UTI
symptoms (26). Daily diaries were reviewed at each post–random
assignment clinic visit, and subjects were queried during telephone
calls between clinic visits regarding their compliance with the
consumption of the study product as well as whether symptoms or
adverse experiences had occurred. If symptoms occurred at any
time during the study, the subject was instructed to call the research
clinic to arrange for a UTI-evaluation visit, which included a pelvic
examination. A clean-catch urine sample was also collected, and
a clinical (symptomatic) UTI was diagnosed by the investigator on
the basis of $1 of the following symptoms: dysuria, urinary fre-
quency, urinary urgency, or suprapubic pain in the absence of other
potential etiologies such as vaginal infection or discharge. In-
vestigators treated a clinical UTI with a standardized antimicrobial
therapy regimen, and subjects continued to consume the study
beverages during treatment. Clean-catch urine samples were also
collected at weeks 21, 0, 8, 16, and 24 for urinalysis and culture.
The presence or absence of pyuria in clean-catch urine samples
was determined by a leukocyte esterase dipstick result (27). In the
United States, the urine culture at the screening visit and the uri-
nalysis from all visits were analyzed by Johnson City Medical
Center (Johnson City, Tennessee), and urine cultures from non-
screening visits were tested by The General Clinical Re-
search Center (University of Washington, Seattle, Washington).
In France, the urine culture at the screening visit and urinalysis
from all visits were analyzed by Synevo Central Laboratory
Poland (Gdansk, Poland), and urine cultures from nonscreening
visits were tested in Barcelona, Spain, by Servei de Micro-
biologia, Hospital Universitari Vall d’Hebron. At weeks 0, 8,
16, and 24, subjects completed questionnaires that assessed
sexual history, food and beverage consumption, and the presence
and severity of gastrointestinal symptoms.
Statistical analyses
The primary outcome variable was the clinical (symptomatic)
UTI incidence density, which was defined as the number of
clinical UTI events in each group (including multiple events per
subject when applicable) per unit of observation time. The in-
cidence density was selected as the primary outcome variable
because UTI episodes often cluster in time (28, 29). The selection
of a clinical UTI as the primary outcome in the current study was
consistent with guidelines for UTI management (30) because
initial treatment decisions are generally made before the avail-
ability of culture results, and the presence of multiple symptoms
in the absence of vaginal discharge in women with a history of
UTI is highly predictive (UTI probability .90%) (7, 31).
The following 3 classifications were used for clinical UTI
analyses: investigator-diagnosed UTIs, probable UTIs, and
possible UTIs. Investigator-diagnosed clinical UTIs were those
for which the investigator evaluated the subject and made the UTI
diagnosis. Probable UTIs were those for which the investigator
did not examine the subject, but a nonstudy health care provider
did examine the subject and prescribed antibiotics. Possible UTIs
were those that did not fall into either of the other 2 categories
including those in which the subject self-treated and instances
when it was not clear whether an episode was a new UTI or
a continuation of a previous infection that had not cleared (e.g.,
when a subject’s symptoms stopped and recurred within 2 wk
with no intervening test-of-cure visit). Results for investigator-
diagnosed UTIs are presented in detail, and results from anal-
yses that included probable and possible UTIs are described as
sensitivity analyses.
Secondary and exploratory outcome variables included the
incidence density for a clinical UTI with pyuria, the time from
random assignment to a first clinical UTI, the time from ran-
dom assignment to a first clinical UTI with pyuria, and the time
from random assignment to a first symptomatic UTI with cul-
ture pos itivity ($10
3
CFU/mL) for any uropathogen and
for Escherichia coli. Safety was assessed by an evaluation of
treatment-emergent adverse events, the frequency and severity
of gastrointestinal signs and symptoms, and the measurement of
vital signs, body weight, and clinical laboratory values.
Fisher’s exact test with the use of G*Power software (free
software available at http://www.gpower.hhu.de) was used to
complete power calculations (32). Because the incidence density
was to be used as the primary outcome variable, it was antici-
pated that the study power would be greater than that reflected
by this calculation (29), which did not account for the occur-
rence of multiple UTIs during the treatment period in some
women. On the basis of the assumption that the proportion of
women who would experience a UTI episode in the placebo
group would be 32% (5), a sample size of 145 subjects/group
was expected to provide $80% power (a= 0.05; 2 sided) to
detect a reduction to 17.8% in the treatment group. An enroll-
ment of 300 subjects (150 subjects/group) was initially planned,
but a decision was later made to increase the enrollment by an
additional 40 subjects because a blinded review showed that the
rate of a first UTI was slightly below initial projections.
Statistical analyses were conducted with the use of SAS for
Windows software (version 9.1.3). All tests for significance were
performed at a= 0.05 (2 sided). The baseline comparability
of treatment groups for subject characteristics was assessed
with the use of ANOVA and chi-square tests. Analyses were
performed in all randomly assigned subjects (intent-to-treat
population) with the observation time censored at the time
that the study product was discontinued for subjects who did
1436 MAKI ET AL.
by guest on June 1, 2016ajcn.nutrition.orgDownloaded from
not complete the full treatment period. Assumptions of nor-
mality of residuals were investigated for each response mea-
surement. In cases in which the normality assumption was
rejected at the 1% level with the use of the Shapiro-Wilk test
(33), an analysis with the use of ranks was performed.
