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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

  • Midwest Center for Metabolic and Cardiovascular Research

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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 cranberry beverage on episodes of clinical UTIs. Design: In this randomized, double-blind, placebo-controlled, multicenter 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 clinical 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 significantly 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 as NCT01776021.
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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
Kevin C Maki,
* Kerrie L Kaspar,
Christina Khoo,
Linda H Derrig,
Arianne L Schild,
and Kalpana Gupta
Biofortis Clinical Research, Addison, IL;
MB Clinical Research, Glen Ellyn, IL;
Ocean Spray Cranberries, Lakeville-Middleboro, MA;
Department of
Medicine, Boston University School of Medicine, Boston, MA; and
VA Boston Healthcare System, Boston, MA
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
as NCT01776021. Am J Clin Nutr 2016;103:1434–42.
Keywords: antibiotics, bacteria, cranberry, inflammation,
proanthocyanidin, urinary tract infection, women
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.
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
Supported by Ocean Spray Cranberries Inc. Beverages were provided by
Ocean Spray Cranberries Inc. This is a free access article, distributed under
terms (
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@
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.
Eligible subjects included women who were 20–70 y of age
with BMI (in kg/m
),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
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
Study-product composition
Component Cranberry beverage Placebo beverage
kcal 36 34
g 6.3 60.1
6.9 60.3
Organic acids,
g 2.0 60.1 1.9 60.2
Vitamin C,
mg ND ND
Proanthocyanidins, mg
DMAC-method I
41.1 67.1 ND
DMAC-method II
119 616.9 ND
mg 1.3 60.8 ND
Phenolic acids,
mg 5.4 60.8 ND
Flavanols and flavonols,
mg 8.3 63.6 ND
Total phenolics,
mg 135 630.7 17.0 65.4
DMAC, 4-dimethylaminocinnamaldehyde; ND, not detected.
Determined with the use of Atwater factors (Covance Laboratory)
Determined with the use of the carbohydrate by difference method
Measured with the use of HPLC (21).
Mean 6SD where applicable per 240-mL serving (all such values).
Measured with the use of ion chromatography (21).
Measured with the use of an iodiometric titration method (22).
Determined with the use of a DMAC colorimetric method with
procyanidin A2 as a standard (23).
Determined with the use of a modified DMAC colorimetric method
with the cranberry proanthocyanidin standard isolated and purified from
cranberry juice concentrate (21, 24).
Determined with the use of HPLC (25).
Determined with the use of the Folin-Ciocalteu reagent colorimetric
method (21).
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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.
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
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 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.
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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.
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).
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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
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
Demographic and baseline characteristics of subjects receiving cranberry or placebo beverages
Characteristic Cranberry group (n= 185) Placebo group (n= 188) P
Age, y 40.9 61.1
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)
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)
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,
n(%) 2 (1.1) 6 (3.2) 0.284
BMI, kg/m
27.0 60.4 26.5 60.4 0.346
Categorical BMI, kg/m
,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,
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)
Baseline comparability of treatment groups for subject characteristics was assessed with the use of ANOVA and chi-
square tests. UTI, urinary tract infection.
Mean 6SEM (all such values).
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.
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.
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.
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.
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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),
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
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
Cranberry group
(n= 185)
Placebo group
(n= 188)
Incidence rate ratio
(95% CI)
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)
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
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)
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
0.43 (0.42, 0.45) 0.67 (0.65, 0.68) 0.63 (0.40, 0.97) 0.037
UTI, urinary tract infection.
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.
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.
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).
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
= 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
Bacterial species identified in urine cultures collected when women who
were consuming cranberry or placebo beverages reported a symptomatic
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)
E.coli and Enterococci 01
Sum 30 34
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.
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... Cranberry trials used either a capsule (A1 [41], A3 [45], A4 [46], A5 [47], A10 [33], A11 [50] and A12 [51]) or juice (A2 [44], A6 [48], A7 [49], A8 [42] and A9 [43]) to administer the active ingredients to their patients (Table 1A). Regarding the cranberry control group, all except trials A6 [48], A10 [33], A11 [50] and A12 [51] used a placebo. ...
