Urology Nurses Online: ARTICLES

Efficacy of Cranberry in Prevention of Urinary Tract Infection in a Susceptible Pediatric Population

Mohamed M.R. Foda, MBBCh, MSc, FRCS (Glasgow),¹
Paul F. Middlebrook, MD, FRCS, ¹
Charles T. Gatfield, MD, BSc.,¹
Ginette Potvin, RN,²
George Wells, MSc, PhD ³ and, John F. Schillinger, MD, FRCS ¹

1 Division of Urology; Children's Hospital of Eastern Ontario (CHEO) and Department of Urology University of Ottawa, Ottawa, Ontario

2 Division of Urology; Children's Hospital of Eastern Ontario, Ottawa, Ontario

3 Clinical Epidemiology Unit, Loeb Research Unit; and Department of Medicine and Community Medicine and Epidemiology University of Ottawa, Ontario

This article was published in The Canadian Journal of Urology, 1995; 2(1):98-102

ABSTRACT

The objective of this study was to evaluate liquid cranberry product as prophylaxis against bacterial urinary tract infection (UTI), in a pediatric neuropathic bladder population.

Forty cases managed by clean intermittent catheterization with or without pharmacotherapy were enrolled in a randomized single-blind cross-over study. Subjects ingested 15 ml/kg/day of cranberry cocktail or water for 6 months followed by the reverse for another 6 months. Initial catheter urine samples and subsequent monthly and interim cultures were obtained. Associated symptoms were recorded along with a follow up attendance/compliance registry. The number of negative culture months to the number of months contributed was tabulated and compared between interventions. Individual, cumulative and antimicrobial subset analysis was performed.

Twenty one completed the study; 12 dropped out for reasons related to the cranberry (taste, caloric load and cost); seven dropped out for other reasons ( too busy, death, no stated reason). Wilcoxon matched-pairs Signed-ranks analysis revealed no difference between intervention periods (2-tailed P=.5566 (whole group); P=.2845(antimicrobial subset) with respect to infection. Fewer infections were observed in nine patients taking cranberry juice and in nine patients given water; no difference was noted in three.

Liquid cranberry product, on a daily basis, at the dosage employed, did not have any effect greater than that of water in preventing UTI in this pediatric neuropathic bladder population.

Introduction

Despite advances with clean intermittent catheterization (CIC) and pharmacotherapy, urinary tract infection(UTI) and possible subsequent renal damage remains a major concern in neuropathic bladder dysfunction¹. Frank UTI demands treatment. The existence of asymptomatic bacteriuria is well recognized but the need for antimicrobial prophylaxis remains controversial. Prophylaxis is necessary in some, most notably those with vesicoureteric reflux. Routine antimicrobial prophylaxis however, presents several problems including possible adverse effects and the emergence of resistance^1-3. The use of commercially available foodstuffs for prophylaxis has been entertained with varying popularity. To this end, cranberry juice has been consumed in North America as "folk medicine". It has been claimed to be successful in alleviating irritative symptomatology and treating UTI. Early in vivo studies determined the effects of cranberry ingestion on urine composition of healthy individuals^4-8. Contrary to most other fruits, the consumption of cranberry produces low pH urine due to the hippuric acid that results from its' metabolism.⁵ Further studies have shown this effect to be transient⁷ and unpredictable⁸.

Few studies exist with patients susceptible to or suffering from UTI^9-12. In a study of 60 adults with UTI symptoms investigators examined possible therapeutic effects of a daily ingestion of 16 ounces of commercial cranberry juice over three weeks. Infection persisted or recurred six weeks after treatment in 27 patients¹⁰. Another study of eight multiple sclerosis patients concluded that the combined daily use of 12 ounces of cranberry juice and 1 g ascorbic acid was able to acidify urine but was unable to produce or maintain an uninfected state¹¹. A third trial was done with 17 spina bifida children, 10 of whom were on CIC. They received 1-3 glasses of cranberry juice daily for 1-2 weeks. Improvement in the physical characteristics of urine was reported but the samples from one third of the children continued to grow Escherichia coli¹².

Description of in vitro anti-adherence properties of cranberry juice against Escherichia coli and other bacterial isolates has revived interest in research^13-16. In vitro studies with urine showed significant anti-adherence activity 1-3 hours after consuming cranberry cocktail ¹³. More recent¹⁴, a randomized controlled study evaluating cranberry cocktail in a female geriatric population has been completed. This trial strongly supported a beneficial effect of liquid cranberry in UTI prophylaxis suggesting a microbiologic justification for the "folk lore" remedy¹⁷.

