Objective
The risk of urinary tract infection (UTI) among women undergoing elective gynecological surgery during which a catheter is placed is high: 10-64% following catheter removal. We conducted the first randomized, double-blind, placebo-controlled trial of the therapeutic efficacy of cranberry juice capsules in preventing UTI after surgery.
Study Design
We recruited patients from a single hospital between August 2011 and January 2013. Eligible participants were undergoing elective gynecological surgery that did not involve a fistula repair or vaginal mesh removal. One hundred sixty patients were randomized and received 2 cranberry juice capsules 2 times a day, equivalent to 2 8 ounce servings of cranberry juice, for 6 weeks after surgery or matching placebo. The primary endpoint was the proportion of participants who experienced clinically diagnosed and treated UTI with or without positive urine culture. Kaplan-Meier plots and log rank tests compared the 2 treatment groups.
Results
The occurrence of UTI was significantly lower in the cranberry treatment group compared with the placebo group (15 of 80 [19%] vs 30 of 80 [38%]; odds ratio, 0.38; 95% confidence interval, 0.19–0.79; P = .008). After adjustment for known confounders, including the frequency of intermittent self-catheterization in the postoperative period, the protective effects of cranberry remained (odds ratio, 0.42; 95% confidence interval, 0.18–0.94). There were no treatment differences in the incidence of adverse events, including gastrointestinal upset (56% vs 61% for cranberry vs placebo).
Conclusion
Among women undergoing elective benign gynecological surgery involving urinary catheterization, the use of cranberry extract capsules during the postoperative period reduced the rate of UTI by half.
See related editorial, page 123
Urinary tract infections (UTIs) remain one of the most common hospital-acquired infections. The vast majority of hospital-associated UTIs is attributed to the use of a urinary catheter. Even following removal of the catheter, the risk of UTIs remains high, with postoperative patients being particularly vulnerable.
Among women undergoing elective urogenital surgery the 6 week cumulative incidence of a symptomatic UTI following catheter removal is 10-64% (reviewed elsewhere ), compared with 3-4% per year for women in the general population. Within hours following insertion, bacteria colonize the urinary catheter surface; the incidence of significant bacteriuria is 5% per day of catheterization, regardless of gender.
A metaanalysis of 7 studies of short-term catheterized patients (including men and women and surgeries of various types) found that antibiotics given at the time of catheter removal reduced UTI incidence by approximately 50%, but the risk remained significant: 4.7% within 4 weeks. However, antibiotic prophylaxis is not an ideal solution because the prevalence of antibiotic resistance among urinary bacterial isolates is very high and continues to increase. Escherichia coli is the most common urinary pathogen; among hospitalized patients in the United States and Europe, approximately 10% of E coli from urinary-associated bacteremia had the extended spectrum beta-lactamase phenotype, and approximately 26% were resistant to levofloxacin.
The American cranberry ( Vaccinium macrocarpon ) has been widely used for the prevention of urinary tract infections. Cranberry juice may prevent UTIs by selecting against more adhesive strains in the stool, by directly preventing E coli from adhering to uroepithelial cells, or by both of these mechanisms. Other effects might include influence on fimbrial subunit synthesis, assembly, or attachment; these effects would be similar to those seen with subinhibitory concentrations of antibiotics. A 2012 systematic review and metaanalysis found an overall protective effect of cranberry on UTIs, but there was considerable heterogeneity in results across trials that varied in dose administered, population study, and sample size.
No previous studies of cranberry have addressed effectiveness in reducing the risk of UTIs after catheterization. We begin to fill this gap by conducting a randomized clinical trial of the effectiveness of cranberry juice capsules in preventing UTIs among women undergoing elective gynecological surgery in which a catheter is in place. This is an especially high-risk group because these operations involve surgery adjacent to the bladder and delayed bladder emptying is common. Because catheter insertion and removal introduces bacteria and causes trauma that may increase UTI risk, we also take into account frequency of intermittent catheterization following removal of the Foley catheter.
Materials and Methods
Study design
We conducted a randomized, double-blind, placebo-controlled study of the therapeutic efficacy of 2 cranberry juice capsules 2 times a day, equivalent to 2 8 ounce servings of cranberry juice, for approximately 6 weeks after elective gynecological surgery in preventing UTIs after catheterization.