... One of the complicating factors in conducting this systematic literature review was that there is little agreement in terms of the measures of success used in the various studies (Table 2). Sixteen of the trials including A1 [41], A2 [44], A3 [45], A4 [46], A5 [47], A6 [48], A7 [49], A8 [42], A9 [43], A10 [33], A11 [50], B1 [52], B2 [53], C1 [54], C2 [55] and D4 [58] measured the number of UTIs experienced by patients during the study period (Table 3). If there was a statistically significant reduction in the number of UTIs, this was deemed successful by the authors. ...
... If there was a statistically significant reduction in the number of UTIs, this was deemed successful by the authors. Six trials were interested in time to first UTI (A1 [41], A2 [44], A3 [45], A4 [46], A10 [33], B1 [52]). Eleven trials calculated the percentage of patients who were free of UTI during the study period as a measure of success (A1 [41], A2 [44], A3 [45], A6 [48], A7 [49], A8 [42], A10 [33], A11 [50], A12 [51], C1 [54], C2 [55]). ...
Full-text available
The use of antibiotics in the treatment of UTIs is contributing to resistance. Hence, the outcome of human clinical trials of nonantibiotic remedies for preventing or treating UTI is of significant interest. This systematic review aimed to identify, summarise and evaluate the evidence for the outcomes of different nonantibiotic options including cranberry, D-mannose and non-steroidal anti-inflammatory drugs (NSAIDs). PubMed, Embase and Scopus were searched for manuscripts relating to nonantibiotic treatment of UTI including cranberry, mannose and NSAIDs. After title and abstract screening, data were extracted from 21 papers that were published in English and related to the treatment or prevention of uncomplicated UTI in adult women. We identified twelve papers examining the effects of cranberry, two papers examining D-mannose, two papers examining combination treatments (cranberry and D-mannose) and five manuscripts investigating the effects of NSAIDs. There is low-level evidence, from a small number of studies, supporting the use of D-mannose or combination treatments for potentially preventing UTIs in adult women without producing burdening side effects. However, larger and more randomised double-blinded trials are needed to confirm this. In comparison, the multiple studies of cranberry and NSAIDs produced conflicting evidence regarding their effectiveness.
... Health benefits evidence also exist for niche berries, but either with less reports available for example with black and red currants (Burgos-Edwards et al., 2020;McDougall et al., 2005;Shimada et al., 2022), or with more specific health benefits for example with cranberries (Al Othaim et al., 2021;Maki et al., 2018Maki et al., , 2016 and elderberries (Ferreira et al., 2022b). ...
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Polyphenols have been extensively profiled and quantified in commercially grown berries, but similar information is sparsely available for wild berries. Because polyphenolic contents are inherently associated with berries health benefits, determining phenolic profiles is an important step for strategizing potential uses by the industry and for health and nutrition outcomes. Here, we profiled phenolic compounds in wild berries commonly encountered and harvested in the Pacific Northwest region of North America. Huckleberries (Vaccinium membranaceum) of varying phenotypes were found to be comparable to related blueberries in terms of general phenolic classes composition. However, all huckleberries exhibited markedly high levels of cyanidins, and delphinidins or peonidins were also higher in specific phenotypes. Wild black elderberries (Sambucus nigra spp. Canadensis) were found to have remarkably high phenolic, especially anthocyanins, in line with reports from cultivated elderberries. Saskatoon serviceberries (Amelanchier alnifolia) were found to exhibit high polyphenol content, but with a less diverse profile dominated by quercetin. The most intriguing berry may be the Oregon grape (Mahonia Aquifolium) being the only one exhibiting more than one g of polyphenols per 100 g; as well as a remarkably even distribution of the different anthocyanin classes. All colored wild berries were found to have at minimum comparable total phenolic contents when compared to cultivated and other wild berries, suggesting they should exhibit comparable human health benefits such as antioxidant and metabolic syndrome preventative potential described for these other berries. Overall, our data represents a valuable resource to explore the potential to valorize wild berry species for their specific phenolic profiles and predicted nutritional and health properties. With repeated phenolic profiling to better understand the impact of the environment, the wild berries described here hold promises both as food ingredient applications as well as valuable complement for healthy dietary patterns.