The UTI incidence density was analyzed with the use of
Poisson regression with terms of treatment, site, country (United
States or France), time since last UTI category (#30, 31–89, or
$90 d), and age category (,50 or $50 y) as well as an offset
variable for the log of time (woman-years) under observation.
The model was reduced until treatment and any significant
terms (P,0.05) remained with the use of a backward-elimination
method. The appropriate fit and overdispersion were assessed
for each model (34), and comparisons of results from full and
reduced models were completed to assess whether the model-
reduction procedure materially altered the point estimates and
95% CIs for the treatment effect. An adjustment for the sus-
ceptible time under observation to account for antibiotic use was
calculated with the use of a subtraction of 7 d from the sus-
ceptible time for each instance of antibiotic use regardless of the
reason for use. The incidence density is presented with and
without this adjustment.
Time-to-event outcome variables were analyzed with the use
of Cox proportional hazards models with the same covariates and
approach as previously described. HRs with 95% CIs and model
variable Pvalues were determined. Assumptions of a constant
relative hazard were verified with the use of the Schoenfeld
residuals goodness-of-fit test (35). Continuous variables were
analyzed with the use of an ANCOVA and a model with a term
for the treatment and baseline included as a covariate.
RESULTS
A total of 373 subjects were randomly assigned to consume the
cranberry beverage (n= 185) or placebo beverage (n= 188), and
322 subjects [cranberry: n= 160 (86.5%); placebo: n= 162
(86.2%)] completed through week 24 of the study (Figure 1). Two
subjects in the cranberry group were randomly assigned in error
(one subject had asymptomatic bacteriuria and another subject did
not have sufficient literacy to understand the consent form). Both
subjects were discontinued from treatment once the errors were
discovered. Three subjects withdrew consent because of adverse
events that were unrelated to the treatment (cranberry group: oral
thrush and dizziness; placebo group: stomach complaints).
Demographic and baseline characteristics are shown in Table
2. Subjects had a mean age of 40.9 y, and the majority of sub-
jects were white (67.0%) and of non-Hispanic or non-Latino
ethnicity (75.6%). The mean 6SEM compliance with daily
study-beverage consumption was 98.1% 60.6% and 98.2% 6
0.5% in the cranberry and placebo groups, respectively.
A total of 53 UTI-assessment visits were completed for
subjects in the cranberry group, and 82 UTI-assessment visits
were completed in the placebo group. These visits resulted in the
diagnosis by study investigators of 39 clinical UTIs in the
cranberry group and 67 clinical UTIs in the placebo group (Tabl e 3).
The fractions of clinical UTI diagnoses for which the subject
reported $2 UTI symptoms at the assessment visits were 97.4%
(38 of 39 diagnoses) for the cranberry condition and 99.0% (66 of
67 diagnoses) for the placebo condition, and for $3UTIsymp-
toms at the assessment visits, these values were 97.4% (38 of 39
diagnoses) for the cranberry condition and 91.0% (61 of 67 di-
agnoses) for the placebo condition. The annualized UTI incidence
density was significantly reduced in the cranberry compared with
FIGURE 1 Subject disposition throughout the trial (Consolidated Standards of Reporting Trials flow diagram).
CRANBERRY JUICE AND CLINICAL UTI 1437
by guest on June 1, 2016ajcn.nutrition.orgDownloaded from
in the placebo arm (incidence rate ratio: 0.62; 95% CI: 0.42, 0.92;
P= 0.017). Adjustment for antibiotic use (139 instances in the
control group and 111 instances in the cranberry group) for the
susceptible time under observation did not materially alter the
point estimate (incidence rate ratio: 0.61; 95% CI: 0.41, 0.91; P=
0.016). For every 3.6 woman-years (95% CI: 2.3, 15.8 woman-
years) of the cranberry intervention, 1 symptomatic UTI event
was prevented. After adjustment for antibiotic use, 1 symptomatic
UTI was prevented for every 3.2 woman-years (95% CI: 2.0, 13.1
woman-years).
Results were not materially influenced by the model reduction
(data not shown). There was no statistical heterogeneity in the
treatment response for subjects ,50 and $50 y of age (P-treatment
by age-group interaction = 0.526).