The Institutional Review Board at the University of Michigan approved the study protocol; all participants gave written informed consent. The use of cranberry capsules for this trial was approved by the Food and Drug Administration (IND 111959) ( ClinicalTrials.gov identifier NCT01346774 ).
Participants
We recruited study participants between August 2011, and January 2013, from patients referred by physicians from the Urogynecology and Minimally Invasive Surgery clinics of the University of Michigan Division of Gynecology at the time of their preoperative visit for elective gynecological surgery. The urogynecology clinic specializes in the surgical management of pelvic organ prolapse, urinary incontinence, and anal incontinence; the Minimally Invasive Surgery clinic specializes in the surgical management of fibroids, endometriosis, and pelvic pain. All surgeries were performed within the University of Michigan Hospital System and followed the hospital’s standard operating procedures.
Eligibility criteria
Eligible participants were nonpregnant women at least 18 years of age without a history of nephrolithiasis, congenital urogenital anomaly or neurogenic bladder, or any known allergy to cranberry products and who did not require therapeutic anticoagulant medicine during the 6 weeks after surgery or whose surgery did not involve a fistula repair or a vaginal mesh removal.
Endpoints
The primary endpoint was the proportion of participants who experienced clinically diagnosed and treated UTI whether or not results from a urine culture were available. Diagnosis and treatment were up to the treating physician. Secondary endpoints included the incidence of UTI caused by E coli and time from randomization to UTI. Safety endpoints included adverse events and serious adverse events.
Therapeutic regimen
TheraCran cranberry and placebo capsules were provided by Theralogix, LLC (Rockville, MD), gratis, asking only that results be made available to them at the time of publication. Based on proanthocyanidin content, the 4 cranberry capsules are equivalent to 2 8 ounce servings of cranberry juice.
Administration
Participants were directed to take 2 capsules by mouth twice each day (once in the morning and once in the evening), starting at the time of discharge for 4-6 weeks, or until their return for their postoperative doctor’s visit. Participants were instructed to drink an 8 ounce glass of water while taking the capsule with or without food.
Concomitant medications, foods, and beverages
Participants were instructed not to consume any cranberry products (including whole fruit, jellies, juices, or dietary supplement capsules containing cranberry) or vitamin C supplements beyond the assigned regimen. Compliance was assessed at each follow-up contact.
Randomization
Participants were randomized at time of surgery, a median of 18.5 days following enrollment (range, 0–146 days). Because bacteriuria increases with age, we balanced treatment groups by age (younger than 60 years vs 60 years or older), based on the expected median age of our study population. Stratified randomization (1:1 Theracran cranberry capsules–placebo) was performed using computer-generated permuted blocks, with a block size known only to the Data Coordinating Center. The Data Coordinating Center provided a randomization schedule for the supplier who printed labels that were placed on each bottle of capsules.
After participants were deemed eligible, study coordinators performed the randomization using the next available randomization number on a stratum-specific list provided by the Data Coordinating Center.
Masking
All study personnel (with the exception of designated individuals at the Data Coordinating Center), treating physicians, and patients were masked to treatment assignment. The Investigational Drug Service at the University of Michigan stored and managed the capsules and conducted drug accountability.
Study procedures and data collection
After giving informed consent, each participant completed a self-administered questionnaire regarding her medical and sexual history, health behaviors, and symptoms. Following hospital admission, a urine specimen was collected upon catheter insertion in the operating room and catheter removal (from the catheter port). At the time of hospital discharge, research staff provided the participant with enough capsules for 8 weeks of the assigned regimen and administered the first dose. Participants were reminded to take the cranberry capsules daily, continuing 2 times per day until their postoperative visit, usually at 6 weeks.
Research staff also instructed the participants to collect a urine sample if they experienced urinary symptoms consistent with a UTI (painful urination, an urgent need to urinate, pain/pressure in the lower abdomen or pubic area, fever of 100°F or more, or flank pain), provided a urine collection kit (containing a preservative), orders for a urine culture (if needed) that included instructions to the laboratory to forward results to the treating physician at the University of Michigan Health System if the culture was performed elsewhere, and written instructions for at-home urine collection. Participants were given a symptom diary to record any urinary symptoms.
Participants were advised to contact research staff immediately and to collect a urine specimen should they experience urinary symptoms consistent with UTI. When participants contacted research staff, they were administered a brief structured interview regarding the type and duration of symptoms and referred to their physicians for diagnosis and treatment. Urine was cultured using standard microbiological techniques for the presence of uropathogens at the clinical laboratory selected by their treating physician.