The aim of our trial was to evaluate commercial liquid cranberry product as effective prophylaxis against bacterial UTI in a susceptible pediatric neuropathic bladder population.

Method & Materials

A single blind, 12 month, crossover design with the treating physician blind to the nature of dietary intervention was employed. Eligibility criteria included outpatients' residence at a distance not exceeding 150 km. from the Children's Hospital of Eastern Ontario (CHEO), with no significant associated medical conditions, to ensure easy access to follow-up. Forty pediatric neuropathic bladder cases followed at the Spina Bifida clinic at CHEO were enrolled. Only one inpatient was recruited. She remained hospitalized throughout the trial. Subjects included 37 with myelodysplasia (20 female;17 male), two with traumatic paraplegia (one female; one male) and one male with transverse myelitis. All patients were managed by CIC with or without pharmacotherapy. Patient age at enrollment ranged from 1.4 to 18 years with a mean of 9.35 years. Cases receiving antibiotic prophylaxis continued to do so for ethical reasons.

During the initial visit, details of the trial were given to the family and consent was subsequently obtained. History and physical examination including weight determination was completed and a sterile catheter urine sample was obtained. Maintaining the primary physician blind to the nature of intervention was emphasized as was the importance of drinking the designated amount of water or the cranberry juice on a daily basis. Patients or parents were asked to avoid cranberry or its products during the water period. Patients were then randomly assigned to start either a calculated (15 ml/kg) daily amount of cranberry cocktail (30 % cranberry concentrate) or water divided into 3-4 doses, in addition to a regular diet and fluid intake. A starting date with subsequent monthly follow-up visits was arranged to obtain sterile catheter urine samples and the primary care physician was notified as to the nature and duration of the study. Parents were encouraged to reschedule missed appointments. Caregivers were instructed to inform the research fellow about dates and locations of interim urine sample and culturing and of any associated symptoms. Reported specimens were traced. Follow up urine sampling was done by the fellow or the nurse at the Spina Bifida Clinic or by the patient's primary care physician after mutual agreement. Urine was collected and handled according to standard sterile catheter sampling procedures and appropriately refrigerated and plated. All culture results were documented as was a record of missed appointments. A bacteriologically significant or positive culture was defined by a count greater than or equal to 10⁵ colony-forming units per litre (CFU/L) of a pathogenic organism after 24 hours incubation. When two organisms were reported, the one with the highest count was used to determine significance. Any growth (i.e.< 10⁵ CFU/L) in a symptomatic patient was significant. A bacteriologically insignificant or negative culture was defined as no growth, or mixed growth with more than two organisms in an asymptomatic patient, a non-pathogenic organism viz. coagulase negative staphylococci, non-hemolytic and alpha-hemolytic streptococci, diphtheroids and lactobacilli or if a pathogenic organism was detected at a count of < 10⁵ CFU/L in an asymptomatic patient. However, any growth of proteus or pseudomonas was considered significant. Monthly telephone contact was made to reinforce compliance. Upon completion of the first six months, assessment of compliance in administering the prescribed fluids was done by direct questioning using a self-administered questionnaire, completed by the patient or the caregiver as appropriate. Non-compliance resulting in exclusion was defined as consistent failure of adhering to the instructions regarding fluid administration, < 75 % (as subjectively reported) or for appearing at < 75 % of the follow up appointments (from objective recording). Measuring compliance through missed follow up was based on the assumption that failure to adhere to follow up would parallel compliance with intervention administration. Adherent patients were reweighed at the conclusion of the first six months, prior to cross-over, and the fluid ration was recalculated using a current weight. At the conclusion of the study, six months later, compliance measurement was repeated.

Statistical analysis included an intra-individual comparison of the proportion negative culture months to culture months contributed and was subject to a Paired Samples t-test (PStT) with and without Arcsin transformation application and a Wilcoxon Matched-pairs Signed-ranks test (WMPSRT). Analysis was performed for all subjects and for the subset on antimicrobial prophylaxis. Dropouts early and late were withdrawn from analysis. Evaluation of appointment compliance between interventions was performed using a chi-square technique.

