[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
Purchase Options:
[Skip to Content Landing]
Figure 1.
Flow Diagram of a Randomized Trial Comparing the Effect of Cranberry Capsules vs Placebo on Bacteriuria Plus Pyuria in Women Residents of Nursing Homes
Flow Diagram of a Randomized Trial Comparing the Effect of Cranberry Capsules vs Placebo on Bacteriuria Plus Pyuria in Women Residents of Nursing Homes
Figure 2.
Bimonthly and Overall Adjusted Percentages of Bacteriuria Plus Pyuria Specimens by Treatment Status (N = 185)
Bimonthly and Overall Adjusted Percentages of Bacteriuria Plus Pyuria Specimens by Treatment Status (N = 185)

Percentage with bacteriuria plus pyuria and corresponding 95% confidence intervals (error bars) were adjusted for the following prespecified baseline variables: bacteriuria, incontinence, age at enrollment, and number of comorbidities (eAppendix in Supplement 2 for additional details). The baseline and bimonthly data represent study participants with bacteriuria plus pyuria while the overall data represent all specimens of bacteriuria plus pyuria over the 6 follow-up time points (months 2-12). See the total number of participants contributing data at each time point in Table 2.

Table 1.  
Baseline Characteristics, Overall and by Treatment Statusa
Baseline Characteristics, Overall and by Treatment Statusa
Table 2.  
Bimonthly and Overall Observed Counts and Percentages of Bacteriuria Plus Pyuria Specimens by Treatment Status (n = 185)
Bimonthly and Overall Observed Counts and Percentages of Bacteriuria Plus Pyuria Specimens by Treatment Status (n = 185)
Table 3.  
Unadjusted Rates and Rate Ratios for Secondary Outcomesa
Unadjusted Rates and Rate Ratios for Secondary Outcomesa
1.
Rowe  TA, Juthani-Mehta  M.  Diagnosis and management of urinary tract infection in older adults.  Infect Dis Clin North Am. 2014;28(1):75-89.PubMedArticle
2.
Juthani-Mehta  M, Datunashvili  A, Tinetti  M.  Tests for urinary tract infection in nursing home residents.  JAMA. 2014;312(16):1687-1688.PubMedArticle
3.
Nicolle  LE, Mayhew  WJ, Bryan  L.  Prospective randomized comparison of therapy and no therapy for asymptomatic bacteriuria in institutionalized elderly women.  Am J Med. 1987;83(1):27-33.PubMedArticle
4.
Abrutyn  E, Mossey  J, Berlin  JA,  et al.  Does asymptomatic bacteriuria predict mortality and does antimicrobial treatment reduce mortality in elderly ambulatory women?  Ann Intern Med. 1994;120(10):827-833.PubMedArticle
5.
Mody  L, Juthani-Mehta  M.  Urinary tract infections in older women: a clinical review.  JAMA. 2014;311(8):844-854.PubMedArticle
6.
Nicolle  LE, Bradley  S, Colgan  R, Rice  JC, Schaeffer  A, Hooton  TM; Infectious Diseases Society of America; American Society of Nephrology; American Geriatric Society.  Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults.  Clin Infect Dis. 2005;40(5):643-654.PubMedArticle
7.
Howell  AB, Vorsa  N, Der Marderosian  A, Foo  LY.  Inhibition of the adherence of P-fimbriated Escherichia coli to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries.  N Engl J Med. 1998;339(15):1085-1086.PubMedArticle
8.
Lavigne  JP, Bourg  G, Combescure  C, Botto  H, Sotto  A.  In-vitro and in-vivo evidence of dose-dependent decrease of uropathogenic Escherichia coli virulence after consumption of commercial Vaccinium macrocarpon (cranberry) capsules.  Clin Microbiol Infect. 2008;14(4):350-355.PubMedArticle
9.
Jepson  RG, Williams  G, Craig  JC.  Cranberries for preventing urinary tract infections.  Cochrane Database Syst Rev. 2012;10:CD001321.PubMed
10.
Wang  CH, Fang  CC, Chen  NC,  et al.  Cranberry-containing products for prevention of urinary tract infections in susceptible populations: a systematic review and meta-analysis of randomized controlled trials.  Arch Intern Med. 2012;172(13):988-996.PubMedArticle
11.
Avorn  J, Monane  M, Gurwitz  JH, Glynn  RJ, Choodnovskiy  I, Lipsitz  LA.  Reduction of bacteriuria and pyuria after ingestion of cranberry juice.  JAMA. 1994;271(10):751-754.PubMedArticle
12.
Wing  DA, Rumney  PJ, Preslicka  CW, Chung  JH.  Daily cranberry juice for the prevention of asymptomatic bacteriuria in pregnancy: a randomized, controlled pilot study.  J Urol. 2008;180(4):1367-1372.PubMedArticle
13.
Wotton  K, Crannitch  K, Munt  R.  Prevalence, risk factors and strategies to prevent dehydration in older adults.  Contemp Nurse. 2008;31(1):44-56.PubMedArticle
14.
Juthani-Mehta  M, Perley  L, Chen  S, Dziura  J, Gupta  K.  Feasibility of cranberry capsule administration and clean-catch urine collection in long-term care residents.  J Am Geriatr Soc. 2010;58(10):2028-2030.PubMedArticle
15.
Bianco  L, Perrelli  E, Towle  V, Van Ness  PH, Juthani-Mehta  M.  Pilot randomized controlled dosing study of cranberry capsules for reduction of bacteriuria plus pyuria in female nursing home residents.  J Am Geriatr Soc. 2012;60(6):1180-1181.PubMedArticle
16.
McMurdo  ME, Bissett  LY, Price  RJ, Phillips  G, Crombie  IK.  Does ingestion of cranberry juice reduce symptomatic urinary tract infections in older people in hospital? a double-blind, placebo-controlled trial.  Age Ageing. 2005;34(3):256-261.PubMedArticle
17.
Terris  MK, Issa  MM, Tacker  JR.  Dietary supplementation with cranberry concentrate tablets may increase the risk of nephrolithiasis.  Urology. 2001;57(1):26-29.PubMedArticle
18.
Prior  RL, Fan  E, Ji  H,  et al.  Multi-laboratory validation of a standard method for quantifying proanthocyanidins in cranberry powders.  J Sci Food Agric. 2010;90(9):1473-1478.PubMedArticle
19.
Juthani-Mehta  M, Quagliarello  V, Perrelli  E, Towle  V, Van Ness  PH, Tinetti  M.  Clinical features to identify urinary tract infection in nursing home residents: a cohort study.  J Am Geriatr Soc. 2009;57(6):963-970.PubMedArticle
20.
Juthani-Mehta  M, Van Ness  PH, McGloin  J,  et al.  A cluster-randomized controlled trial of a multicomponent intervention protocol for pneumonia prevention among nursing home elders.  Clin Infect Dis. 2015;60(6):849-857.PubMedArticle
21.
Stone  ND, Ashraf  MS, Calder  J,  et al; Society for Healthcare Epidemiology Long-Term Care Special Interest Group.  Surveillance definitions of infections in long-term care facilities: revisiting the McGeer criteria.  Infect Control Hosp Epidemiol. 2012;33(10):965-977.PubMedArticle
22.
Pop-Vicas  A, Tacconelli  E, Gravenstein  S, Lu  B, D’Agata  EM.  Influx of multidrug-resistant, gram-negative bacteria in the hospital setting and the role of elderly patients with bacterial bloodstream infection.  Infect Control Hosp Epidemiol. 2009;30(4):325-331.PubMedArticle
23.
SAS/STAT User’s Guide.  Version 14.1. Cary, NC: SAS Institute Inc; 2015.
24.
Diggle  P, Heagerty  P, Liang  KY, Zeger  SL.  Analysis of Longitudinal Data. 2nd ed. New York, NY: Oxford University Press; 2002.
25.
van Buuren  S.  Multiple imputation of discrete and continuous data by fully conditional specification.  Stat Methods Med Res. 2007;16(3):219-242.PubMedArticle
26.
Haverkorn  MJ, Mandigers  J.  Reduction of bacteriuria and pyuria using cranberry juice.  JAMA. 1994;272(8):590.PubMedArticle
27.
Jepson  R, Craig  J, Williams  G.  Cranberry products and prevention of urinary tract infections.  JAMA. 2013;310(13):1395-1396.PubMedArticle
28.
Hopkins  WJ, Heisey  DM, Jonler  M, Uehling  DT.  Reduction of bacteriuria and pyuria using cranberry juice.  JAMA. 1994;272(8):588-589.PubMedArticle
29.
Caljouw  MA, van den Hout  WB, Putter  H, Achterberg  WP, Cools  HJ, Gussekloo  J.  Effectiveness of cranberry capsules to prevent urinary tract infections in vulnerable older persons: a double-blind randomized placebo-controlled trial in long-term care facilities.  J Am Geriatr Soc. 2014;62(1):103-110.PubMedArticle
30.
van den Hout  WB, Caljouw  MA, Putter  H, Cools  HJ, Gussekloo  J.  Cost-effectiveness of cranberry capsules to prevent urinary tract infection in long-term care facilities: economic evaluation with a randomized controlled trial.  J Am Geriatr Soc. 2014;62(1):111-116.PubMedArticle
31.
Foxman  B, Cronenwett  AE, Spino  C, Berger  MB, Morgan  DM.  Cranberry juice capsules and urinary tract infection after surgery: results of a randomized trial.  Am J Obstet Gynecol. 2015;213(2):194.e1-194.e8. PubMedArticle
Original Investigation
November 8, 2016