Study staff contacted participants within 3 days, and at 2 and 4 weeks after hospital discharge to assess compliance to study protocol, to identify whether the participant had urinary symptoms consistent with UTI, and to elicit any adverse events. These items were also assessed at the 6 week postoperative doctor’s visit using a self-administered questionnaire. At study exit, capsule bottles were collected so capsules could be counted to assess compliance.
Medical records of all randomized study participants were reviewed to identify any missed postoperative symptomatic UTI episodes, adverse events, and medications prescribed. All study participants received an intravenous antibiotic administration prior to the start of the surgical procedure, including urinary catheter insertion (as per hospital protocol).
There were no changes to the methods or trial outcomes after the trial began. There were no interim analyses or stopping guidelines.
The study protocol, including definitions of adverse events, is available upon request.
Statistical methods
Sample size was based on logistical and statistical principles. Estimates of the incidence of symptomatic UTI in our patient population were unavailable, and thus, we assumed the UTI rate to be similar to that in the literature for patients receiving prophylactic antibiotics (15–18%). We believed we could enroll approximately 200 participants (100 per treatment group) and calculated that this sample size would provide at least 80% power with a 2-sided type I error of 5% to detect a large treatment difference (65–75% relative risk reduction) if the UTI rate was 15–20% in the placebo group (based on a 2-sample binomial test, performed using EAST, version 5.1, 2007; Cytel, Cambridge, MA). Recruitment was stopped at 160 randomized participants because of budgetary and timing constraints.
Baseline sociodemographic and medical history characteristics were summarized using descriptive statistics. Primary analyses used an intent-to-treat approach. We used logistic regression to model the incidence of the primary endpoint and to take into account all prespecified risk factors including age, UTI history, the presence of a Foley catheter, and intermittent self-catheterization.
We also summarized treatment differences in the time to UTI using Kaplan-Meier methods and tested these differences with log rank tests. A sensitivity analysis was performed for the primary endpoint, using a modified intent-to-treat analysis population that included only randomized participants who took at least 1 dose of the study medication. In addition, we assessed treatment differences in culture-confirmed UTI and culture-confirmed when E coli was the pathogen. We tested for differences in compliance and safety using the χ 2 test.
All analyses were performed using SAS software, version 9.3 (SAS Institute, Cary, NC).
Results
Study population
Between August 2011 and January 2013, 359 women presenting for elective gynecological surgery were screened for eligibility; 160 met the inclusion criteria, agreed to participate and were randomized. Almost all (94%) received the allocated intervention (cranberry: 74 of 80 vs placebo: 76 of 80). Reasons for not receiving the intervention included the patient was discharged when staff were not available (n = 2), the participant could not swallow the capsules or returned the bottle unopened (n = 4), the capsules were lost (n = 1), the participant’s physician told her to avoid cranberry (n = 1), the surgery was cancelled (n = 1), or the participant withdrew (n = 1) ( Figure 1 ).
Follow-up was not statistically different by group: 73 of 80 of those allocated to cranberry (91%) and 72 of 80 assigned to the placebo (90%) completed at least 1 follow-up ( P = .79); and 41 of 80 of those allocated to cranberry (51%) and 32 of 80 allocated to placebo (40%) completed all 3 follow-up visits. The primary endpoint was obtained for all randomized participants via a review of medical records.
Participants ranged in age from 23 to 88 years (mean ± SD for cranberry: 56 ± 12.5; placebo: 56 ± 14.3). Sociodemographic characteristics and most medical history features were not statistically significantly different by treatment group ( Table 1 ), including the number of UTIs in the 12 months prior to surgery (cranberry: 0.39 ± 0.88; placebo: 0.38 ± 0.80) and treating physician (data not shown). However, those assigned to cranberry were significantly less likely to have required intermittent self-catheterization during the recovery period (31% vs 50%; P = .02), and reported a lower number of self-catheterization episodes per day (cranberry 3.7 ± 3.1 vs placebo 5.5 ± 4.9; P = .08).