... Concerning the effects of cranberry products in vivo, several recent studies have reported interesting results. Maki et al., in a randomized, doubleblind, placebo-controlled multicenter clinical trial involving 373 women with a recent history of UTIs consuming 240 mL of cranberry beverage per day, reported a 40% reduction in the incidence of UTIs compared to the placebo with one clinical UTI event prevented for every 3.2 women [78]. In an analogous study by Koradia et al. involving 81 women followed up for 26 weeks, the supplementation of cranberry products significantly lowered the number of UTIs (with 90% of patients in the intervention group which did not report a UTI event compared to 67% of the control group) and increased the time to first UTI (174 days versus 90 days) [79]. ...
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Urinary tract infections represent a common and significant health concern worldwide. The high rate of recurrence and the increasing antibiotic resistance of uropathogens are further worsening the current scenario. Nevertheless, novel key ingredients such as D-mannose, chondroitin sulphate, hyaluronic acid, and N-acetylcysteine could represent an important alternative or adjuvant to the prevention and treatment strategies of urinary tract infections. Several studies have indeed evaluated the efficacy and the potential use of these compounds in urinary tract health. In this review, we aimed to summarize the characteristics, the role, and the application of the previously reported compounds, alone and in combination, in urinary tract health, focusing on their potential role in urinary tract infections.
... Recent randomised trials (using various placebos and cranberry products) to assess the effects of cranberries in young women with recurrent UTIs produced mixed results, with one trial showing a significant reduction in UTI incidence as compared to placebo; three trials didn't show any significant difference between the two groups in reducing UTIs 15,16,17,18 and conflicting results were found in clinical trials in the paediatric population 14 . In individuals receiving radiotherapy, chemotherapy, or being pregnant, there is no conclusive data to support the usefulness of cranberries in preventing UTIs. ...
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Cranberry (Vaccinium macrocarpon) is known to have a therapeutic potential on human health. Several phytochemicals found in cranberry namely flavonol glysodies, proanthocyanidins and phenolic acids are known to contribute to its anti-microbial, anti-oxidant, and anti-inflammatory properties. In vitro studies have shown that cranberry may be potential therapeutic agents for the prevention and management of periodontal disease. This review focused on the beneficial effect of cranberry on oral and periodontal health and three possible mechanisms of action of cranberry on inhibiting the periodontal tissue destruction. Three possible targets of cranberry PACs include (i) periodontopathogens, (ii) host inflammatory immune response, and (iii) osteoclast differentiation and activity. Given that cranberry and its phytochemical constituents have shown beneficial effects in vitro, clinical trials are warranted to better evaluate the potential of these constituents for controlling and prevention of periodontal tissue destruction.
... Several clinical studies suggest that the intake of cranberry juice or cranberry supplements can reduce the occurrence of UTIs in healthy women [36,37]. These observations were supported by the results of in vitro research, which show that compounds derived from cranberry (polyphenols and type A proanthocyanidins, for example) can interfere with bacterial adherence to epithelial cells of the urinary tract, attenuate the uropathogenic reservoir in the gastrointestinal tract, and suppress the inflammatory cascade [38,39]. ...
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Cranberry is scientifically known as Vaccinium macrocarpon, belongs to the family of Ericaceae grows in humid environments, such as forests and swamps in North American countries. It is widely used by Native American peoples and by Europeans as a food and also in traditional medicine by health benefits such as cardioprotective, anticarcinogenic and prevention of stomach ulcers. According to the research by Salo claim that the fruit is composed of 88% water, acid organic, fruits, vitamin C, flavonoids, catechins and anthocyanidins. It can be found in the form of dried fruits, extracts and juices, which usually contain only 10 to 25% Cranberry concentrate. In addition, reveal that anthocyanidins and the proanthocyanidins present in Cranberry, are tannins with a natural defense function against microorganisms, such as those responsible for urinary tract infections (UTI). This berry has a potential curative and preventive effect for various diseases, especially urinary tract infection. Therefore, it becomes relevant to clarify the effect of this natural product on different types of diseases.
... The exploration and investigation of alternative immunomodulatory therapies, such as cranberry extract (which increases the Tamm-Horsfall glycoprotein to inhibit bacterial adhesion) [60][61][62][63], vitamin C and anthocyanins (which inhibit reactive oxygen species production to prevent urinary infections) [64][65][66][67], dietary restriction of iron, and lactoferrin supplementation (which reduces bacterial density in the urinary tract, particularly in cases with siderophore characteristics) [68,69], and subcutaneous insulin injections in diabetic patients (to promote the secretion of RNase 7, RNase4, and lipocalin-2 to prevent cystitis) [70,71], as well as vaccines [72,73] and probiotics [52], present promising avenues for future medical advancements. However, studies that investigated the use of immunomodulatory therapies as alternatives to antibiotics currently lack clinical significance, leading to a debate on the use and applications of these therapies. ...
