This article is part of our May 2022 Healthy Aging special issue. Download the full issue here.
Reference
Xia JY, Yang C, Xu DF, Xia H, Yang LG, Sun GJ. Consumption of cranberry as adjuvant therapy for urinary tract infections in susceptible populations: a systematic review and meta-analysis with trial sequential analysis. PLoS One. 2021;16(9):e0256992.
Study Objective
To synthesize the data from studies involving the use of cranberry-containing products in the prevention of recurrent urinary tract infections (UTIs)
Key Takeaway
Supplementing with cranberry preparations in patients suffering from recurrent UTIs can play a significant role in reducing recurrence and, thus, reduce overprescription of antibiotics.
Design
Systematic review, meta-analysis containing randomized trials
Participants
Inclusion criteria:
The study was limited to only randomized controlled trials. For the intervention used, the authors included only trials that:
- Compared cranberry-containing products to a placebo or nonplacebo control group;
- Had outcomes that can be calculated or reported as the number of participants experiencing a UTI; and
- Included nonheterogenous at-risk populations, including those experiencing recurrent UTIs, elderly men and women, pregnant women, children, participants with indwelling catheter, and participants with neuropathic bladder.
Exclusion criteria:
- Trials whose intervention contained a cranberry in combination with another bioactive compound, animal studies, case reports, reviews, conference papers, editorials, and studies with insufficient data.
Interventions
Interventions ranged and varied in the studies.
Investigators included 15 trials: 2 administered cranberry juice, whereas 1 trial used both cranberry juice and cranberry tablets, and 12 trials used cranberry capsules.
Eleven trials used cranberry-based products from the manufacturer Ocean Spray.
Daily cranberry amount ranged from 0.4 to 194.4 g.
The actual cranberry amount was not reported in the 11 trials.
Twenty-three trials used a formula placebo, whereas 5 trials did not use a placebo.
Also, some studies used capsules or tablets based on cranberry amount (g/d; in proanthocyanidin [PAC] content, mg/d). This ranged from 0.2 g per day to 2 g per day.
Note: The clinical criteria of UTI threshold varied in the studies. Clinical symptoms to define UTI were required in most trials (eg, frequent micturition), and baseline bacteriuria were not excluded in 18 trials.
In addition, the thresholds of bacteriuria ranged from 10,000 to 100,000 colony forming units (CFU)/mL. The presence of UTI symptoms was not required in 11 trials.
The studies tracked frequency of UTIs by varied definitions over a period of time ranging from 1 month to 1 year.
Study Parameters Assessed
Investigators used the Cochrane risk-of-bias tool covering 7 domains of bias, including: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other bias. Each item was scored as “high risk,” “low risk,” or “unclear” for all selected studies.
Key Findings
Supplementing cranberry may be beneficial in preventing and treating UTIs in susceptible populations, particularly for women with recurrent UTIs (RR=0.68; 95% CI: 0.56-0.81), children (RR=0.55; 95% CI: 0.31-0.97) and patients using indwelling catheters (RR=0.49; 95% CI: 0.33).
Overall, the meta-analysis results revealed a 30% reduction in the risk of developing a UTI in susceptible populations who consumed cranberry-containing products than those who did not (RR=0.70; 95% CI: 0.59-0.83; I2=48%).
The daily recommended intake of PACs, to decrease the number of recurrent UTIs, is not lower than 36 mg, and inconsistent dosages among different studies may cause different outcomes.
Transparency
There were no conflicts of interests reported by study authors, but it is concerning that 1 trial that had quite a bit of quantitative power in the study (Maki, et al) was funded by Ocean Spray, and the authors did not point this out.
Practice Implications & Limitations
Cranberry-based supplements and/or juice are a welcome alternative for patients and health care providers alike, especially with growing concerns of antibiotic resistance against uropathogenic Escherichia coli strains (UPEC).1 Confidence in the form, dosage, and setting for cranberry use in chronic recurrent UTIs is needed. While cranberry preparations in UTI prevention have been studied in individual controlled trials, Xia et al (2021) conducted a helpful systematic review and meta-analysis of the research to further synthesize research data.
There are 150 million cases of UTIs worldwide, and they are responsible for 130,000 deaths per year. Women are particularly susceptible to infection, largely due to the short length of the urethra in females. It is estimated that 20% to 30% of adult women will experience a recurrent UTI in their lifetime.2 Other populations at risk for recurrent UTIs are pregnant women, children, elderly, those with a neuropathic bladder disorder, and those with indwelling urinary catheters.