The incidence density for symptomatic UTIs with pyuria
(adjusted for antibiotic use) was significantly reduced in the
cranberry arm compared with in the placebo arm (Table 3)
(incidence rate ratio: 0.63; 95% CI: 0.40, 0.97; P= 0.037). With
the use of the classifications of investigator-diagnosed plus
probable symptomatic UTIs (47 and 72 UTIs in the cranberry
TABLE 2
Demographic and baseline characteristics of subjects receiving cranberry or placebo beverages
1
Characteristic Cranberry group (n= 185) Placebo group (n= 188) P
Age, y 40.9 61.1
2
41.0 61.0 0.896
Age subgroup, y, n(%) 0.999
,50 131 (70.8) 133 (70.7)
$50 54 (29.2) 55 (29.3)
Race,
3
n(%) 0.329
White 122 (65.9) 128 (68.1)
Black/African American 30 (16.2) 29 (15.4)
American Indian/Alaskan Native 0 (0.0) 2 (1.1)
Asian or Pacific Islander 3 (1.6) 7 (3.7)
Multiracial origin 2 (1.1) 1 (0.5)
Other 3 (1.6) 0 (0.0)
Missing
4
25 (13.5) 21 (11.2)
Ethnicity, n(%) 0.661
Hispanic/Latino 25 (13.5) 21 (11.2)
Not Hispanic/Latino 136 (73.5) 146 (77.7)
Missing 24 (13.0) 21 (11.2)
Treated UTIs in past 6 mo, n1.6 60.1 1.7 60.1 0.647
Most recent UTI history, d, n(%) 0.837
#30 17 (9.2) 21 (11.2)
31–89 80 (43.2) 79 (42.0)
$90 88 (47.6) 88 (46.8)
Vaginal intercourse frequency in past 4 wk, n4.9 60.4 5.7 60.6 0.434
Sexual partners in past 4 wk, n(%)
0 58 (31.4) 50 (26.6) 0.399
1 123 (66.5) 135 (71.8)
$2 2 (1.1) 3 (1.6)
History of diabetes,
5
n(%) 2 (1.1) 6 (3.2) 0.284
BMI, kg/m
2
27.0 60.4 26.5 60.4 0.346
Categorical BMI, kg/m
2
,n(%) 0.116
,25 79 (42.7) 92 (48.9)
25 to ,30 57 (30.8) 40 (21.3)
$30 49 (26.5) 56 (29.8)
Alcoholic drinks,
6
n/wk 0.5 (0.0, 10.0) 0.4 (0.0, 12.0) 0.962
Smoking status, n(%) 0.282
Nonsmoker 134 (72.4) 145 (77.1)
Current smoker 19 (10.3) 11 (5.9)
Past smoker 32 (17.3) 32 (17.0)
1
Baseline comparability of treatment groups for subject characteristics was assessed with the use of ANOVA and chi-
square tests. UTI, urinary tract infection.
2
Mean 6SEM (all such values).
3
Race and ethnicity were self-reported by subjects as part of a medical history questionnaire that was completed at
screening to allow comparison with the racial and ethnic compositions of the country.
4
For clinical studies in France, data regarding ethnicity can only be collected if justified by the type of research. In this
study of cystitis, there was no justification to investigate ethnicity, and therefore, this information was not collected from
subjects enrolled at the clinical site in France.
5
Previous history of a medical diagnosis of diabetes as recorded in the medical history. In the cranberry group, 2
subjects with diabetes were $50 y of age; in the placebo group, 2 subjects with diabetes were ,50 y of age, and 4 subjects
were $50 y of age.
6
All values are medians; minimums, maximums in parentheses. These data were not normally distributed (normality
assumption was rejected at the 1% level with the use of the Shapiro-Wilk test) and were ranked in the analyses.
1438 MAKI ET AL.
by guest on June 1, 2016ajcn.nutrition.orgDownloaded from
and placebo groups, respectively) and investigator-diagnosed
plus probable and possible symptomatic UTIs (48 and 74 UTIs
in the cranberry and placebo groups, respectively), the antibiotic-
adjusted incidence rate ratios at week 24 were 0.68 (95% CI:
0.47, 0.99; P= 0.043) and 0.68 (95% CIs: 0.47, 0.98; P= 0.037),
respectively.
Kaplan-Meier curves are shown in Figure 2. By the end of the
24-wk treatment period, 33 subjects (17.8%) in the cranberry
group had experienced a first symptomatic UTI compared with
50 subjects (26.6%) in the placebo group (HR: 0.67; 95% CI:
0.43, 1.05; P= 0.078). There were no significant differences
between treatment groups in the time from random assignment
to the first clinical UTI with pyuria (HR: 0.69; 95% CI: 0.43,
1.12; P= 0.131), with microbiological positivity (HR: 0.97;
95% CI: 0.56, 1.67; P= 0.914), or positive for E.coli (HR: 1.38;
95% CI: 0.73, 2.59; P= 0.323).
A total of 30 investigator-diagnosed clinical UTIs in the
cranberry group and 34 investigator-diagnosed clinical UTIs in
the placebo group were microbiologically positive. The bacterial
species identified in the cultures that were positive for bacteria are
shown in Table 4. A majority of the microbiologically positive
infections in both treatment groups were positive for E.coli [27
infections (90.0%) and 24 infections (70.6%) in the cranberry
and placebo groups, respectively]. Analyses of urine samples
collected at the scheduled post–random assignment visits indi-
cated no significant differences between treatment groups in the
fractions of subjects with asymptomatic bacteriuria (for cran-
berry and control groups: at week 8, 4.3% and 3.7%, respec-
tively; at week 16, 8.1% and 8.0%, respectively; and at week 24,
9.2% and 11.2%, respectively).