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The genitourinary microbiome plays a crucial role in the establishment and maintenance of urinary and reproductive health in women throughout their lives. Particularly during the reproductive stage, resident microorganisms contribute to implantation and protect against perinatal complications, including preterm birth, stillbirth, and low birth weight, while also serving as the first line of defense against pathogens that can cause infections, such as urinary tract infections and bacterial vaginosis. This review aimed to elucidate the relationship between a healthy microbiome environment and women’s overall health. We examine the variability and dynamics of the microbiome during different developmental stages, ranging from the prepubertal to the postmenopausal stage. Furthermore, we explore the significance of a healthy microbiota in successful implantation and pregnancy development and investigate potential differences between women experiencing infertility. In addition, we analyze the local and systemic inflammatory responses associated with the establishment of a dysbiotic state and compare it to a condition where a healthy microbiome was established. Lastly, we present the most recent evidence regarding preventive measures, such as dietary interventions and the use of probiotics to promote and maintain a healthy microbiome, thereby ensuring comprehensive women’s health. By highlighting the importance of the genitourinary microbiome in reproductive health, this review aimed to enhance this microbiome’s visibility and significance in the field.
The gut and local esophageal microbiome progressively shift from healthy commensal bacteria to inflammatory-linked pathogenic bacteria in patients with gastroesophageal reflux disease, Barrett's esophagus and esophageal adenocarcinoma (EAC). However, mechanisms by which microbial communities and metabolites contribute to reflux-driven EAC remain incompletely understood and challenging to target. Herein, we utilized a rat reflux-induced EAC model to investigate targeting the gut microbiome-esophageal metabolome axis with cranberry proanthocyanidins (C-PAC) to inhibit EAC progression. Sprague Dawley rats, with or without reflux-induction received water or C-PAC ad libitum (700 μg/rat/day) for 25 or 40 weeks. C-PAC exerted prebiotic activity abrogating reflux-induced dysbiosis, and mitigating bile acid metabolism and transport, culminating in significant inhibition of EAC through TLR/NF-κB/P53 signaling cascades. At the species level, C-PAC mitigated reflux-induced pathogenic bacteria (Clostridium perfringens, Escherichia coli, and Proteus mirabilis). C-PAC specifically reversed reflux-induced bacterial, inflammatory and immune-implicated proteins and genes including Ccl4, Cd14, Crp, Cxcl1, Il6, Il1β, Lbp, Lcn2, Myd88, Nfkb1, Tlr2 and Tlr4 aligning with changes in human EAC progression, as confirmed through public databases. C-PAC is a safe promising dietary constituent that may be utilized alone or potentially as an adjuvant to current therapies to prevent EAC progression through ameliorating reflux-induced dysbiosis, inflammation and cellular damage.
Shelf-stable cranberry juice precipitate has not been well characterized. Here, we describe using 1H-13C heteronuclear single quantum coherence-nuclear magnetic resonance (HSQC-NMR) spectroscopy for cranberry juice analysis, focusing on proanthocyanidins and the precipitate. HSQC-NMR cross-peaks from juices were categorized as aliphatic, olefinic, aromatic, carbohydrate backbone, or anomeric signals. An average cranberry juice precipitate had significantly more aromatic and significantly less carbohydrate backbone signals than an average supernatant. The precipitate was a collection of biomolecules held together by a mix of weak and strong intermolecular forces. Proanthocyanidin signals from precipitates of juices showed 22 ± 2 to 29.9 ± 0.7% A-type interflavan linkages and 34 ± 2 to 48 ± 3% of flavan-3-ol units with trans stereochemistry between the C2 and C3 positions. Based on this work, 1H-13C HSQC-NMR is useful to analyze cranberry juice and reveals the complex chemical nature of components in the soluble and insoluble phases.