Effect of Cranberry Capsules on Bacteriuria Plus Pyuria Among Older Women in Nursing HomesA Randomized Clinical Trial

Author Affiliations
  • 1Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
  • 2Section of Geriatrics, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
  • 3Yale Center for Analytical Sciences, Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut
JAMA. 2016;316(18):1879-1887. doi:10.1001/jama.2016.16141
Key Points

Question  Do cranberry capsules with sufficient proanthocyanidin content affect the presence of bacteriuria plus pyuria in older women living in nursing homes?

Findings  In this randomized clinical trial of 185 women nursing home residents, after adjusting for missing data and covariates, there was no statistically significant difference in presence of bacteriuria plus pyuria between the treatment (29.1%) and control (29.0%) groups over 1 year.

Meaning  Among older women living in nursing homes, cranberry capsules, compared with placebo, did not have a significant effect on the presence of bacteriuria plus pyuria over 1 year.

Abstract

Importance  Bacteriuria plus pyuria is highly prevalent among older women living in nursing homes. Cranberry capsules are an understudied, nonantimicrobial prevention strategy used in this population.

Objective  To test the effect of 2 oral cranberry capsules once a day on presence of bacteriuria plus pyuria among women residing in nursing homes.

Design, Setting, and Participants  Double-blind, randomized, placebo-controlled efficacy trial with stratification by nursing home and involving 185 English-speaking women aged 65 years or older, with or without bacteriuria plus pyuria at baseline, residing in 21 nursing homes located within 50 miles (80 km) of New Haven, Connecticut (August 24, 2012-October 26, 2015).

