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Cranberry juice capsules and urinary tract infection after surgery: results of a randomized trial

Published:April 13, 2015DOI:https://doi.org/10.1016/j.ajog.2015.04.003

      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.

      Key words

      See related editorial, page 123
      Urinary tract infections (UTIs) remain one of the most common hospital-acquired infections.
      • Magill S.S.
      • Hellinger W.
      • Cohen J.
      • et al.
      Prevalence of healthcare-associated infections in acute care hospitals in Jacksonville, Florida.
      The vast majority of hospital-associated UTIs is attributed to the use of a urinary catheter.
      • Hooton T.M.
      • Bradley S.F.
      • Cardenas D.D.
      • et al.
      Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America.
      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
      • Falagas M.E.
      • Athanasiou S.
      • Iavazzo C.
      • Tokas T.
      • Antsaklis A.
      Urinary tract infections after pelvic floor gynecological surgery: prevalence and effect of antimicrobial prophylaxis. A systematic review.
      ), compared with 3-4% per year for women in the general population.
      • Foxman B.
      Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden.
      Within hours following insertion, bacteria colonize the urinary catheter surface; the incidence of significant bacteriuria is 5% per day of catheterization, regardless of gender.
      • Maki D.G.
      • Tambyah P.A.
      Engineering out the risk for infection with urinary catheters.
      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.
      • Marschall J.
      • Carpenter C.R.
      • Fowler S.
      • Trautner B.W.
      Antibiotic prophylaxis for urinary tract infections after removal of urinary catheter: meta-analysis.
      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.
      • Sader H.S.
      • Flamm R.K.
      • Jones R.N.
      Frequency of occurrence and antimicrobial susceptibility of Gram-negative bacteremia isolates in patients with urinary tract infection: results from United States and European hospitals (2009–2011).
      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.
      • Sobota A.E.
      Inhibition of bacterial adherence by cranberry juice: potential use for the treatment of urinary tract infections.
      • Ofek I.
      • Goldhar J.
      • Zafriri D.
      • Lis H.
      • Adar R.
      • Sharon N.
      Anti-Escherichia coli adhesin activity of cranberry and blueberry juices.
      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.
      • Lee Y.L.
      • Owens J.
      • Thrupp L.
      • Cesario T.C.
      Does cranberry juice have antibacterial activity?.
      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.
      • Wang C.-H.
      • Fang C.-C.
      • Chen N.-C.
      • et al.
      Cranberry-containing products for prevention of urinary tract infections in susceptible populations: a systematic review and meta-analysis of randomized controlled trials.
      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%).
      • Marschall J.
      • Carpenter C.R.
      • Fowler S.
      • Trautner B.W.
      Antibiotic prophylaxis for urinary tract infections after removal of urinary catheter: meta-analysis.
      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 χ2 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).
      Figure thumbnail gr1
      Figure 1CONSORT flow diagram
      Enrollment and exclusions, allocation to treatment, follow-up, and reasons for loss are shown.
      CONSORT, Consolidated Standards of Reporting Trials.
      Foxman. Cranberry juice capsules and UTI. Am J Obstet Gynecol 2015.
      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).