Adverse events that occurred in $5% of subjects in either
treatment group included headache [cranberry group: n=16
(8.6%); placebo group: n= 12 (6.4%)], sinusitis [cranberry
group: n= 10 (5.4%); placebo group: n= 6 (3.2%)], and upper
respiratory infection [cranberry group: n= 13 (7.0%); placebo
group: n= 13 (6.9%)]. One subject in the cranberry group had
a serious adverse event (chest pain), and 4 subjects in the pla-
cebo group had a serious adverse event (ischemic colitis leading
to septic shock, miscarriage, in-patient hospitalization for ap-
pendicitis, and surgery for a rectal prolapse). All serious adverse
events were classified as either unrelated or unlikely to be re-
lated to the treatment.
The only significant difference between treatment groups in
the gastrointestinal tolerability questionnaire was at week 8 with
3 subjects (1.6%) in the cranberry group and 11 subjects (5.9%) in
the placebo group reporting a nausea rating of “somewhat more
TABLE 3
Symptomatic episodes of UTI diagnosed and treated by study investigators and symptomatic UTIs with pyuria in subjects consuming cranberry or placebo
beverages for 24 wk
1
Cranberry group
(n= 185)
Placebo group
(n= 188)
Incidence rate ratio
(95% CI)
2
P
Subjects reporting a symptomatic UTI, episodes, n(%)
0 152 (82.2) 138 (73.4) — —
1 27 (14.6) 36 (19.2) — —
2 6 (3.2) 11 (5.9) — —
3 0 (0.0) 3 (1.6) — —
$1 33 (17.8) 50 (26.6) — —
Total UTIs, n39 67 — —
UTI, annualized incidence density (95% CI)
2
0.48 (0.33, 0.63) 0.75 (0.56, 0.94) 0.62 (0.42, 0.92) 0.017
Incidence density (95% CI) adjusted for antibiotic use
3
0.54 (0.38, 0.70) 0.85 (0.65, 1.05) 0.61 (0.41, 0.91) 0.016
Subjects with a symptomatic UTI with pyuria, episodes, n(%)
0 157 (84.7) 147 (78.2) — —
1 24 (13.0) 31 (16.5) — —
2 4 (2.2) 8 (4.3) — —
3 0 (0.0) 2 (1.1) — —
$1 28 (15.1) 41 (21.8) — —
Total UTIs with pyuria, n32 53 — —
UTI with pyuria, annualized incidence density (95% CI)
2
0.40 (0.39, 0.41) 0.59 (0.58, 0.61) 0.63 (0.41, 0.98) 0.041
Incidence density (95% CI) adjusted for antibiotic use
3
0.43 (0.42, 0.45) 0.67 (0.65, 0.68) 0.63 (0.40, 0.97) 0.037
1
UTI, urinary tract infection.
2
Incidence rate ratios and Pvalues for the number of UTIs (or UTIs with pyuria) per woman-year of observation were determined from the generalized
linear model with the log link and Poisson distribution specified along with the offset log for observation time. The model was reduced until treatment, and any
significant terms (P,0.05) remained with the use of a backward elimination method.
3
Observation time was adjusted by subtracting 7 d from the observation time for every instance of antibiotic use regardless of the indication.
FIGURE 2 Time to first symptomatic UTI (week 24 survival time) in
subjects receiving a cranberry beverage (n= 185) or a placebo beverage (n=
188). The HR for the difference between cranberry and placebo groups in the
number of subjects who had experienced a first symptomatic UTI by the end
of the 24-wk treatment period was 0.67 (95% CI: 0.43, 1.05; P= 0.078).
UTI, urinary tract infection.
CRANBERRY JUICE AND CLINICAL UTI 1439
by guest on June 1, 2016ajcn.nutrition.orgDownloaded from
than usual” or “much more than usual” (P= 0.044). There were
no significant differences between treatment groups at baseline
or during the study in systolic or diastolic blood pressures, heart
rates, or body weights (data not shown).
DISCUSSION
In this randomized, double-blind, placebo-controlled, multi-
center study in women with a recent UTI history, the daily
consumption of a cranberry beverage for 24 wk produced a 39%
(95% CI: 9%, 59%) reduction in clinical UTI episodes. The rate
of clinical UTI with pyuria episodes was also reduced by 37%
(95% CI: 3%, 60%) although no difference between the groups
was observed for microbiologically positive UTIs. A course of
antibiotic therapy for a clinical UTI was prevented for every 3.2
woman-years (95% CI: 2.0, 13.1 woman-years) (adjusted for
antibiotic use) of the cranberry intervention.
To our knowledge, this is the largest study to date to evaluate
the influence of cranberry-product consumption on UTI inci-
dence in women and was designed to address some of the
limitations of previous trials, which have included an inadequate
statistical power because of low UTI-event rates, small sample
sizes, poor compliance with study-product consumption, and
high dropouts (13). The current study had greater statistical
power to detect differences than did previous trials because of its
larger sample size, the use of the incidence density to account for
the tendency of clinical UTI events to cluster in time within an
individual, a high average level of compliance with study-product
consumption in both groups (w98%), and a comparatively large
percentage of subjects in each group who completed the treat-
ment period (w86%).