Interventions  Two oral cranberry capsules, each capsule containing 36 mg of the active ingredient proanthocyanidin (ie, 72 mg total, equivalent to 20 ounces of cranberry juice) vs placebo administered once a day in 92 treatment and 93 control group participants.

Main Outcomes and Measures  Presence of bacteriuria (ie, at least 105 colony-forming units [CFUs] per milliliter of 1 or 2 microorganisms in urine culture) plus pyuria (ie, any number of white blood cells on urinalysis) assessed every 2 months over the 1-year study surveillance; any positive finding was considered to meet the primary outcome. Secondary outcomes were symptomatic urinary tract infection (UTI), all-cause death, all-cause hospitalization, all multidrug antibiotic–resistant organisms, antibiotics administered for suspected UTI, and total antimicrobial administration.

Results  Of the 185 randomized study participants (mean age, 86.4 years [SD, 8.2], 90.3% white, 31.4% with bacteriuria plus pyuria at baseline), 147 completed the study. Overall adherence was 80.1%. Unadjusted results showed the presence of bacteriuria plus pyuria in 25.5% (95% CI, 18.6%-33.9%) of the treatment group and in 29.5% (95% CI, 22.2%-37.9%) of the control group. The adjusted generalized estimating equations model that accounted for missing data and covariates showed no significant difference in the presence of bacteriuria plus pyuria between the treatment group vs the control group (29.1% vs 29.0%; OR, 1.01; 95% CI, 0.61-1.66; P = .98). There were no significant differences in number of symptomatic UTIs (10 episodes in the treatment group vs 12 in the control group), rates of death (17 vs 16 deaths; 20.4 vs 19.1 deaths/100 person-years; rate ratio [RR], 1.07; 95% CI, 0.54-2.12), hospitalization (33 vs 50 admissions; 39.7 vs 59.6 hospitalizations/100 person-years; RR, 0.67; 95% CI, 0.32-1.40), bacteriuria associated with multidrug-resistant gram-negative bacilli (9 vs 24 episodes; 10.8 vs 28.6 episodes/100 person-years; RR, 0.38; 95% CI, 0.10-1.46), antibiotics administered for suspected UTIs (692 vs 909 antibiotic days; 8.3 vs 10.8 antibiotic days/person-year; RR, 0.77; 95% CI, 0.44-1.33), or total antimicrobial utilization (1415 vs 1883 antimicrobial days; 17.0 vs 22.4 antimicrobial days/person-year; RR, 0.76; 95% CI, 0.46-1.25).

Conclusions and Relevance  Among older women residing in nursing homes, administration of cranberry capsules vs placebo resulted in no significant difference in presence of bacteriuria plus pyuria over 1 year.

Trial Registration  clinicaltrials.gov Identifier: NCT01691430

Introduction

Quiz Ref IDUrinary tract infection (UTI) is the most commonly diagnosed infection among nursing home residents. Distinguishing symptomatic UTI from asymptomatic bacteriuria is problematic among nursing home residents because of challenges with symptom assessment.1 Bacteriuria is prevalent in 25% to 50% of women living in nursing homes, and pyuria is present in 90% of those with bacteriuria.2 A randomized trial of antibiotic treatment vs no treatment of bacteriuria in nursing home women showed no decrease in genitourinary morbidity or mortality with treatment.3 This study along with others4 led to the recommendation that bacteriuria should not be treated with antibiotics in older institutionalized adults.3 Bacteriuria plus pyuria is a necessary but not sufficient condition to make the diagnosis of UTI in this population.5,6

Quiz Ref IDCranberry products represent a potential nonantimicrobial method for UTI prevention. Cranberry proanthocyanidins have been shown to inhibit adherence of P-fimbriated Escherichia coli to uroepithelial cells,7 and this effect on virulence is dose dependent.8 Because E coli represents the majority of urinary isolates among nursing home residents, cranberry products remain an appealing UTI prevention strategy, but evidence is conflicting.9,10 Most published reports have used cranberry juice and postulated reasons for lack of benefit have included insufficient participant adherence to cranberry juice consumption and insufficient proanthocyanidins in the tested cranberry product.9 Among older women (ie, mean age, 78.5 years), 300 mL (ie, approximately 10 ounces) of cranberry juice cocktail containing 36 mg of proanthocyanidins reduced bacteriuria plus pyuria over 6 months.11 However, the acrid flavor of cranberry juice is difficult to tolerate in large volumes,12 especially for nursing home residents because of swallowing disorders, exacerbation of incontinence, and impaired thirst.13

Prior studies showed that cranberry capsule administration and urine collection is feasible, and 2 cranberry capsules (each containing 36 mg proanthocyanidins [total 72 mg proanthocyanidins], equivalent to 20 ounces of cranberry juice) are an optimal dose to test among women living in nursing homes.14,15 The primary aim of this trial was to test the effect of 2 oral cranberry capsules once a day, compared with placebo, on the presence of bacteriuria plus pyuria among older women nursing home residents.

Methods
Study Design and Oversight

This study was a double-blind, randomized, placebo-controlled efficacy trial comparing 2 cranberry capsules vs 2 placebo capsules once per day. The unit of randomization was each participant. Nursing homes targeted for participation had at least 90 beds, within a 50-mile (80 km) radius of New Haven, Connecticut, that had UTI rates and sociodemographic characteristics similar to national averages. The Yale Human Investigation Committee approved the study; all nursing home administrators signed letters of participation and signed consent was obtained from participants or their surrogates.