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Background: Cranberries contain proanthocyanidins (PACs), which inhibit the adherence of p-fimbriated Escherichia coli to the urothelial cells lining the bladder. Cranberry products have been used widely for several decades to prevent urinary tract infections (UTIs). This is the fifth update of a review first published in 1998 and updated in 2003, 2004, 2008, and 2012. Objectives: To assess the effectiveness of cranberry products in preventing UTIs in susceptible populations. Search methods: We searched the Cochrane Kidney and Transplant Specialised Register up to 13 March 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register Search Portal (ICTRP) and Selection criteria: All randomised controlled trials (RCTs) or quasi-RCTs of cranberry products compared with placebo, no specific treatment or other intervention (antibiotics, probiotics) for the prevention of UTIs were included. Data collection and analysis: Two authors independently assessed and extracted data. Information was collected on methods, participants, interventions and outcomes (incidence of symptomatic UTIs, positive culture results, side effects, adherence to therapy). Risk ratios (RR) with 95% confidence intervals (CI) were calculated where appropriate. Study quality was assessed using the Cochrane risk of bias assessment tool. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results: For this update 26 new studies were added, bringing the total number of included studies to 50 (8857 randomised participants). The risk of bias for sequence generation and allocation concealment was low for 29 and 28 studies, respectively. Thirty-six studies were at low risk of performance bias, and 23 studies were at low risk of detection bias. Twenty-seven, 41, and 17 studies were at low risk of attrition bias, reporting bias and other bias, respectively. Forty-five studies compared cranberry products with placebo or no specific treatment in six different groups of participants. Twenty-six of these 45 studies could be meta-analysed for the outcome of symptomatic, culture-verified UTIs. In moderate certainty evidence, cranberry products reduced the risk of UTIs (6211 participants: RR 0.70, 95% CI 0.58 to 0.84; I² = 69%). When studies were divided into groups according to the treatment indication, cranberry products probably reduced the risk of symptomatic, culture-verified UTIs in women with recurrent UTIs (8 studies, 1555 participants: RR 0.74, 95% CI 0.55 to 0.99; I² = 54%), in children (5 studies, 504 participants: RR 0.46, 95% CI 0.32 to 0.68; I² = 21%) and in people with a susceptibility to UTIs due to an intervention (6 studies, 1434 participants: RR 0.47, 95% CI 0.37 to 0.61; I² = 0%). However, in low certainty evidence, there may be little or no benefit in elderly institutionalised men and women (3 studies, 1489 participants: RR 0.93, 95% CI 0.67 to 1.30; I² = 9%), pregnant women (3 studies, 765 participants: RR 1.06, 95% CI 0.75 to 1.50; I² = 3%), or adults with neuromuscular bladder dysfunction with incomplete bladder emptying (3 studies, 464 participants: RR 0.97, 95% CI 0.78 to 1.19; I² = 0%). Other comparisons were cranberry products with probiotics (three studies) or antibiotics (six studies), cranberry tablets with cranberry liquid (one study), and different doses of PACs (two studies). Compared to antibiotics, cranberry products may make little or no difference to the risk of symptomatic, culture-verified UTIs (2 studies, 385 participants: RR 1.03, 95% CI 0.80 to 1.33; I² = 0%) or the risk of clinical symptoms without culture (2 studies, 336 participants: RR 1.30, 95% CI 0.79 to 2.14; I² = 68%). Compared to probiotics, cranberry products may reduce the risk of symptomatic, culture-verified UTIs (3 studies, 215 participants: RR 0.39, 95% CI 0.27 to 0.56; I = 0%). It is unclear whether efficacy differs between cranberry juice and tablets or between different doses of PACs as the certainty of the evidence was very low. The number of participants with gastrointestinal side effects probably does not differ between those taking cranberry products and those receiving placebo or no specific treatment (10 studies, 2166 participants: RR 1.33, 95% CI 1.00 to 1.77; I² = 0%; moderate certainty evidence). There was no clear relationship between compliance with therapy and the risk for repeat UTIs. No difference in the risk for UTIs could be demonstrated between low, moderate and high doses of PACs. Authors' conclusions: This update adds a further 26 studies taking the total number of studies to 50 with 8857 participants. These data support the use of cranberry products to reduce the risk of symptomatic, culture-verified UTIs in women with recurrent UTIs, in children, and in people susceptible to UTIs following interventions. The evidence currently available does not support its use in the elderly, patients with bladder emptying problems, or pregnant women.