| Characteristic | Cranberry (n = 80) | Placebo (n = 80) | ||
|---|---|---|---|---|
| n | (%) | n | (%) | |
| Age <60 y | 47 | (59) | 48 | (60) |
| Married | 54 | (68) | 54 | (68) |
| Education (highest level completed) | ||||
| High school or less | 17 | (21) | 12 | (15) |
| College (at least some) | 40 | (50) | 48 | (60) |
| Postcollege education (at least some) | 23 | (29) | 20 | (25) |
| Average annual household income | ||||
| ≤$21,000 | 7 | (9) | 8 | (11) |
| $21,001–62,000 | 28 | (36) | 30 | (41) |
| ≥$62,001 | 43 | (55) | 36 | (49) |
| Race/ethnicity | ||||
| Non-Hispanic white | 66 | (84) | 70 | (88) |
| Non-Hispanic black | 4 | (5) | 4 | (5) |
| Other or mixed race | 9 | (11) | 6 | (7) |
| Use of NSAIDs in 4 wks prior to enrollment | 57 | (72) | 62 | (78) |
| Use of NSAIDs in postoperative period | 45 | (68) | 41 | (68) |
| Ever experienced UTI in life | 49 | (64) | 50 | (63) |
| Experienced a UTI in the past 12 mo | 18 | (23) | 19 | (24) |
| Postmenopausal | 54 | (69) | 54 | (68) |
| Reasons for surgery a | ||||
| Fibroids | 11 | (14) | 9 | (11) |
| Pelvic organ prolapse | 51 | (64) | 56 | (70) |
| Stress urinary incontinence | 21 | (26) | 23 | (29) |
| Chronic pelvic pain | 2 | (3) | 3 | (4) |
| Endometriosis | 0 | (0) | 2 | (3) |
| Abnormal uterine bleeding | 11 | (14) | 6 | (8) |
| Adnexal mass | 4 | (5) | 4 | (5) |
| Other | 9 | (11) | 18 | (23) |
| Surgery type a | ||||
| Urinary incontinence operation | 24 | (30) | 24 | (30) |
| Kelly plication | 2 | (3) | 1 | (1) |
| Midurethral-retropubic | 16 | (20) | 20 | (25) |
| Pubovaginal sling | 5 | (6) | 2 | (3) |
| Other | 1 | (1) | 1 | (1) |
| Prolapse/reconstructive | 52 | (65) | 58 | (73) |
| Abdominal or laparoscopic sacrocolpopexy | 10 | (13) | 11 | (14) |
| Anterior (cystocele) repair | 24 | (30) | 34 | (43) |
| Colpocleisis | 2 | (3) | 2 | (3) |
| Enterocele repair (closure of peritoneum) | 1 | (1) | 5 | (6) |
| McCalls culdoplasty | 0 | (0) | 2 | (3) |
| Posterior (rectocele) repair (colpoperineorrhaphy) | 30 | (38) | 34 | (43) |
| Sacrospinous ligament suspension | 19 | (24) | 18 | (23) |
| Uterosacral ligament suspension | 5 | (6) | 9 | (11) |
| Other | 1 | (1) | 4 | (5) |
| Hysterectomy/other extirpative | 35 | (44) | 42 | (53) |
| Abdominal total hysterectomy | 0 | (0) | 1 | (1) |
| Laparoscopic supracervical hysterectomy | 9 | (11) | 6 | (8) |
| Laparoscopic total hysterectomy | 3 | (4) | 10 | (13) |
| Supracervical hysterectomy | 1 | (1) | 0 | (0) |
| Vaginal hysterectomy | 9 | (11) | 20 | (25) |
| Ureterolysis | 0 | (0) | 2 | (3) |
| Removal of tube(s) | 8 | (10) | 20 | (25) |
| Removal of 1 ovary | 1 | (1) | 3 | (4) |
| Removal of both ovaries | 5 | (6) | 10 | (13) |
| Exploratory laparotomy | 1 | (1) | 2 | (3) |
| Laparoscopy | 3 | (4) | 2 | (3) |
| Myomectomy (laparotomy) | 1 | (1) | 1 | (1) |
| Myomectomy (laparoscopy) | 5 | (6) | 2 | (3) |
| Lysis of adhesions | 3 | (4) | 4 | (5) |
| Resection of endometriosis | 0 | (0) | 3 | (4) |
| Other | 5 | (6) | 7 | (9) |
| Other | 4 | (5) | 4 | (5) |
| Intermittent catheterization during postoperative period b | 25 | (31) | 40 | (50) |
| Sent home with an indwelling catheter (Foley) | 3 | (4) | 4 | (5) |
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