Results

Twenty one (twelve male, nine female) completed the study, 18 with myelodysplasia, two were traumatic paraplegic and one had transverse myelitis. Eleven (five male, six female) received cranberry first while 10 (seven male, three female) started with water. In 17 patients a past history of UTI was obtained; seven patients complained of frequent UTI. Twelve patients continued a prophylactic antibiotic for the duration of the study. Patients who completed the study contributed a total of 229 months with a mean of 10.9 months per subject (Table 1).

In three patients, an increase of 50% or more was noted in the number of negative culture months to months observed in favour of cranberry. However, intra-individual comparison employing either a PStT with and without Arcsin transformation or WMPSRT revealed no significant difference between interventions for the whole group (p>.5) or for the subset receiving antibiotic prophylaxis (p>.25) (Table 2). WMPSRT analysis revealed a two-tailed p = .5566 for the whole group and p = .2845 for the subset taking antibiotics. PStT yielded similar results.

The 21 patients missed 23 follow up appointments. Among these no culture was obtained for 14 months on cranberry and for nine months on water. No difference in compliance in keeping appointments between groups was noted (p>.05). In addition to the 21 that completed the study, eight late (> 3 months) and 11 early (< 3 months) dropouts occurred. Reason, time and dietary intervention at dropout are presented in Table 3.

Organisms isolated include gram negative bacilli (E. coli, Klebsiella, enterobacter, Proteus mirabilis and vulgaris, citrobacter, Pseudomonas aeruginosa and, Morganella morgani); gram positive cocci (S. aureus, coagulase negative S. epidermidis and saprophyticus, alpha- and beta-hemolytic streptococci, S. fecalis and non-hemolytic streptococci); gram positive bacilli (diphtheroids and lactobacilli); gram negative cocci (acinetobacter) and mixed flora. No patient required hospitalization for urinary tract infection.

Discussion

Twenty one patients completed the study, each contributing a mean of 10.9 of the planned 12 months reflecting a high degree of motivation and compliance in this group. Consumption / compliance questionnaires corroborated. Other methods were entertained as compliance checks. Assessment by bottle count was believed to be inconclusive evidence of the subjects' actual intake. Measuring compliance by urine pH was felt to be inconclusive as cranberry is known to have no sustained effect on urine acidity. Questionnaires and follow up attendance were selected as compliance measures. No difference in keeping appointments during periods in which patients were assigned to receive either cranberry or water was found. This observation was in contradistinction to the compliance of the eight late dropouts who contributed a significantly smaller number of months when they were assigned to receive cranberry as opposed to water, undoubtedly in part due to a dislike of the cocktail as seven of eight late dropouts received water during the initial six months of the trial and six of these dropped out after the switch to cranberry. The other dropped out prior to change over, not stating a reason. Results obtained from the late dropouts illustrate a lack of universal appeal of cranberry juice and are otherwise meaningless. Of clinical importance is the fact that 12 (30%) dropped out citing reasons directly related to the cocktail. Taste, cost and caloric content, > 600 calories per litre of cranberry cocktail limit acceptance. Future trials would benefit from a run-in period to assess compliance. This would have reduced non-compliance from 48% to 18%.

The group of 21 included 12 who continued to receive antibiotic prophylaxis for the duration of the trial thus eliminating any possible added efficacy to the antimicrobial of cranberry as compared to water, given that no difference in the occurrence of negative cultures was observed. Water at a standard volume was used to control for any diuretic effect that the cranberry juice may have contributed.

Again, intra-individual analysis revealed no significant difference in negative culture months between interventions regardless of antibiotic prophylaxis. The efficacy of the commercial liquid cranberry product for antibacterial UTI prophylaxis was therefore not found to be better than water. This finding although in agreement with some clinical studies ^9-12 is refuted by the work of Lipsitz et al which provides evidence supporting the effectiveness of cranberry in prophylaxing UTI in a female geriatric population.

Conclusion

Consumption of commercial liquid cranberry product on a daily basis, at the dosage employed, does not have any effect greater than that of water in preventing UTI in the defined population. We do not support the use of cranberry product for anti-bacterial prophylaxis in pediatric neuropathic bladders.

Further work on anti-adherence properties may serve as the impetus to re-evaluate this position while qualifying the use of cranberry for certain susceptible populations. Regardless of this taste, cost and caloric content will undoubtedly limit clinical acceptance.

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