Cranberry (Vaccinium spp.) has been used by North American Indians to treat many medicinal properties. It is also recommended for the treatment of urinary tract infection (UTI) which is caused by adhesion of bacteria called Escherichia coli. We conducted this meta-analysis to assess the effect of cranberry in preventing the adhesion of E. coli in the urinary tract. Cranberry appears to work by inhibiting the adhesion of type I and P-fimbriated Escherichia coli to the uroepithelium, thus hinder the colonization and upcoming infections. Adhesion is prevented by 2 ingredients of cranberries: laevulose that prevents binding of type 1 fimbriae and pro-anthocyanidins, which prevents p- fimbriae binding. The anti-adherent effect began in 2 hours and remains for up to 10 hours after consumption. These results suggest that cranberry can be an effective in preventing and treating urinary tract infections; however, larger high-quality studies are needed to confirm these findings.
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(See the Major Article by Cai et al on pages 1655–61.) In this issue of Clinical Infectious Diseases, Cai et al present a follow-up study [1] to their previously published prospectively randomized cohort study in which female patients with recurrent urinary tract infection (UTI) were followed clinically, but also investigated microbiologically at regular visits up to 1 year [2]. One group (A) was not treated, and the other group (B) was treated if asymptomatic bacteriuria was diagnosed, with the result that more symptomatic UTIs occurred in group B than in group A. The present study started immediately after the end of the first study. The patients remained in their groups and were followed every 6 months up to about 3 years. However, in the follow-up study [1], patients received antibiotic therapy only in case of a symptomatic UTI. Nevertheless, group B experienced statistically significantly more symptomatic UTIs than group A, although the therapeutic strategy was the same. In addition, the resistance rates of isolated Escherichia coli against amoxicillin-clavulanic acid, cotrimoxazole, and ciprofloxacin were significantly higher in group B than in group A. This finding is especially interesting, as these antibiotics were used only in a few cases during the follow-up study. In 2 previous studies, continuous antibiotic prophylaxis with cotrimoxazole was compared to prophylaxis with cranberry [3] or lactobacilli [4]. Both studies showed higher resistance rates of commensal E. coli to cotrimoxazole in urine and feces in the antibiotic arms compared with the nonantibiotic arms. Thus, the question arises whether the higher antibiotic resistance in the studies by Cai et al occurred already during the first study [2], because in the current study [1], both groups were treated with the same antibiotic strategy. Considering both studies together, a somewhat higher antibiotic consumption was found in group B, which apparently translated also into higher antibiotic resistance rates of the urinary pathogens. The results of all these studies confirm the current guidelines [5] to preferably incorporate nonantibiotic strategies for prevention of these very frequent, but generally benign infections, if these strategies are confirmed to be effective in well-designed clinical studies [6]. Such strategies may also be important to decrease the general antibiotic consumption in the population and thus to slow down emergence of antibiotic resistance; as shown in an interventional comparative study, antibiotic resistance, once established, has a low probability to be reversed, at least for trimethoprim and cotrimoxazole [7].
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Background: Women suffering from recurrent urinary tract infections (rUTIs) are routinely treated for asymptomatic bacteriuria (AB), but the consequences of this procedure on antibiotic resistance are not fully known. The aim of this study was to evaluate the impact of AB treatment on antibiotic resistance among women with rUTIs. Methods: The study population consisted of 2 groups of women who had previously been enrolled in a randomized clinical trial: group A was not treated, and group B was treated. All women were scheduled for follow-up visits every 6 months, or more frequently if symptoms arose. Microbiological evaluation was performed only in symptomatic women. All women were followed up for a mean of 38.8 months to analyze data from urine cultures and antibiograms. Results: The previous study population consisted of 673 women, but 123 did not attend the entire follow-up period. For the final analysis, 257 of the remaining 550 patients were assigned to group A, and 293 to group B. At the end of follow-up, the difference in recurrence rates was statistically significant (P < .001): 97 (37.7%) in group A versus 204 (69.6%) in group B. Isolated Escherichia coli from group B showed higher resistance to amoxicillin-clavulanic acid (P = .03), trimethoprim-sulfamethoxazole (P = .01), and ciprofloxacin (P = .03) than that from group A. Conclusions: This study shows that AB treatment is associated with a higher occurrence of antibiotic-resistant bacteria, indicating that AB treatment in women with rUTIs is potentially dangerous.
