Dems Da Berries? Cranberries or Antibiotics to Prevent UTIs

Abstract & Commentary

By Russell H. Greenfield, MD

Synopsis: In a lengthy intervention trial, antibiotic prophylaxis against recurrent urinary tract infections in premenopausal women was more effective than a cranberry extract; however, development of antibiotic resistance was significant.

Source: Beerepoot MAJ, et al. Cranberries vs antibiotics to prevent urinary tract infections. A randomized double-blind noninferiority trial in premenopausal women. Arch Intern Med 2011;171:1270-1278.

Cranberry (vaccinium macrocarpon) juice and extracts have long been promoted as effective interventions against recurrent urinary tract infections (rUTIs). The researchers behind this study sought to compare the use of a standardized cranberry extract in capsule form and antibiotic therapy as prophylaxis against rUTIs over the course of 1 year in a double-blind, double-dummy, randomized noninferiority trial in premenopausal women.

Community women aged 18 years or older with a history of at least three symptomatic UTIs (self-report) during the prior year were recruited via advertisements and physician and hospital referrals from throughout the Netherlands. Exclusion criteria included active UTI symptoms, pregnancy, and recent use of antibiotics or cranberries in the previous 2 weeks. Subjects were randomized to take over the ensuing year either (1) 1 tablet with 480 mg trimethoprim-sulfamethoxazole (TMP-SMX) at night and 1 placebo capsule twice daily, or (2) 1 capsule with 500 mg cranberry extract (Cran-Max; Proprietary Nutritionals, Inc, Kearny, New Jersey) twice daily and 1 placebo tablet at night. Patients were asked to avoid prophylactic antibiotics or cranberries during the intervention period and for 3 months following discontinuation of the intervention.

Immediately before initiation of the study medication and monthly thereafter until 3 months after discontinuation, subjects completed a questionnaire addressing UTI symptoms, adverse events, infections other than UTI, and antibiotic consumption. At these same specified time points, participants also were asked to collect urine (a dipslide and a sample to measure antibacterial activity) and feces. Adherence to antibiotic prophylaxis was assessed by measuring antibacterial activity in urine. Urine and fecal samples obtained at study entry, after 1 and 12 months of prophylaxis use, and 1 and 3 months after discontinuation of study medication were analyzed for antibiotic resistance of Escherichia coli isolates, and susceptibility to antibiotics most commonly prescribed for the treatment of UTI was determined. When symptoms compatible with rUTI developed, subjects were asked to collect urine using a dipslide and send it to the laboratory for culture.

Primary clinical outcomes of interest were mean number of self-reported rUTI (termed clinical recurrences, or CRs, and defined on the basis of symptoms including dysuria, frequency, and urgency) over 12 months; proportion of subjects with at least one symptomatic UTI during prophylaxis; and median time to first symptomatic UTI. Additional analysis of the primary outcomes was performed for the 3 months after discontinuation of the study medication. Secondary outcomes included mean number of microbiologically confirmed symptomatic rUTI (termed microbiologic recurrences, or MRs, and defined as a UTI on the basis of a combination of clinical symptoms and bacteriuria); percentage of partcipants with at least 1 MR; median time to first MR during prophylaxis and in the 3 months thereafter. Prevalence of asymptomatic bacteriuria at 1 and 12 months of prophylaxis, and proportion of patients experiencing serious adverse events, also were monitored.

Following 12 months' prophylaxis, the mean number of CRs was 1.8 (0.8-2.7) in the TMP-SMX and 4.0 (2.3-5.6) in the cranberry group. The between-group difference of 2.2 CRs (95% confidence interval, 0.3-4.2; P = 0.02) was outside the noninferiority margin of 1.3 CRs. Proportion of patients with at least 1 symptomatic UTI was also higher in the cranberry than in the TMP-SMX group (78.2% vs 71.1%). Median time to first recurrence was 8 months for the TMP-SMX and 4 months for the cranberry group (P = 0.03). After 1 month of TMP-SMX prophylaxis, resistance to TMP-SMX, TMP, and amoxicillin increased from 21.1%-27.8% to 72.5%-90.5% in both feces and urine, with a return to baseline resistance levels 3 months after antibiotic therapy was stopped.

E. coli was the most prevalent causative microorganism (78.9% TMP-SMX, 75.9% in the cranberry group). Resistance percentages of the E. coli isolates causing UTIs in the TMP-SMX group were similar to, and in the cranberry group somewhat lower than, corresponding resistance percentages of E. coli from feces or urine of asymptomatic women. Resistance rates for ciprofloxacin and norfloxacin in urinary E. coli isolates increased, from 8.3% at baseline to 23.1% after 12 months of TMP-SMX. After 1 month, 22 of the 83 women in the TMP-SMX group (26.5%) and 32 of the 89 women in the cranberry group (36.0%) had asymptomatic bacteriuria. At 12 months, these percentages were 30.2% (16 of 53) and 37.0% (17 of 46), respectively. Antibacterial activity was present in 632 of 722 urine samples (87.5%) obtained from women during TMP-SMX prophylaxis use. There were no statistically significant differences between the two groups with respect to adverse effects; however, one subject in the TMP-SMX group developed Stevens-Johnson syndrome.

The study authors concluded that once daily antibiotic therapy with TMP-SMX is more effective in premenopausal women against rUTI than cranberry capsules, but at the price of increased bacterial resistance to antibiotics.

Commentary

Recurrent urinary tract infection is a significant problem associated with significant morbidity and negative impacts on quality of life. Prevalence is high, and although prolonged antibiotic prophylaxis may be effective, many women fear the potential complication of infection with a resistant organism. The use of cranberry or blueberry juice or extracts have become very popular in this setting, and have been reported to also be effective, likely due to their ability to inhibit bacterial adhesion to the bladder wall. This study shows, however, that antibiotic therapy is the more effective of the two interventions. The price of added effectiveness, however, is high.

The study results may be called into question if for no other reasons than some of those put forth by the authors themselves — the adequate dose of cranberry extract has yet to be determined, and the concentrations of type A proanthocyanidins (deemed responsible for anti-adherence activity) necessary may be significantly higher than those employed here — there were 9.1 mg/g of type A proanthocyanidins present in the cranberry extract, but recent in vitro data cited by the authors suggest 72 mg/d may be required for a protective effect.1 In addition, subject adherence with the cranberry extract dosing could not be confirmed in an absolute sense, nor could the incidence of CRs, and there was a significant dropout rate. All this stated, the study was extremely well-done. Which leaves the clinician to ponder, "What intervention might be best?"

Use of cranberry or blueberry extracts, or juice (the low-sugar varieties might be best), remain reasonable options for many women with rUTI, especially if the incidence is relatively low. For those with more frequent rUTI antibiotic therapy may be necessary, perhaps with the addition of a probiotic.

Reference

1. Howell AB, et al. Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: A multicentric randomized double blind study. BMC Infect Dis 2010;10:94.