Participants

Nursing homes were approached sequentially, and all residents in participating facilities were screened. Once enrollment was initiated at one nursing home, screening began at the next home. A Health Insurance Portability and Accountability Act waiver (http://www.hhs.gov/hipaa/for-professionals/privacy) was obtained for recruitment purposes. Inclusion criteria were (1) female; (2) long-term care residents; (3) English speaking; and (4) 65 years or older. Quiz Ref IDOnly women were included in this study for the following reasons: (1) a prior study included women only11; (2) women are the majority of nursing home residents; (3) there is limited evidence that cranberry products reduce bacteriuria plus pyuria in men; (4) the predominant risk factor for UTI in men is underlying structural or functional abnormalities of the urinary tract; and (5) the prevalence of bacteriuria plus pyuria is lower in men.

Exclusion criteria were (1) not expected to be in the nursing home for at least 1 month (ie, short-term rehabilitation, pending discharge, terminal life expectancy <1 month); (2) taking chronic suppressive antibiotic or anti-infective (ie, mandelamine) therapy for recurrent UTI; (3) undergoing dialysis for end-stage renal disease; (4) unable to produce a baseline clean catch urine specimen; (5) receiving warfarin therapy, which could cause an interaction with cranberry juice16; (6) history of nephrolithiasis because cranberry products may increase the risk of nephrolithiasis17; (7) presence of an indwelling bladder catheter; (8) allergy to cranberry products; (9) treatment with cranberry products; and (10) nursing home residence for less than 4 weeks. Women with and without bacteriuria plus pyuria were eligible for the study.

Nursing home staff identified whether a resident was able to provide self-consent or required surrogate consent. Assent was attempted for residents with surrogate consent. After written consent, a baseline urine specimen was obtained to ensure that subsequent clean catch urine collection was possible. Subsequent waves of recruitment occurred in each nursing home every 3 months.

Randomization and Intervention

Participants were randomly assigned to take 2 cranberry capsules (manufactured by Pharmatoka, each containing 36 mg of proanthocyanidins, confirmed by BL-DMAC)18 or 2 placebo capsules, once a day, using a permuted block design with a variable block size (randomly set to 4 or 6) and equal allocation (Figure 1). Stratification by nursing home accounted for potentially different standards of care. The trial statistician designed the randomization scheme, the statistical programmer implemented it, and the Investigational Drug Services pharmacist made treatment assignments. Only the statistical programmer and pharmacist had access to the randomization codes during enrollment. Cranberry or placebo capsules were administered for 360 days (ie, 12 thirty-day blister packs per participant), and the total surveillance of each participant was 365 days.

Data and Outcomes

Research nurses recorded baseline descriptive characteristics from review of the medical chart including age, race, ethnicity, medications, comorbidities, and history of UTI. The primary nurse or certified nursing assistant (CNA) was asked questions adapted from the Minimum Data Set regarding cognitive status, behavior, activities of daily living, continence, and degree of mobility, similar to previously conducted studies.15,19,20 At study initiation in each nursing home, the senior intervention nurse educator organized a series of “in-service” training sessions for nurses and CNAs regarding methods of urine specimen collection and capsule administration. Clean catch urine specimens were targeted for collection in containers with Boritex (boric acid preservative tablet keeping urine stable for up to 96 hours) by nursing home staff between 5 and 7 am to optimize pharmacokinetic properties of proanthocyanidins8 and feasibility of collection and then were refrigerated once obtained. If the specimen was not collected on the due date, attempts at specimen collection continued for 2 additional weeks at any time of the day before classifying the specimen as missing. All specimens were transported in a cooler to Yale New Haven Health on the day obtained for processing at a single central laboratory.

Surveillance for the primary outcome (ie, the presence of bacteriuria plus pyuria) occurred every 2 months after randomization for a total of 6 assessments over 12 months. Urine specimens were obtained by clean catch since catheterization of participants requiring surrogate consent was not authorized by the institutional review board (IRB). Presence of bacteriuria was defined as at least 105 colony-forming units (CFUs) per milliliter of 1 or 2 organisms. Absence of bacteriuria was defined as a urine culture with no growth, mixed flora (≥3 organisms), or less than the highest quantitation of bacteriuria reported by the laboratory. Pyuria was defined as any number of white blood cells on urinalysis as in a previous study.11 Any positive specimen during the surveillance period was considered a positive primary outcome. Two members of the outcome adjudication committee, blinded to treatment assignment, reviewed the primary outcomes. Urinary tract–specific symptoms were assessed at each bimonthly assessment.

Secondary outcomes included symptomatic UTI, all-cause death, all-cause hospitalization, all multidrug antibiotic–resistant organisms, antibiotics for suspected UTI, and total antimicrobial prescriptions. Symptomatic UTI, adapted from National Healthcare Safety Network criteria, was defined as

1. (a) acute dysuria or (b) fever or leukocytosis and at least 1 of the following symptoms: acute costovertebral angle pain or tenderness; suprapubic pain; gross hematuria, new or marked increase in incontinence, urgency, or frequency or (c) 2 or more of new or marked increase in incontinence, urgency, frequency, suprapubic pain, new gross hematuria; and

2. (a) a voided urine culture with 105 CFUs/mL or more of a single predominant organism or 2 gram-negative organisms or (b) a specimen collected by in and out catheter with 102 CFUs/mL or more of any number of organisms (criteria 1 and 2 must be met).21 All antimicrobials administered during the trial were recorded via chart review. Multidrug-resistant organisms were defined as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and multidrug-resistant gram-negative bacilli (ie, defined as resistance to ≥3 of the following antibiotics: ampicillin-sulbactam, cefazolin, ceftriaxone, ceftazidime, fluoroquinolones, piperacillin-tazobactam, meropenem, imipenem, and trimethoprim-sulfamethoxazole).22

Adherence was determined by the number of capsules administered to each participant relative to the prescribed number. Thirty-day blister packs were delivered each month; adherence was determined from the number of capsules remaining from the previous 30-day supply. Reasons for lack of adherence were obtained from review of the medication administration record. High adherence was defined as administration of 80% or more of prescribed capsules. All adverse events were recorded based on chart review and discussion with nursing staff on a monthly basis. A safety report was generated every 6 months and reviewed by an independent safety monitor.