A 2008 Cochrane review of 10 clinical studies reported that the
consumption of cranberry products (juice or tablets) significantly
reduced UTI incidence compared with that from placebo con-
sumption (RR: 0.65; 95% CI: 0.46, 0.90), which is a reduction
that is similar in magnitude to the effect reported in the current
study (36). Another meta-analysis of 13 trials reported a pro-
tective effect of cranberry consumption against recurrences of
UTI (RR: 0.53; 95% CI: 0.33, 0.83) (5). However, a more recent
Cochrane review reported a nonsignificant reduction in risk of
repeat UTIs with cranberry treatment compared with a placebo or
no treatment (RR: 0.74; 95% CI: 0.42, 1.31) but with substantial
heterogeneity in the results (I
2
= 65%) that were largely attrib-
utable to a single study that included only microbiologically
positive UTIs in the analysis (37). When that study was omitted,
the pooled RR was 0.58 (95% CI: 0.39, 0.86) (13).
Stapleton et al. (38) reported results from a randomized
controlled trial of cranberry juice consumption that was similar in
many respects to those of the current trial. The investigators
showed a nonsignificantly reduced HR for the cranberry beverage
compared with the placebo beverage of 0.68 (95% CI: 0.33, 1.39;
P= 0.29) for the outcome of the time to a first clinical UTI
event. Note that the point estimate for the effect was nearly
identical to that observed in the current trial for the secondary
outcome of the time to a first clinical UTI for which the HR was
0.67 (95% CI: 0.43, 1.05; P= 0.078), and significance was
present for the primary incidence density outcome. Therefore,
results from the current investigation are consistent in direction
and magnitude with those from most previous studies of the
effects of cranberry consumption on the prevention of clinical
UTIs in women and are also concordant with those of Barbosa-
Cesnik et al. (37) in showing no significant difference in culture-
positive UTI incidence.
All subjects had a recent UTI history, and a large majority of
participants had multiple symptoms in the absence of vaginal
discharge or irritation at diagnosis, which was consistent with
.90% probability of UTI (31). These results suggest a low
likelihood of a substantial misdiagnosis, and because this was
a double-blind study, the diagnostic criteria were unlikely to
have been applied in a differential manner between treatment
groups. A majority of microbiologically positive UTI events are
typically due to E.coli infection (39). In the current study,
90.0% (cranberry) and 70.6% (placebo) of the microbiologically
positive UTI events showed the presence of E.coli, which was
very similar to the results reported by Barbosa-Cesnik (37) in
which E.coli was present in 93.3% (cranberry) and 58.3%
(placebo) of culture-positive UTIs. Because the 2 largest studies
completed to date on cranberry use to reduce episodes of UTI
have shown no evidence of a difference in the microbiologically
positive UTI incidence, the mechanisms responsible may not
have influenced this outcome.
Results from in vitro and ex vivo studies have suggested that
cranberry interferes with the attachment of uropathogenic E.coli
to epithelial cells in the bladder, periurethral region, and gas-
trointestinal tract (40–43). In addition, cranberry consumption
appears to produce anti-inflammatory effects (44–46), which
may help to explain the reduction in clinical UTI episodes
without a difference in the incidence of microbiologically pos-
itive UTI events. One possible explanation is that cranberry
consumption may reduce the proportion of asymptomatic bac-
teriuria episodes that progress to symptomatic UTIs (11).
Cranberry may also suppress inflammation associated with the
activation of intracellular bacterial communities during a recur-
rent UTI episode (44, 46). Anti-inflammatory activity has the
potential to prevent the development of symptoms but also to
lower intercellular bacterial propagation, and thus reduce the
severity of a UTI episode as well as the propensity for a chronic
infection (44, 46, 47). Such effects have been shown for anti-
inflammatory agents such as cyclooxygenase inhibitors and
TABLE 4
Bacterial species identified in urine cultures collected when women who
were consuming cranberry or placebo beverages reported a symptomatic
UTI
1
Species
UTIs positive for the microorganism, n
Cranberry group
(n= 185)
Placebo group
(n= 188)
Escherichia coli 27 23
Staphylococcus saprophyticus 11
Enterococci 03
Klebsiella spp. 0 2
Enterobacter spp. 1 0
Citrobacter spp. 0 2
Group B Streptococcus 02
Other gram-negative rods
(Escherichia vulneris)
10
E.coli and Enterococci 01
Sum 30 34
1
UTI, urinary tract infection.
1440 MAKI ET AL.
by guest on June 1, 2016ajcn.nutrition.orgDownloaded from
dexamethasone (48–50). Mechanistic studies are needed to
more-clearly define the mechanisms through which cranberry is
affecting clinical UTI recurrence.
One limitation of the current study is the evaluation of only
a single level of once-daily cranberry beverage intake. An addi-
tional investigation will be necessary to evaluate other intakes and
delivery forms such as powdered extracts. In addition, subjects
were volunteers with a self-reported history of a recent UTI who
may not have been fully representative of women who are treated
in clinical practice, although the similarities in the sizes of the
effects in the current and previous trials suggested that the results
may be generalizable. The fraction of women in the placebo group
with $1 UTI (50 of 188 women; 27%) was within the expected
range of 25–35% (1, 5). The percentage of women with $1UTI
in France was somewhat lower (10%) but with wide confidence
limits because of the small number of subjects (n=21assignedto
receive the placebo in France).
