Tuesday, 30 August 2016

Re: Cranberry Products May Be an Effective Option for Preventing Recurrent Urinary Tract Infections in Pediatric Patients

  • Cranberry (Vaccinium macrocarpon, Ericaceae)
  • Urinary Tract Infections
  • Children
Date: 08-15-2016 HC# 011642-550

Durham SH, Stamm PL, Eiland LS. Cranberry products for the prophylaxis of urinary tract infections in pediatric patients. Ann Pharmacother. December 2015;49(12):1349-1356.
Cranberry (Vaccinium spp., Ericaceae) products have been shown to be effective in preventing recurrent urinary tract infections (UTIs) in women, 30% of whom experience a UTI in their lifetime, compared with 1% of men.* Once thought to acidify the urinary tract (studies show pH does not actually change), it is now thought that cranberry compounds, specifically A-type proanthocyanidins (PACs), inhibit P-fimbriated Escherichia coli bacteria from binding to epithelial walls. E. coli causes 90% of initial UTIs and 75% of recurring infections; more than 90% of nephritogenic E. coli have P fimbriae. Also, cranberry is thought to inhibit biofilm formation. Cranberry products do not disrupt gastric flora or promote bacterial resistance; in addition, they are easy to obtain and use.
UTIs are common in the pediatric population, with 8% of girls and 2% of boys diagnosed with a UTI by age 11. Up to 35% of patients have recurrent UTIs that may have long-term effects. UTI risk factors include obstruction to urinary flow and urinary stasis; the latter can be caused by vesicoureteral reflux (VUR), anatomical abnormalities, neuropathic bladder, or indwelling catheters. Besides E. coli, UTIs in children are often caused by Pseudomonas spp., especially in children with neurogenic bladder, frequent instrumentation, or indwelling catheters. Prophylactic low-dose antibiotics may be used in children with obstructive disease or VUR to lower risks of recurrent UTIs, but international trials report conflicting results for the practice. A 2011 Cochrane review concluded that prophylaxis reduced risks of recurrence but found the benefit small compared to risks. Several studies report that use of antibiotic prophylaxis leads to bacterial resistance. With a need for new strategies for treating UTIs in children, researchers have studied cranberry's beneficial effects. The authors searched PubMed database entries spanning 1966 to June 2015, identifying eight relevant randomized controlled trials (RCTs).
Three RCTs involving otherwise healthy children used cranberry juice as their active intervention; however, they varied by the following: sample size; whether or not the UTI was caused exclusively by E. coli; whether or not they included children with VUR, and, if so, what grade VUR; whether they included females only or both sexes; and the products used. Only one study used cranberry juices with known PAC percentages (37% in the active arm, 0% in the control arm). Despite these and other differences in design and procedures, all three studies found benefits for cranberry juice over placebo, no intervention, or Lactobacillus spp. drink; two reported significant risk reductions for UTIs.
In children with anatomical abnormalities, five RCTs had mixed results as follows:
(1) A randomized, single-blind, crossover trial treated 40 children with neuropathic bladders, but only 21 (52.5%) completed the study; 12 dropped out because of the taste, cost, and/or caloric content of the cranberry juice used. On study completion, there were no significant differences in UTI incidence between groups (P = 0.5566), or in the subset receiving prophylactic antibiotics (P = 0.2845).
(2) In a double-blind, crossover RCT assessing effects of cranberry prophylaxis on neurogenic bladder due to myelomeningocele and clean intermittent catheterization, 15 children received either cranberry concentrate or placebo for 12 weeks, then crossed over for an additional 12 weeks. They were followed for six months, with no difference found in the percentage of urine cultures testing positive for a UTI pathogen in the groups at the end of the study. Researchers theorized that the voiding difficulty caused by neurogenic bladder may have overwhelmed effects of the cranberry product. They further hypothesized that patients with urogenital abnormalities or chronic medical conditions may have UTIs caused by E. coli that do not express adhesins and would thus not benefit from cranberries.
(3) Another crossover RCT in a similar population as the second study included 20 patients. After a year, significant reductions were seen in UTI rates in the cranberry arm (P = 0.012), in females (P = 0.008), in patients without VUR (P = 0.029), and in patients with renal scarring (P = 0.033). In addition, 16 patients experienced pyuria during the placebo arm, whereas only two experienced this during the cranberry arm (P = 0.000).
(4, 5) Finally, in two trials comparing cranberry products directly to prophylactic antibiotics, there was no significant difference in infection rates in children with VUR given cefaclor or children with a history of recurrent UTIs (VUR of any degree accepted) given trimethoprim and those given cranberry, leading researchers to conclude that cranberry juice was not inferior to either antibiotic in preventing UTIs.
In several studies, high dropout rates were attributed to cranberry's tartness, though in one study, only one patient (8.3%) in the cranberry group could not drink the juice because of the tartness, a contrast from previous studies. Cranberry tablets may increase excretion of oxalate and other lithogenic ions, a risk to those with nephrolithiasis. Different products, doses, and dosing schedules used, and the lack of data regarding PAC content except in one study, make specific recommendations difficult.
Cranberry products differ substantially. Quantifying PAC is achieved by several methods; however, even the best method, dimethylaminocinnamaldehyde (DMAC), cannot distinguish amounts or types of A-type PAC oligomers and is accurate only for juice-based products, not those made from the cranberry skins or pomace. American cranberry (V. macrocarpon) has more PAC content than small cranberry (V. oxycoccos) and should be used for UTI prevention. White cranberry contains PAC precursors which do show anti-adhesion activity in vitro. Processing and storage can alter PAC levels, yet in cranberry powders, extracts, tablets, and capsules, labeled doses do not reflect PAC content.** In juice cocktails and mixes, the percentage of juice does not reflect PAC content. Levels may vary in different lots of juice from the same producer. No dosing studies have been conducted in children, and optimal PAC doses are undefined in all populations. Pharmacokinetic information is lacking except for limited studies of cranberry juice. Based on the results of the eight clinical trials, cranberry juice, dosed from 2 to 5 mL/kg/day, showed the most benefit. In the absence of more definitive studies, a minimum PAC dose of 36 mg/d in one daily dose or two 36-mg doses for acute cases is suggested. [Note: The article incorrectly reported a dosage of 36 g/d.] Larger studies are needed.
—Mariann Garner-Wizard
*However, during the first year of life, males have more UTIs than females.
**Not all powders are whole cranberry. The cheaper products are usually made from the dried skins or pomace after the juice is removed. These are not soluble and cannot be measured accurately with DMAC. These have delayed urinary anti-adhesion activity which is stunted compared to the soluble juice-based powders in which the PACs can be measured by DMAC. The juice powders are more expensive and act more quickly, producing a more rapid anti-adhesion effect. The labels on powdered cranberry supplements are currently not required to list if they are juice or pomace-based, so consumers typically buy the cheaper, less-effective products. Separate PAC quantification methods must be used for each product type or the levels of PAC will not be reported correctly.