      Table 1Sociodemographic, baseline, and postoperative characteristics of randomized participants by treatment group
      CharacteristicCranberry (n = 80)Placebo (n = 80)
      n(%)n(%)
      Age <60 y47(59)48(60)
      Married54(68)54(68)
      Education (highest level completed)
       High school or less17(21)12(15)
       College (at least some)40(50)48(60)
       Postcollege education (at least some)23(29)20(25)
      Average annual household income
       ≤$21,0007(9)8(11)
       $21,001–62,00028(36)30(41)
       ≥$62,00143(55)36(49)
      Race/ethnicity
       Non-Hispanic white66(84)70(88)
       Non-Hispanic black4(5)4(5)
       Other or mixed race9(11)6(7)
      Use of NSAIDs in 4 wks prior to enrollment57(72)62(78)
      Use of NSAIDs in postoperative period45(68)41(68)
      Ever experienced UTI in life49(64)50(63)
      Experienced a UTI in the past 12 mo18(23)19(24)
      Postmenopausal54(69)54(68)
      Reasons for surgery
      Categories are not mutually exclusive
       Fibroids11(14)9(11)
       Pelvic organ prolapse51(64)56(70)
       Stress urinary incontinence21(26)23(29)
       Chronic pelvic pain2(3)3(4)
       Endometriosis0(0)2(3)
       Abnormal uterine bleeding11(14)6(8)
       Adnexal mass4(5)4(5)
       Other9(11)18(23)
      Surgery type
      Categories are not mutually exclusive
       Urinary incontinence operation24(30)24(30)
      Kelly plication2(3)1(1)
      Midurethral-retropubic16(20)20(25)
      Pubovaginal sling5(6)2(3)
      Other1(1)1(1)
       Prolapse/reconstructive52(65)58(73)
      Abdominal or laparoscopic sacrocolpopexy10(13)11(14)
      Anterior (cystocele) repair24(30)34(43)
      Colpocleisis2(3)2(3)
      Enterocele repair (closure of peritoneum)1(1)5(6)
      McCalls culdoplasty0(0)2(3)
      Posterior (rectocele) repair (colpoperineorrhaphy)30(38)34(43)
      Sacrospinous ligament suspension19(24)18(23)
      Uterosacral ligament suspension5(6)9(11)
      Other1(1)4(5)
       Hysterectomy/other extirpative35(44)42(53)
      Abdominal total hysterectomy0(0)1(1)
      Laparoscopic supracervical hysterectomy9(11)6(8)
      Laparoscopic total hysterectomy3(4)10(13)
      Supracervical hysterectomy1(1)0(0)
      Vaginal hysterectomy9(11)20(25)
      Ureterolysis0(0)2(3)
      Removal of tube(s)8(10)20(25)
      Removal of 1 ovary1(1)3(4)
      Removal of both ovaries5(6)10(13)
      Exploratory laparotomy1(1)2(3)
      Laparoscopy3(4)2(3)
      Myomectomy (laparotomy)1(1)1(1)
      Myomectomy (laparoscopy)5(6)2(3)
      Lysis of adhesions3(4)4(5)
      Resection of endometriosis0(0)3(4)
      Other5(6)7(9)
       Other4(5)4(5)
      Intermittent catheterization during postoperative period
      P < .05.
      25(31)40(50)
      Sent home with an indwelling catheter (Foley)3(4)4(5)
      Percentages are based on total responses. Incomplete responses were received for marital status (cranberry: n = 1); income (cranberry: n = 2, placebo: n = 6); race (cranberry: n = 1); NSAID use in the postoperative period (cranberry: n = 14, placebo: n = 20); UTI history (cranberry: n = 3, placebo: n = 2); and postmenopausal status (cranberry: n = 2).
      NSAID, nonsteroidal antiinflammatory drug; UTI, urinary tract infection.
      Foxman. Cranberry juice capsules and UTI. Am J Obstet Gynecol 2015.
      a Categories are not mutually exclusive
      b P < .05.
      Participants who self-catheterized were more likely to have a history of UTI (72% vs 54%; P = .01; data not shown). Seven women used an indwelling Foley catheter at home for part of the follow-up period (cranberry: n = 3; placebo: n = 4). The decision to discharge a patient with intermittent self-catheterization or a Foley catheter was left to the individual physicians. Patients discharged with a Foley catheter usually are unable to perform catheterization or decline to do so.