In conclusion, the consumption of a cranberry juice beverage
significantly reduced the clinical UTI incidence density in
women with a history of $2 UTIs in the previous year. These
results suggest that the consumption of cranberry is a useful
strategy for reducing recurrent clinical UTI episodes and anti-
biotic use that is associated with the treatment of these events.
We thank the following individuals for assistance with this trial: Ann
Stapleton, Marsha Cox, and Aurelio Silvestroni from the University of
Washington, Seattle, Washington (specimen analyses); Antonio Andreau
Domingo from the Servei de Microbiologia Hospital Universitari Vall
d’Hebron, Barcelona, Spain (specimen analyses); Thomas M Hooton from
the University of Miami Health Systems, Miami, Florida (study-design as-
sistance); and Barbara Davis, who is currently with PLT Health Solutions,
Morristown, New Jersey (study-design assistance). We also thank the fol-
lowing individuals who are affiliated with Biofortis Clinical Research,
Addison, Illinois, for their assistance: Jennifer Baldwin (monitoring of clin-
ical sites), Patti Shatkus (monitoring of clinical sites), DeAnn Liska (assis-
tance with the analysis and interpretation of the data), Mary Dicklin (writing
and editing assistance), and Mitchell Silverman (data management). The
UTI Study Group included the following principal investigators and sites:
Kathleen Kelley, Biofortis Clinical Research, Addison, Illinois; Jeffrey
Geohas, Evanston Premier Healthcare Research, Evanston, Illinois; Rovena
Reagan, Women’s Health Care Research Corp., San Diego, California;
Derek Muse, Jean Brown Research, Salt Lake City, Utah; Albert Tejada,
Radiant Research, Scottsdale, Arizona; Randall Severance, Radiant Re-
search, Chandler, Arizona; Michelle Reynolds, Radiant Research, Dallas,
Texas; Douglas Schumacher, Radiant Research, Columbus, Ohio; Larry
Kotek, Radiant Research, Edina, Minnesota; Stephen Halpern, Radiant Re-
search, Santa Rosa, California; Michael Noss, Radiant Research, Cincinnati,
Ohio; David Bolshoun, Radiant Research, Denver, Colorado; James Kopp,
Radiant Research, Anderson, South Carolina; E William Parker Jr. and
David Young, Physicians’ Research Options/Central Utah Clinic Women’s
Health, Pleasant Grove, Utah; Khai Chang, Lakeview Medical Research,
Summerfield, Florida; Susan Hole, Riverside Clinical Research, Edgewater,
Florida; Miriam Lara, Apple Med Research Inc., Miami, Florida; and David
Gendre, Biofortis SAS, France.
The authors’ responsibilities were as follows—KCM: designed and
conducted the research, performed the statistical analysis, wrote the manu-
script, and had primary responsibility for the final content of the manuscript;
KLK and CK: designed and conducted the research and wrote the manu-
script; LHD: conducted the research; ALS: performed the statistical analysis;
KG: designed the research and wrote the manuscript; and all authors: read
and approved the final manuscript. KCM, LHD, and ALS received research
grant funding from Ocean Spray Cranberries Inc., and KLK and CK are
employees of Ocean Spray Cranberries Inc., which is the manufacturer of
the product studied. KG reported no conflicts of interest related to the study.
REFERENCES
1. Foxman B, Barlow R, D’Arcy H, Gillespie B, Sobel JD. Urinary tract
infection: self-reported incidence and associated costs. Ann Epidemiol
2000;10:509–15.
2. Litwin MS, Saigal CS, Yano EM, Avila C, Gescgwind SA, Hanley JM,
Joyce GF, Madison R, Pace J, Polich SM, et al. Urologic Diseases in
America Project: analytical methods and principal findings. J Urol
2005;173:933–7.
3. Foxman B. Urinary tract infection syndromes: occurrence, recurrence,
bacteriology, risk factors, and disease burden. Infect Dis Clin North
Am 2014;28:1–13.
4. Schappert SM, Rechtsteiner EA. Ambulatory medical care utilization
estimates for 2007. Vital Health Stat 13 2011;169:1–38.
5. WangCH,FangCC,ChenNC,LiuSS,YuPH,WuTY,ChenWT,LeeCC,
Chen SC. Cranberry-containing products for prevention of urinary tract
infections in susceptible populations: a systemic review and meta-analysis
of randomized controlled trials. Arch Intern Med 2012;172:988–96.
6. Beerepoot MA, ter Riet G, Nys S, van der Wal WM, de Borgie CA, de
Reijke TM, Prins JM, Koeijers J, Verbon A, Stobberingh E, et al.
Cranberries vs antibiotics to prevent urinary tract infections: a ran-
domized double-blind noninferiority trial in premenopausal women.
Arch Intern Med 2011;171:1270–8.
7. Hooton TM. Uncomplicated urinary tract infection. N Engl J Med
2012;366:1028–37.