Statistical Analyses

All analyses were performed by intention to treat (ie, participants were analyzed as randomized, regardless of adherence). A 2-sided P value of .05 was used for the level of statistical significance. SAS 9.4 statistical software23 was used for analyses. Sample size was determined to detect a difference between the proportion with bacteriuria plus pyuria over time in the treatment vs placebo group using the method of Diggle et al24 for repeated binary outcomes. The following assumptions were made for this sample size calculation: type I error of 5% (2-sided), 80% power, a serial correlation of 0.35 between 6 repeated participant outcomes, an overall bacteriuria plus pyuria rate of 0.45 in the control group,15 a 33% lower rate of bacteriuria plus pyuria in the treatment group (ie, bacteriuria plus pyuria rate of 0.30),11 and 20% inflation for deaths, transfers, and missing cultures. Based on these assumptions, the total sample size was 180 participants (90 per group).

The adjusted analysis of the primary outcome was conducted using generalized estimating equations (GEE) with inverse probability weighting at the observation level for missing monotone values. The SAS PROC GEE procedure, which permits explicit modeling of the missing data mechanism as the means for determining inverse probability weights, was used instead of the initially planned generalized linear mixed model. Missing intermittent values and 2-month values for participants with no recorded outcomes were singly imputed using the fully conditional specification method, a prerequisite for using the inverse probability weighting GEE method.25 This regression-modeling approach for handling missing values under the assumption of data missing at random was chosen because of the unexpected amount and mechanism of the missing data because it allowed for the explicit modeling of the missing data mechanism without adding covariates to the regression model that were not prespecified and because it avoided making unreasonable assumptions regarding random effects needed for a generalized linear mixed model with binary outcomes. Prespecified baseline variables for bacteriuria, incontinence, age at enrollment, and number of comorbidities were included in the model as covariates. A covariate for surveillance time was also added and assessed both for its linear association with the outcome and for its interaction with treatment. An unstructured correlation matrix was used to model the serial correlation of repeated participant outcomes.

The adjusted percentage with bacteriuria plus pyuria for each treatment group at each surveillance time point was estimated by transforming the GEE model estimates using an inverse logit link function. The secondary outcomes were analyzed by a generalized linear regression model with a Poisson distribution, a treatment status explanatory variable, a natural logarithm of the time at risk as an offset, and adjustments for overdispersion (see Protocol in Supplement 1 and the eAppendix in Supplement 2 for additional details of all methods). Because the primary proposed mechanism of action of cranberry products is targeted toward E coli, exploratory analyses examined the percentage of E coli urinary isolates vs others that met the criteria for bacteriuria in bimonthly urine specimens. Additionally, exploratory analyses of participants without bacteriuria plus pyuria at baseline were conducted. No tests of significance were conducted for exploratory analyses.

Results

Figure 1 shows the flow of nursing homes and study participants. From August 24, 2012, through October 7, 2014, 5045 nursing home residents in 21 nursing homes were screened for participation, 806 (16.0%) of whom were eligible, 248 (30.8%) of those consented, and 185 (74.6%) of those who consented were able to provide a baseline clean catch urine specimen and be randomized. Surrogate consent had to be obtained for 93.5% of participants. Surveillance for all outcome and safety data ended on October 26, 2015. Table 1 displays the baseline demographic characteristics of participants. The mean age of participants was 86.4 years (SD, 8.2). The treatment and control groups were generally comparable. Rates of incontinence, bacteriuria, and number of episodes of UTI in the past year were similar; however, the control group had more coexisting conditions, specifically arrhythmia and hemiplegia.

One hundred forty-seven participants completed 1 year of surveillance, and 33 participants died. Twenty participants, 9 in the treatment group and 11 in the control group, became incontinent prior to the first outcome assessment and were unable to provide any of the scheduled urine specimens. Over the course of the study, 45 participants stopped taking the capsules, 24 in the treatment and 21 in the control groups; 21 refused, 19 transitioned to hospice care, 4 started taking warfarin, and 1 refused via family.

Overall adherence to capsule administration was 80.1%, 77.5% in the treatment group and 82.6% in the control group. Adherence was 83.7% (n = 185) in the first 6 months and 76.7% (n = 168) in the second 6 months.

Table 2 depicts the percentage of urine specimens that met the primary outcome of bacteriuria plus pyuria over 12 months of surveillance. The overall unadjusted results showed rates of 25.5% (95% CI, 18.6%-33.9%) in the treatment group vs 29.5% (95% CI, 22.2%-37.9%) in the control group. The adjusted analysis, accounting for missing data and prespecified covariates, showed no significant difference between groups (29.1% vs 29.0%; OR, 1.01; 95% CI, 0.61-1.66; P = .98; Figure 2). Of the 723 urinary specimens obtained, 9 participants (7 with 1 symptom [3 in treatment group, 4 in control group] and 2 with 2 symptoms [1 in each group]) had urinary tract–specific symptoms at a bimonthly assessment.