      Association of cranberry with UTI

      Overall, 45 of the 160 participants (28%) had a UTI. The incidence of UTI was significantly lower in the cranberry than the placebo group (15 of 80 [19%] vs 30 of 80 [38%]; odds ratio [OR], 0.38; 95% confidence interval [CI], 0.19–0.79; P = .008). Among participants with a UTI diagnosis, the percentage of those confirmed by culture did not differ between the women assigned placebo or cranberry (77% [23 of 35] vs 80% [12 of 15]; P = .31). When the endpoint was limited to those with culture confirmed diagnosis (>103 CFU/mL urine
      • Rubin R.H.
      • Shapiro E.D.
      • Andriole V.T.
      • Davis R.J.
      • Stamm W.E.
      Evaluation of new anti-infective drugs for the treatment of urinary tract infection. Infectious Diseases Society of America and the Food and Drug Administration.
      ), the incidence of UTI was also significantly lower in the cranberry than the placebo group (12 of 18 [15%] vs 23 of 80 [29%]; OR, 0.44; 95% CI, 0.20–0.96; P = .037).
      The median time to UTI was significantly longer among those in the cranberry than the placebo group (18 days vs 8.5 days, Figure 2, log rank test, P = .0005). Results did not change in the sensitivity analysis using the modified intent-to-treat analysis population, which excluded the 10 participants who did not take a single dose of study medication.
      Figure thumbnail gr2
      Figure 2Time to urinary tract infection by treatment group
      Kaplan-Meier estimates and 95% Hall-Wellner confidence bands are provided by treatment group. The number at risk for UTI is shown on the horizontal axis.
      UTI, urinary tract infection.
      Foxman. Cranberry juice capsules and UTI. Am J Obstet Gynecol 2015.
      The beneficial effect of cranberry treatment remained after adjusting for frequency of postoperative self-catheterization and having an indwelling Foley catheter at home in a logistic regression model (OR, 0.42; 95% CI, 0.18–0.94; P = .037) (Table 2). Women who self-catheterized during the postoperative period had a significantly higher incidence of UTI (33 of 65 [51%] vs 12 of 95 [13%]; OR, 7.13; 95% CI, 15.5–3.28; P < .001), but there was no interaction between frequency of self-catheterization and treatment (P = .63). Furthermore, of the 7 participants with an indwelling catheter for part or all of the postoperative recovery period, 1 of 3 assigned to cranberry and 3 of 4 assigned to placebo had a UTI. (The one woman who had a Foley catheter throughout the entire study period developed a UTI based on endpoint criteria.)
      Table 2Effect of cranberry juice pills on risk of urinary tract infection, adjusting for having an indwelling catheter at home, and frequency of self-catheterization
      ParameterEstimateSEOR(95% CI)
      Cranberry juice pills−0.86610.41520.42(0.18–0.94)
      Indwelling catheter (Foley)1.98760.83687.30(1.42–42.07)
      Log frequency of self-catheterization
      Variable was log transformed because it was highly skewed
      0.62990.12441.88
      OR is interpreted as an 88% increase in UTI risk for each 10 times a woman self-catheterized.
      (1.48–2.42)
      Intercept−1.55530.3344
      CI, confidence interval; OR, odds ratio; UTI, urinary tract infection.