8. Trautner BW, Gupta K. The advantages to second best: comment on
Lactobacilli vs antibiotics to prevent urinary tract infections. Arch
Intern Med 2012;172:712–4.
9. Gupta K. Emerging antibiotic resistance in urinary tract pathogens.
Infect Dis Clin North Am 2003;17:243–59.
10. World Health Organization. Antimicrobial resistance global report on
surveillance [Internet]. 2014 (cited 2015 Apr 14). Available from: http://
apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf.
11. Cai T, Nesi G, Mazzoli S, Meacci F, Lanzafame P, Caciagli P, Mereu L,
Tateo S, Malossini G, Selli C, et al. Asymptomatic bacteriuria treat-
ment is associated with a higher prevalence of antibiotic resistant
strains in women with urinary tract infections. Clin Infect Dis 2015;61:
1655–61.
12. Wagenlehner FME, Naber KG. Treatment of asymptomatic bacteriuria
might be harmful. Clin Infect Dis 2015;61:1662–3.
13. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary
tract infections. Cochrane Database Syst Rev 2012;10:CD001321.
14. Eells SJ, McKinnell JA, Miller LG. Daily cranberry prophylaxis to
prevent recurrent urinary tract infections may be beneficial in some
populations of women. Clin Infect Dis 2011;52:1393–4.
15. Foxman B, Freichs RR. Epidemiology or urinary tract infection: II. Diet,
clothing, and urination habits. Am J Public Health 1985;75:1314–7.
16. Foxman B, Geiger AM, Palin K, Gillespie B, Koopman JS. First-time
urinary tract infection and sexual behavior. Epidemiology 1995;6:162–8.
17. Foxman B, Gillespie B, Koopman J, Zhang L, Pallin K, Tallman P,
Marsh JV, Spear S, Dobel JD, Marty MJ, et al. Risk factors for second
urinary tract infection among college women. Am J Epidemiol 2000;
151:1194–205.
18. Kontiokari T, Laitinen J, Jarvi L, Pokka R, Sundqvist K, Uhari M.
Dietary factors protecting women from urinary tract infection. Am J
Clin Nutr 2003;77:600–4.
19. United States Department of Agriculture. Composition of foods. In:
Agriculture handbook no. 8. Beltsville (MD): USDA; 1975. p. 159–160.
20. United States Department of Agriculture. Energy values of foods. In:
Agriculture handbook no. 74. Beltsville (MD): USDA; 1973. p. 2–11.
21. Martín MA, Ramos S, Mateos R, Marais JPJ, Bravo-Clemente L,
Khoo C, Goya L. Chemical characterization and chemo-protective
activity of cranberry phenolic powders in a model cell culture. Re-
sponse of the antioxidant defenses and regulation of signaling path-
ways. Food Res Int 2015;71:68–82.
22. United States Pharmacopeial Convention. Food chemical codex.
Baltimore (MD): United Book Press Inc.; 2010.
23. Prior RL, Fan E, Ji H, Howell A, Nio C, Payne MJ, Reed J. Multi-
laboratory validation of a standard method for quantifying proantho-
cyanidins in cranberry powders. J Sci Food Agric 2010;90:1473–8.
24. Krueger CG, Chesmore N, Chen X, Parker J, Khoo C, Marais JPJ,
Shanmuganayagam D, Crump P, Reed JD. Critical reevaluation of the
4-(dimethylamino)cinnamaldehyde assay: cranberry proanthocyanidin
standard is superior to procyanidin A2 dimer for accurate quantification of
proanthocyanidins in cranberry products. J Funct Foods 2016;22:13–9.
CRANBERRY JUICE AND CLINICAL UTI 1441
by guest on June 1, 2016ajcn.nutrition.orgDownloaded from
25. McKay DL, Chen CY, Zampariello CA, Blumberg JB. Flavonoids and
phenolic acids from cranberry juice are bioavailable and bioactive in
healthy older adults. Food Chem 2015;168:233–40.
26. Clayson D, Wild D, Doll H, Keating K, Gondek K. Validation of a patient-
administered questionnaire to measure the severity and bothersomeness of
lower urinary tract symptoms in uncomplicated urinary tract infection (UTI):
the UTI Symptom Assessment questionnaire. BJU Int 2005;96:350–9.
27. St John A, Boyd JC, Lowes AJ, Price CP. The use of urinary dipstick
tests to exclude urinary tract infection: a systematic review of the lit-
erature. Am J Clin Pathol 2006;126:428–36.
28. Nosseir SB, Lind LR, Winkler HA. Recurrent uncomplicated urinary
tract infections in women: a review. J Womens Health (Larchmt) 2012;
21:347–54.
29. Salo J, Uhari M, Helminen M, Korppi M, Nieminen T, Pokka T,
Kontiokari T. Cranberry juice for the prevention of recurrences of
urinary tract infections in children: a randomized placebo-controlled
trial. Clin Infect Dis 2012;54:340–6.