Of 350 episodes of clinically suspected UTI in 131 participants, there were 10 symptomatic UTIs in the treatment group (8 participants with 1 episode and 1 participant with 2 episodes) and 12 symptomatic UTIs in the control group (7 participants with 1 episode, 1 participant with 2 episodes, and 1 participant with 3 episodes). Although blood cultures were requested for 35 episodes of clinically suspected UTI, there was only 1 episode of septicemia, which occurred in the control group. Table 3 shows that there were no significant differences in rates of death, hospitalization, multidrug-resistant gram-negative bacilli bacteriuria (from scheduled and suspected UTI urine cultures), antibiotics administered for suspected UTI, or total antimicrobial utilization. There was one MRSA urinary isolate identified in the treatment group and no VRE urinary isolates identified. There were a total of 3830 adverse events (eTable 1 in Supplement 2), 116 serious (83 hospitalizations and 33 deaths, all protocol-unrelated and anticipated) and 3714 nonserious (14 protocol-related and anticipated). The frequency of the 14 protocol-related and anticipated nonserious adverse events (ie, altered mental status, gastrointestinal disturbance, oral cavity disturbance, skin and soft tissue event, weight loss) was similar in both treatment groups.

Exploratory analyses of the percentage of E coli isolates showed that in the treatment group, the percentage of E coli at study start was 19.6%, at month 2 was 25%; month 4, 20.6%; month 6, 15.6%; month 8, 20.0%; month 10, 17.7%; and month 12, 22.7%. In the control group, the percentage of E coli at study start was 21.5%, at month 2 was 23.1%; month 4, 24.6%; month 6, 22.4%; month 8, 18.3%; month 10, 18.5%; and month 12, 17.4%. Exploratory analyses in the subset of 127 women (n = 66 in the treatment group, n = 61 in the control group) who did not have bacteriuria plus pyuria at baseline showed that the overall rate of bacteriuria plus pyuria over 1 year was 15% (n = 39) in the treatment group and 11.4% (n = 28) in the control group (eTable 2 in Supplement 2).

Discussion

Quiz Ref IDDespite prior studies demonstrating that cranberry juice reduced bacteriuria plus pyuria in older women and that 2 cranberry capsules with 72 mg of proanthocyanidins (equivalent to 20 ounces of cranberry juice) was an appropriate dose to test,11,15,26 the findings from this trial demonstrated no significant difference in presence of bacteriuria plus pyuria among women who received cranberry capsules vs placebo over 1 year. The lack of statistically significant differences in any of the secondary outcomes is consistent with this finding. Many studies of cranberry products have been conducted over several decades with conflicting evidence of its utility for UTI prevention. The results have led to the recommendation that cranberry products do not prevent UTI overall but may be effective in older women.9,27 This trial did not show a benefit of cranberry capsules in terms of a lower presence of bacteriuria plus pyuria among older women living in nursing homes.

Some studies evaluated cranberry products solely among older adults. In a recent Cochrane review,9 2 reports showed a reduction in bacteriuria plus pyuria,11,26 whereas 2 others did not show a clinical benefit of cranberry products.14,16 In 1 study of older women in nursing homes and assisted living facilities, 300 mL of cranberry juice cocktail containing 36 mg of proanthocyanidins showed a benefit, but the placebo group had a higher rate of prior history of UTI and likely higher risk of bacteriuria plus pyuria.28 A more recent study of 1 cranberry capsule twice a day (18 mg proanthocyanidins total) in long-term care facility residents with high risk of UTI (ie, need for long-term catheterization, diabetes mellitus, or at least 1 UTI in the preceding year) showed that participants receiving cranberry capsules had a lower incidence of clinically defined UTI (ie, one of the following: specific and nonspecific micturition-related symptoms and signs; a positive nitrite, leukocyte esterase, dipslide, or culture; antibiotic treatment for UTI; or UTI reported in the medical record). The UTI definition used was very broad, and there was no difference between the treatment and control groups using a strict UTI definition or for either definition in the low risk UTI group. Hence, cranberry capsules have not shown meaningful clinical benefit and have not been cost-effective.29,30

There are several potential explanations for why cranberry capsules, compared with placebo, did not result in a difference in the presence of bacteriuria plus pyuria in this trial. First, there appeared to be an initial effect on bacteriuria plus pyuria in the first 6 months, but these rates returned to baseline in the second 6 months of study. Slightly lower adherence in the second 6 months could have contributed to this finding. Additionally, it is possible that because of worsening incontinence and changes to the vaginal microbiome with age, the effects of cranberry capsules were not sustained. Although the exploratory analysis of those without bacteriuria plus pyuria at baseline is limited because the benefit of randomization is lost, it did not support the premise that cranberry capsules prevented bacteriuria plus pyuria over the surveillance period. Second, cranberry capsules do not provide the hydration of cranberry juice. A recent study among women undergoing elective gynecological surgery with urinary catheter removal showed that 2 cranberry capsules twice a day (equivalent to 16 ounces of cranberry juice) over 6 weeks were able to reduce the rate of UTI by half.31 However, all participants were instructed to drink 8 ounces of water twice a day with each capsule administration, so it is possible that the fluid load was necessary along with cranberry product. Hydration may also be a necessary component to reduce bacteriuria and urinary symptoms in older women.5 Third, although adherence was high as measured by capsules removed from the blister pack, participants might not have actually ingested the capsules.