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The spread of multidrug-resistant microorganisms globally has created an urgent need for novel therapeutic strategies to combat urinary tract infections (UTIs). Immunomodulatory therapy may provide benefit, as treatment of mice with dexamethasone during acute UTI improved outcome by reducing the development of chronic cystitis, which predisposes to recurrent infection. Here we discovered soluble biomarkers engaged in myeloid cell development and chemotaxis that were predictive of future UTI recurrence when elevated in the sera of young women with UTI. Translation of these findings revealed that temperance of the neutrophil response early during UTI, and specifically disruption of bladder epithelial transmigration of neutrophils by inhibition of cyclooxygenase-2, protected mice against chronic and recurrent cystitis. Further, proteomics identified bladder epithelial remodeling consequent to chronic infection that enhances sensitivity to neutrophil damage. Thus, cyclooxygenase-2 expression during acute UTI is a critical molecular trigger determining disease outcome and drugs targeting cyclooxygenase-2 could prevent recurrent UTI.
This greatly expanded second edition of Survival Analysis- A Self-learning Text provides a highly readable description of state-of-the-art methods of analysis of survival/event-history data. This text is suitable for researchers and statisticians working in the medical and other life sciences as well as statisticians in academia who teach introductory and second-level courses on survival analysis. The second edition continues to use the unique "lecture-book" format of the first (1996) edition with the addition of three new chapters on advanced topics: Chapter 7: Parametric Models Chapter 8: Recurrent events Chapter 9: Competing Risks. Also, the Computer Appendix has been revised to provide step-by-step instructions for using the computer packages STATA (Version 7.0), SAS (Version 8.2), and SPSS (version 11.5) to carry out the procedures presented in the main text. The original six chapters have been modified slightly to expand and clarify aspects of survival analysis in response to suggestions by students, colleagues and reviewers, and to add theoretical background, particularly regarding the formulation of the (partial) likelihood functions for proportional hazards, stratified, and extended Cox regression models David Kleinbaum is Professor of Epidemiology at the Rollins School of Public Health at Emory University, Atlanta, Georgia. Dr. Kleinbaum is internationally known for innovative textbooks and teaching on epidemiological methods, multiple linear regression, logistic regression, and survival analysis. He has provided extensive worldwide short-course training in over 150 short courses on statistical and epidemiological methods. He is also the author of ActivEpi (2002), an interactive computer-based instructional text on fundamentals of epidemiology, which has been used in a variety of educational environments including distance learning. Mitchel Klein is Research Assistant Professor with a joint appointment in the Department of Environmental and Occupational Health (EOH) and the Department of Epidemiology, also at the Rollins School of Public Health at Emory University. Dr. Klein is also co-author with Dr. Kleinbaum of the second edition of Logistic Regression- A Self-Learning Text (2002). He has regularly taught epidemiologic methods courses at Emory to graduate students in public health and in clinical medicine. He is responsible for the epidemiologic methods training of physicians enrolled in Emory’s Master of Science in Clinical Research Program, and has collaborated with Dr. Kleinbaum both nationally and internationally in teaching several short courses on various topics in epidemiologic methods.
The 4-(dimethylamino)cinnamaldehyde (DMAC) assay is currently used to quantify proanthocyanidin (PAC) content in cranberry products. In a multi-operator/multi-day study design, a cranberry proanthocyanidin (c-PAC) standard was compared to procyanidin A2 (ProA2) dimer for accurate quantification of PAC in commercial cranberry juices, lab generated cranberry blends and cranberry powders. The c-PAC standard reflects the structural heterogeneity of cranberry PAC degree of polymerization, hydroxylation pattern and ratios of ‘A-type’ to ‘B-type’ interflavanyl bonds. Use of the c-PAC standard to quantify PAC content in cranberry samples resulted in values that were 3.6 times higher than those determined by ProA2. Overall, there was no effect (P > 0.05) of operator or day on estimation of PAC concentration. The adoption of c-PAC standard should be considered as an improvement over the use of ProA2 for accurate quantification of cranberry PAC. Improved standardization of bioactive PAC components in functional cranberry foods will aid in establishment of dosage guidelines.