30. Gupta K, Hooton TM, Naber KG, Wult B, Colgan R, Miller LG, Moran
GJ, Nicolle LE, Raz R, Schaeffer AJ, et al. International clinical
practice guidelines for the treatment of acute uncomplicated cystitis
and pyelonephritis in women: a 2010 update by the Infectious Diseases
Society of America and the European Society for Microbiology and
Infectious Diseases. Clin Infect Dis 2011;52:e103–20.
31. Bent S, Nallamothu BK, Simel DL, Fihn SD, Saint S. Does this woman have
an acute uncomplicated urinary tract infection. JAMA 2002;287:2701–10.
32. Faul F, Erdfelder E, Lang AG, Buchner AG. G*Power 3: a flexible
statistical power analysis program for the social, behavioral, and bio-
medical sciences. Behav Res Methods 2007;39:175–91.
33. Shapiro SS, Wilk MB. An analysis of variance test for normality
(complete samples). Biometrika 1965;52:591–611.
34. Stokes MA, Davis S, Koch GG. Categorical data analysis using the
SAS system. 2nd ed. Cary (NC): SAS Institute Inc.; 2000.
35. Kleinbaum DG, Klein M. Survival analysis. A self learning text. 2nd
ed. New York: Springer; 2005.
36. Jepson RG, Craig JC. Cranberries for preventing urinary tract in-
fections. Cochrane Database Syst Rev 2008;1:CD001321.
37. Barbosa-Cesnik C, Brown MB, Buxton M, Zhang L, De Busscher J,
Foxman B. Cranberry juice fails to prevent recurrent urinary tract in-
fection: results from a randomized placebo-controlled trial. Clin Infect
Dis 2011;52:23–30.
38. Stapleton AE, Dziura J, Hooton TM, Cox ME, Yarova-Yarova Y, Chen
S, Gupta K. Recurrent urinary tract infection and urinary Escherichia
coli in women ingesting cranberry juice daily: a randomized controlled
trial. Mayo Clin Proc 2012;87:143–50.
39. Zhang L, Foxman B. Molecular epidemiology of Escherichia coli
mediated urinary tract infections. Front Biosci 2003;8:e235–44.
40. Lavigne JP, Bourg G, Combescure C, Botto H, Sotto A. In-vitro and in-
vivo evidence of dose-dependent decrease of uropathogenic Escherichia
coli virulence after consumption of commercial Vaccinium macrocarpon
(cranberry) capsules. Clin Microbiol Infect 2008;14:350–5.
41. Harmidy K, Tufenkji N, Gruenheid S. Perturbation of host cell cyto-
skeleton by cranberry proanthocyanidins and their effect on enteric
infections. PLoS One 2011;6:e27267.
42. Feliciano RP, Meudt JJ, Shanmuganayagam D, Krueger CG, Reed JD.
Ratio of “A-type” to “B-type” proanthocyanidin interflavan bonds af-
fects extra-intestinal pathogenic Escherichia coli invasion of gut epi-
thelial cells. J Agric Food Chem 2014;62:3919–25.
43. Krueger CG, Reed JD, Feliciano RP, Howell AB. Quantifying and
characterizing proanthocyanidins in cranberries in relation to urinary
tract health. Anal Bioanal Chem 2013;405:4385–95.
44. Huang Y, Nikolic D, Pendland S, Doyle BJ, Locklear TD, Mahady GB.
Effects of cranberry extracts and ursolic derivatives on P-fimbriated
Escherichia coli, COX-2 activity, pro-inflammatory cytokine release
and the NF-kappa-beta transcriptional response in vitro. Pharm Biol
2009;47:18–25.
45. Vasileiou I, Katsargyris A, Theocharis S, Giagninis C. Current clinical
status on the preventive effects of cranberry consumption against uri-
nary tract infections. Nutr Res 2013;33:595–607.
46. Denis MC, Desjardins Y, Furtos A, Marcil V, Dudonne S, Montoudis
A, Garofalo C, Delvin E, Marette A, Levy E. Prevention of oxidative
stress, inflammation and mitochondrial dysfunction in the intestine by
different cranberry phenolic fractions. Clin Sci (Lond) 2015;128:197–
212.
47. Robino L, Algorta G, Zunino P, Vignoli R. Detection of intracellular
bacterial communities in a child with Escherichia coli recurrent urinary
tract infections. Pathog Dis 2013;68:78–81.
48. Finer G, Landau D. Pathogenesis of urinary tract infections with nor-
mal female anatomy. Lancet Infect Dis 2004;4:631–5.
49. Hannan TJ, Mysorekar IU, Hung CS, Isaacson-Schmid ML, Hultgren
SJ. Early severe inflammatory responses to uropathogenic E. coli
predispose to chronic and recurrent urinary tract infection. PLoS
Pathog 2010;6:e1001042.
50. Hannan TJ, Roberts PL, Riehl TE, van der Post S, Binkley JM,
Schwartz DJ, Myoshi H, Mack M, Schwendener RA, Hooton TM, et al.
Inhibition of cyclooxygenase-2 prevents chronic and recurrent cystitis.
EBioMedicine 2014;1:46–57.
1442 MAKI ET AL.
by guest on June 1, 2016ajcn.nutrition.orgDownloaded from