Quiz Ref IDThis trial had several strengths. Nursing home residents exclusively were enrolled, the dose of proanthocyanidins was standardized, adherence to capsule administration by the planned assessment method was high, and nursing home staff were trained to optimize outcome assessments. However, this trial also had limitations. First, since participants could not be catheterized to obtain bimonthly urine specimens, only residents capable of providing a clean catch urine specimen were randomized. Exclusion of residents for complete incontinence limited the generalizability of these findings. For randomized participants, 20 became incontinent prior to the first outcome assessment and were unable to provide any urine specimens. Others became incontinent or were transitioned to hospice care, so urine specimens were not obtained. Nevertheless, 65% of planned urine specimens were collected. Second, 78 nursing homes either did not respond or declined to participate and 7 agreed to participate but subsequently declined. Third, antiadhesion of E coli to uroepithelial cells in the urine specimens of participants in the trial was not tested. Adhesion studies to date have been conducted on patients enrolled for relatively short observation periods.7,8 Since there were multiple assessment time points and it was not possible to ensure adherence to capsule ingestion on the day prior to obtaining a urine specimen for adhesion testing, the antiadhesion testing was not feasible. Fourth, the baseline rate of bacteriuria plus pyuria and percentage of E coli bacteriuria in this trial population was lower than in the pilot dosing study.15 Fifth, this study enrolled women with or without bacteriuria plus pyuria at baseline. Therefore, it was not possible to definitively determine the specific role of cranberry capsules for prevention of new occurrence of bacteriuria plus pyuria among women without bacteriuria plus pyuria at baseline nor for reduction of bacteriuria plus pyuria among women with prevalent bacteriuria plus pyuria at baseline.

Conclusions

Among older women residing in nursing homes, administration of cranberry capsules compared with placebo resulted in no significant difference in presence of bacteriuria plus pyuria over 1 year.

Back to top
Article Information

Corresponding Author: Manisha Juthani-Mehta, MD, Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, PO Box 208022, New Haven, CT 06520 (manisha.juthani@yale.edu).

Published Online: October 27, 2016. doi:10.1001/jama.2016.16141

Author Contributions: Drs Juthani-Mehta and Van Ness had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Juthani-Mehta, Argraves, Acampora, Quagliarello, Peduzzi.

Acquisition, analysis, or interpretation of data: Juthani-Mehta, Van Ness, Bianco, Rink, Rubeck, Ginter, Argraves, Charpentier, Trentalange, Quagliarello, Peduzzi.

Drafting of the manuscript: Juthani-Mehta, Van Ness, Argraves, Acampora, Quagliarello.

Critical revision of the manuscript for important intellectual content: Van Ness, Bianco, Rink, Rubeck, Ginter, Argraves, Charpentier, Acampora, Trentalange, Quagliarello, Peduzzi.

Statistical analysis: Van Ness, Argraves, Trentalange, Peduzzi.

Administrative, technical, or material support: Bianco, Rink, Rubeck, Ginter, Argraves, Charpentier, Acampora.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This study was supported by grants P30 AG021342 Claude D. Pepper Older Americans Independence Center, R01 AG041153, and K07 AG030093 all from the National Institute on Aging, National Institutes of Health. Cranberry and placebo capsules used in this study were manufactured and donated by Pharmatoka.

Role of Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Pharmatoka had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Leo M. Cooney Jr, MD, Humana Foundation Professor of Medicine (Geriatrics), Yale School of Medicine, for serving as the independent safety monitor for this study. Dr Cooney did not receive compensation for serving in this role.