Context Symptoms suggestive of acute urinary tract infection (UTI) constitute one of the most common reasons for women to visit clinicians. Although the clinical encounter typically involves taking a history and performing a physical examination, the diagnostic accuracy of the clinical assessment for UTI remains uncertain.Objective To review the accuracy and precision of history taking and physical examination for the diagnosis of UTI in women.Data Sources We conducted a MEDLINE search for articles published from 1966 through September 2001 and manually reviewed bibliographies, 3 commonly used clinical skills textbooks, and contacted experts in the field.Study Selection Studies were included if they contained original data on the accuracy or precision of history or physical examination for diagnosing acute uncomplicated UTI in women. One author initially screened titles and abstracts found by our search. Nine of 464 identified studies met inclusion criteria.Data Extraction Two authors independently abstracted data from the included studies. Disagreements were resolved by discussion and consensus with a third author.Data Synthesis Four symptoms and 1 sign significantly increased the probability of UTI: dysuria (summary positive likelihood ratio [LR], 1.5; 95% confidence interval [CI], 1.2-2.0), frequency (LR, 1.8; 95% CI, 1.1-3.0), hematuria (LR, 2.0; 95% CI, 1.3-2.9), back pain (LR, 1.6; 95% CI, 1.2-2.1), and costovertebral angle tenderness (LR, 1.7; 95% CI, 1.1-2.5). Four symptoms and 1 sign significantly decreased the probability of UTI: absence of dysuria (summary negative LR, 0.5; 95% CI, 0.3-0.7), absence of back pain (LR, 0.8; 95% CI, 0.7-0.9), history of vaginal discharge (LR, 0.3; 95% CI, 0.1-0.9), history of vaginal irritation (LR, 0.2; 95% CI, 0.1-0.9), and vaginal discharge on examination (LR, 0.7; 95% CI, 0.5-0.9). Of all individual diagnostic signs and symptoms, the 2 most powerful were history of vaginal discharge and history of vaginal irritation, which significantly decreased the likelihood of UTI when present (LRs, 0.3 and 0.2, respectively). One study examined combinations of symptoms, and the resulting LRs were more powerful (24.6 for the combination of dysuria and frequency but no vaginal discharge or irritation). One study of patients with recurrent UTI found that self-diagnosis significantly increased the probability of UTI (LR, 4.0).Conclusions In women who present with 1 or more symptoms of UTI, the probability of infection is approximately 50%. Specific combinations of symptoms (eg, dysuria and frequency without vaginal discharge or irritation) raise the probability of UTI to more than 90%, effectively ruling in the diagnosis based on history alone. In contrast, history taking, physical examination, and dipstick urinalysis are not able to reliably lower the posttest probability of disease to a level where a UTI can be ruled out when a patient presents with 1 or more symptoms.
Oxidative stress and reactive oxygen species (ROS)-mediated cell damage are implicated in various chronic pathologies. Emerging studies show that polyphenols may act by increasing endogenous antioxidant defense potential. Cranberry has one of the highest polyphenol content among commonly consumed fruits. In this study, the hepato-protective activity of a cranberry juice (CJ) and cranberry extract (CE) powders against oxidative stress was screened using HepG2 cells, looking at ROS production, intracellular non-enzymatic and enzymatic antioxidant defenses by reduced glutathione concentration (GSH), glutathione peroxidase (GPx) and glutathione reductase (GR) activity and lipid peroxidation biomarker malondialdehyde (MDA). Involvement of major protein kinase signaling pathways was also evaluated. Both powders in basal conditions did not affect cell viability but decreased ROS production and increased GPx activity, conditions that may place the cells in favorable conditions against oxidative stress. Powder pre-treatment of HepG2 cells for 20 h significantly reduced cell damage induced by 400 μM tert-butylhydroperoxide (t-BOOH) for 2 h. Both powders (5–50 μg/ml) reduced t-BOOH-induced increase of MDA by 20% (CJ) and 25% (CE), and significantly reduced over-activated GPx and GR. CE, with a significantly higher amount of polyphenols than CJ, prevented a reduction in GSH and significantly reduced ROS production. CJ reversed the t-BOOH-induced increase in phospho-c-Jun N-terminal kinase. This study demonstrates that cranberry polyphenols may help protect liver cells against oxidative insult by modulating GSH concentration, ROS and MDA generation, antioxidant enzyme activity and cell signaling pathways.