      Foxman. Cranberry juice capsules and UTI. Am J Obstet Gynecol 2015.
      a Variable was log transformed because it was highly skewed
      b OR is interpreted as an 88% increase in UTI risk for each 10 times a woman self-catheterized.
      The increased risk of UTI associated with discharge with an indwelling Foley catheter remained after adjusting for frequency of intermittent catheterization following Foley removal during the postoperative period and the effects of cranberry (OR, 7.3; 95% CI, 1.42–42.07; P = .018 [Table 2]). There was no association between UTI history (both in the previous 12 months and any time during life) and UTI risk after surgery (data not shown).
      E coli was the most common infecting organism (cranberry: 38%; placebo: 46% [Table 3]). Considering only those with a UTI caused by E coli, the risk of UTI among those taking cranberry was reduced by an estimated 62% (OR, 0.38; 95% CI, 0.13–1.13; P = .07). The second most common infecting bacterial species was Klebsiella pneumoniae among the cranberry group (23%) and Enterococcus among the placebo group (23%). The vast majority of cultures had 105 CFU/mL urine or greater of the infecting bacteria (92% for cranberry and 81% for placebo), and all urine cultures had at least 1 species occurring at greater than 104 CFU/mL urine; 4 positive cultures reported 2 bacterial species.
      Table 3Distribution of microorganisms causing urinary tract infection by treatment group
      Of the 45 participants who had a primary outcome (UTI) culture results were not available for 10 participants (cranberry: n = 3, placebo: n = 7) with clinically diagnosed and treated urinary tract infection. Numbers may not sum to totals because more than 1 species was present in 4 cultures (cranberry: n = 1, placebo: n = 3). Greater than 104 CFU/mL urine of a potential uropathogen were detected in all positive cultures. In the culture positive for yeast, there were 105 CFU/mL urine; the culture positive for Lactobacillus (103 CFU/mL urine) also had 105 CFU/mL urine of Escherichia coli. There were 105 CFU/mL urine reported for the mixed culture.
      OrganismCranberry (n = 12)Placebo (n =23)
      n(%)n(%)
      Escherichia coli5(38)12(46)
      Klebsiella pneumoniae3(23)2(8)
      Enterococcus species1(8)6(23)
      Enterobacter species2(15)2(8)
      Streptococcus aglactiae1(8)1(4)
      Proteus mirabilis1(8)0(0)
      Lactobacillus01(4)
      Yeast01(4)
      Mixed01(4)
      Total species detected13(100)26(101)
      UTI, urinary tract infection.
      Foxman. Cranberry juice capsules and UTI. Am J Obstet Gynecol 2015.
      a Of the 45 participants who had a primary outcome (UTI) culture results were not available for 10 participants (cranberry: n = 3, placebo: n = 7) with clinically diagnosed and treated urinary tract infection. Numbers may not sum to totals because more than 1 species was present in 4 cultures (cranberry: n = 1, placebo: n = 3). Greater than 104 CFU/mL urine of a potential uropathogen were detected in all positive cultures. In the culture positive for yeast, there were 105 CFU/mL urine; the culture positive for Lactobacillus (103 CFU/mL urine) also had 105 CFU/mL urine of Escherichia coli. There were 105 CFU/mL urine reported for the mixed culture.