References
1.
Rowe  TA, Juthani-Mehta  M.  Diagnosis and management of urinary tract infection in older adults.  Infect Dis Clin North Am. 2014;28(1):75-89.PubMedArticle
2.
Juthani-Mehta  M, Datunashvili  A, Tinetti  M.  Tests for urinary tract infection in nursing home residents.  JAMA. 2014;312(16):1687-1688.PubMedArticle
3.
Nicolle  LE, Mayhew  WJ, Bryan  L.  Prospective randomized comparison of therapy and no therapy for asymptomatic bacteriuria in institutionalized elderly women.  Am J Med. 1987;83(1):27-33.PubMedArticle
4.
Abrutyn  E, Mossey  J, Berlin  JA,  et al.  Does asymptomatic bacteriuria predict mortality and does antimicrobial treatment reduce mortality in elderly ambulatory women?  Ann Intern Med. 1994;120(10):827-833.PubMedArticle
5.
Mody  L, Juthani-Mehta  M.  Urinary tract infections in older women: a clinical review.  JAMA. 2014;311(8):844-854.PubMedArticle
6.
Nicolle  LE, Bradley  S, Colgan  R, Rice  JC, Schaeffer  A, Hooton  TM; Infectious Diseases Society of America; American Society of Nephrology; American Geriatric Society.  Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults.  Clin Infect Dis. 2005;40(5):643-654.PubMedArticle
7.
Howell  AB, Vorsa  N, Der Marderosian  A, Foo  LY.  Inhibition of the adherence of P-fimbriated Escherichia coli to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries.  N Engl J Med. 1998;339(15):1085-1086.PubMedArticle
8.
Lavigne  JP, Bourg  G, Combescure  C, Botto  H, Sotto  A.  In-vitro and in-vivo evidence of dose-dependent decrease of uropathogenic Escherichia coli virulence after consumption of commercial Vaccinium macrocarpon (cranberry) capsules.  Clin Microbiol Infect. 2008;14(4):350-355.PubMedArticle
9.
Jepson  RG, Williams  G, Craig  JC.  Cranberries for preventing urinary tract infections.  Cochrane Database Syst Rev. 2012;10:CD001321.PubMed
10.
Wang  CH, Fang  CC, Chen  NC,  et al.  Cranberry-containing products for prevention of urinary tract infections in susceptible populations: a systematic review and meta-analysis of randomized controlled trials.  Arch Intern Med. 2012;172(13):988-996.PubMedArticle
11.
Avorn  J, Monane  M, Gurwitz  JH, Glynn  RJ, Choodnovskiy  I, Lipsitz  LA.  Reduction of bacteriuria and pyuria after ingestion of cranberry juice.  JAMA. 1994;271(10):751-754.PubMedArticle
12.
Wing  DA, Rumney  PJ, Preslicka  CW, Chung  JH.  Daily cranberry juice for the prevention of asymptomatic bacteriuria in pregnancy: a randomized, controlled pilot study.  J Urol. 2008;180(4):1367-1372.PubMedArticle
13.
Wotton  K, Crannitch  K, Munt  R.  Prevalence, risk factors and strategies to prevent dehydration in older adults.  Contemp Nurse. 2008;31(1):44-56.PubMedArticle
14.
Juthani-Mehta  M, Perley  L, Chen  S, Dziura  J, Gupta  K.  Feasibility of cranberry capsule administration and clean-catch urine collection in long-term care residents.  J Am Geriatr Soc. 2010;58(10):2028-2030.PubMedArticle
15.
Bianco  L, Perrelli  E, Towle  V, Van Ness  PH, Juthani-Mehta  M.  Pilot randomized controlled dosing study of cranberry capsules for reduction of bacteriuria plus pyuria in female nursing home residents.  J Am Geriatr Soc. 2012;60(6):1180-1181.PubMedArticle
16.
McMurdo  ME, Bissett  LY, Price  RJ, Phillips  G, Crombie  IK.  Does ingestion of cranberry juice reduce symptomatic urinary tract infections in older people in hospital? a double-blind, placebo-controlled trial.  Age Ageing. 2005;34(3):256-261.PubMedArticle
17.
Terris  MK, Issa  MM, Tacker  JR.  Dietary supplementation with cranberry concentrate tablets may increase the risk of nephrolithiasis.  Urology. 2001;57(1):26-29.PubMedArticle
18.
Prior  RL, Fan  E, Ji  H,  et al.  Multi-laboratory validation of a standard method for quantifying proanthocyanidins in cranberry powders.  J Sci Food Agric. 2010;90(9):1473-1478.PubMedArticle
19.
Juthani-Mehta  M, Quagliarello  V, Perrelli  E, Towle  V, Van Ness  PH, Tinetti  M.  Clinical features to identify urinary tract infection in nursing home residents: a cohort study.  J Am Geriatr Soc. 2009;57(6):963-970.PubMedArticle
20.
Juthani-Mehta  M, Van Ness  PH, McGloin  J,  et al.  A cluster-randomized controlled trial of a multicomponent intervention protocol for pneumonia prevention among nursing home elders.  Clin Infect Dis. 2015;60(6):849-857.PubMedArticle
21.
Stone  ND, Ashraf  MS, Calder  J,  et al; Society for Healthcare Epidemiology Long-Term Care Special Interest Group.  Surveillance definitions of infections in long-term care facilities: revisiting the McGeer criteria.  Infect Control Hosp Epidemiol. 2012;33(10):965-977.PubMedArticle
22.
Pop-Vicas  A, Tacconelli  E, Gravenstein  S, Lu  B, D’Agata  EM.  Influx of multidrug-resistant, gram-negative bacteria in the hospital setting and the role of elderly patients with bacterial bloodstream infection.  Infect Control Hosp Epidemiol. 2009;30(4):325-331.PubMedArticle
23.
SAS/STAT User’s Guide.  Version 14.1. Cary, NC: SAS Institute Inc; 2015.
24.
Diggle  P, Heagerty  P, Liang  KY, Zeger  SL.  Analysis of Longitudinal Data. 2nd ed. New York, NY: Oxford University Press; 2002.
25.
van Buuren  S.  Multiple imputation of discrete and continuous data by fully conditional specification.  Stat Methods Med Res. 2007;16(3):219-242.PubMedArticle
26.
Haverkorn  MJ, Mandigers  J.  Reduction of bacteriuria and pyuria using cranberry juice.  JAMA. 1994;272(8):590.PubMedArticle
27.
Jepson  R, Craig  J, Williams  G.  Cranberry products and prevention of urinary tract infections.  JAMA. 2013;310(13):1395-1396.PubMedArticle
28.
Hopkins  WJ, Heisey  DM, Jonler  M, Uehling  DT.  Reduction of bacteriuria and pyuria using cranberry juice.  JAMA. 1994;272(8):588-589.PubMedArticle
29.
Caljouw  MA, van den Hout  WB, Putter  H, Achterberg  WP, Cools  HJ, Gussekloo  J.  Effectiveness of cranberry capsules to prevent urinary tract infections in vulnerable older persons: a double-blind randomized placebo-controlled trial in long-term care facilities.  J Am Geriatr Soc. 2014;62(1):103-110.PubMedArticle
30.
van den Hout  WB, Caljouw  MA, Putter  H, Cools  HJ, Gussekloo  J.  Cost-effectiveness of cranberry capsules to prevent urinary tract infection in long-term care facilities: economic evaluation with a randomized controlled trial.  J Am Geriatr Soc. 2014;62(1):111-116.PubMedArticle
31.
Foxman  B, Cronenwett  AE, Spino  C, Berger  MB, Morgan  DM.  Cranberry juice capsules and urinary tract infection after surgery: results of a randomized trial.  Am J Obstet Gynecol. 2015;213(2):194.e1-194.e8. PubMedArticle
×