      Compliance

      The average amount of time from a participant’s surgery, when they started study drug, to their termination from the study was 38 days (SD, 24; range, 0–227). At study exit, of the 130 participants with information available, 110 (85%) reported taking 2 capsules twice a day most or all of the time. Most participants reported following the prescribed regimen at the 2 week (89%) and 4 week (82%) follow-up contacts. Pill counts were available for a similar number of participants by treatment assignment (cranberry: n = 57, placebo: n = 60); participants averaged 3 capsules per day in both treatment groups. Compliance was not statistically significantly different by treatment group using any measure of compliance.

      Adverse effects

      The proportion of participants with adverse events and serious adverse events did not differ by treatment groups (P = .28 and P = 1.00, respectively). Seventy-five participants experienced 328 adverse events in the cranberry group, and 78 participants experienced 423 adverse events in the placebo group. Four participants experienced 5 severe adverse events in the cranberry group and 4 participants experienced 7 adverse events in the placebo group. Gastrointestinal upset was the most commonly reported event in both groups (cranberry: n = 45 [56%]; placebo: 49 [61%]).

      Comment

      This is the first report of a double-blind, placebo-controlled randomized clinical trial demonstrating a statistically and clinically significant benefit of taking cranberry in preventing UTI after elective gynecological surgery during which a urinary catheter is placed. This reduction in UTI risk is similar in magnitude to that reportedly obtained by administering antibiotics at the time of catheter removal
      • Marschall J.
      • Carpenter C.R.
      • Fowler S.
      • Trautner B.W.
      Antibiotic prophylaxis for urinary tract infections after removal of urinary catheter: meta-analysis.
      and avoids the collateral damage associated with antibiotic use, including pressure for antibiotic resistance.
      Our study addresses the major limitations identified in previous studies of the effects of cranberry products.
      • Jepson R.
      • Craig J.
      • Williams G.
      Cranberry products and prevention of urinary tract infections.
      We compared cranberry capsules with placebo; subanalyses of previous trials suggest capsules are somewhat more effective than juice, perhaps because of increased compliance.
      • Wang C.-H.
      • Fang C.-C.
      • Chen N.-C.
      • et al.
      Cranberry-containing products for prevention of urinary tract infections in susceptible populations: a systematic review and meta-analysis of randomized controlled trials.
      In our previous cranberry trial conducted among college students during which we used juice, the placebo juice contained similar levels of vitamin C to that found in cranberry juice. We observed no effect of cranberry in that trial, perhaps because vitamin C has been observed to have a beneficial effect on UTI risk.
      • Barbosa-Cesnik C.
      • Brown M.B.
      • Buxton M.
      • Zhang L.
      • DeBusscher J.
      • Foxman B.
      Cranberry juice fails to prevent recurrent urinary tract infection: results from a randomized placebo-controlled trial.
      Several strengths in the study design and analysis of this trial make it unlikely that the difference in outcome was due to (alpha) error. The design, conduct, and analysis of the trial, including randomization scheme, blinding of study personnel and participants, and active surveillance for outcomes, were held to the highest standards. Furthermore, after analyses took into account known risk factors (the need for intermittent self-catheterization, UTI history, and age), the findings remained consistent, with cranberry mitigating the risk for UTI. This suggests that our results might be generalized to women undergoing laparoscopic or vaginal surgery for benign gynecological procedures in which a catheter is placed.
      Developing practices to reduce UTI risk is a promising area for quality improvement. Considering the use of intermittent catheterization is a potential example. Each time a catheter is inserted, the bladder is inoculated with bacteria, and there is some subtle trauma, increasing a risk of infection. Among the 65 women who reported intermittent catheterization, the median number of times was 15 (mean, 32; range, 1–216 times) during the postoperative period. Developing patient education to reduce the number of times that intermittent catheterization is undertaken might reduce UTI risk. Moreover, our results suggest that discharging a patient from the hospital with an indwelling catheter in place should be avoided if possible. These women experienced a 7-fold increase in UTI risk after adjusting for cranberry use and frequency of intermittent catheterization.
      Future studies might aim to optimize the time of catheter insertion and removal and to develop strategies to reduce the frequency of intermittent catheterization. At least 1 previous trial compared different timings of urinary catheter removal following abdominal hysterectomy. Removal immediately following surgery was associated with increased urinary retention and removal after 24 hours with increased risk of UTI; removal at 6 hours resulted in the fewest adverse events.
      • Ahmed M.R.
      • Sayed Ahmed W.A.
      • Atwa K.A.
      • Metwally L.
      Timing of urinary catheter removal after uncomplicated total abdominal hysterectomy: a prospective randomized trial.
      Strategies to decrease the length of time associated with catheterization may need to be carefully considered in each case, weighing the risks of postoperative urinary retention and overdistension against that of UTI, but are promising areas for future research to decrease this common infection.

      Acknowledgments

      We thank Dr Jack Sobel for serving as data and safety monitor; the staff at Statistical Analysis of Biomedical and Educational Research unit for technical assistance; the participating patients, physicians, physician assistants, and nurses at the Urogynecology and Minimally Invasive Gynecologic Surgery clinics and University of Michigan Hospitals; and Alexandra Beach, Erin Case, and Marian Turner for outstanding work as recruiters. We are also very grateful to Bill Reisdorph of the Michigan Institute for Clinical and Health Research (MICHR) (2UL1TR000433-06) for his assistance with obtaining the reporting requirements for an investigational new drug designation, and Michigan Institute for Clinical and Health Research for clinical monitoring. We also thank Theralogix, LLC (Rockville, MD) for providing cranberry juice capsules and placebo for use in this study.

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