The classic symptoms of a lower UTI are frequent micturition, dysuria, suprapubic tenderness, and sometimes low back or flank pain. Given their distinct and somewhat unmistakable symptoms, UTIs have a high rate of self-diagnosis. Some people will purchase over-the-counter screening tests to confirm suspected infections (yet these tests lack culture and sensitivity testing). This high level of self-treatment/self-diagnosis has both the potential for improving outcomes with early intervention, and also the potential for increased harm if the infection is not controlled early. In some studies, up to 94% of self-diagnosed UTI patients ended up getting treated with antibiotics for their UTIs.4 Here it is important to mention that a great deal of self-diagnosis might be being made for asymptomatic bacteriuria (ASB) where there is a lack of classic UTI symptoms, but the patient may be experiencing an odor in their urine or urine cloudiness and may contact their provider. There is no evidence supporting treatment of ASB with antibiotics, except in pregnant women.5
The proanthocyanidins may reduce the adherence of UPEC to the bladder wall, thereby reducing infection risk."
While it may appear on the surface to make a clinician’s job easier if a patient has good self-diagnosis probability, the grave possibility of an unresolved lower UTI progressing into a kidney infection (acute pyelonephritis) is the counterbalance to this. The potential consequences of acute pyelonephritis, including sepsis, shock, and death, are well-documented and engraved in every clinician’s mind when confronted with a patient who has a UTI. While the classic clinical presentation of acute pyelonephritis includes bladder symptoms (micturition, dysuria, urinary urgency, suprapubic pain) and systemic inflammation (fever, malaise, chills, flank pain), it's vital to note that over 20% of pyelonephritis patients do not present any bladder symptoms and would only be caught by urinalysis or through clinical acumen of other symptoms. It is also essential to note that 3% or less of cases of lower UTIs/cystitis and asymptomatic bacteriuria progress to pyelonephritis.6
Many guidelines for clinicians involve initiating treatment at the earliest symptoms of UTI and obtaining a urine culture and antibiotic sensitivity test of the urine as soon as possible. So, it’s understandable that the use of antibiotics has been deployed as a catchall treatment for anyone presenting with UTI symptoms. Yet, many lower UTIs will resolve untreated or with limited intervention (eg, hydration). This provides some opportunity to reduce the overuse of antibiotics and the potential resistance that ensues by using less-aggressive but proven-effective natural alternatives like cranberry preparations.
Antibiotic resistance is increasing in the treatment of recurrent UTIs. The most common microbial species causing UTIs is uropathogenic Escherichia coli (UPEC), which accounts for 80% of complicated urinary tract infections, 95% of community-acquired infections, and 50% of hospital-acquired infections.3
Other species that can cause UTIs include Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Staphylococcus saprophyticus, Enterococcus faecalis, Streptococcus bovis, and the fungus Candida albicans.3
UPEC is part of an extraintestinal pathogenic E coli (EXPEC) that seems to originate from the gut. This is clearly elicited in children (especially female) who have chronic constipation and/or encopresis, as both groups suffer from recurrent UTIs.
UPEC has growing resistance to commonly used antibiotics, such as amoxicillin-clavulanic acid, worldwide. In the United States, the resistance of UPEC to amoxicillin-clavulanic acid is between 3.1% and 40%, and it is worse in developing countries. For example, in Jordan it is 83%. Moreover trimethoprim-sulfamethoxazole, another frequently prescribed UPEC antibiotic, has resistance in the United States of 17.4%; this is as high as 82% in Pakistan. Finally, ciprofloxacin, a commonly prescribed broad-spectrum fluoroquinolone antibiotic with well-documented side effects (ie, tendinopathy, Clostridium difficile infection), has growing resistance in developed countries, such as in the United States, with 5.1% to 12.1% resistance rates and an amazingly high rate of 85.5% in Ethiopia.7
Not to despair, the first-line therapies of fosfomycin or nitrofurantoin still have largely low resistance rates. Fosfomycin has an overall resistance to UPEC of <1.5% worldwide, and nitrofurantoin has an overall resistance of <1.5% to 15.5% worldwide.7
One of the key risk factors of UTIs is dehydration. Most people quickly blame recurrent UTIs on postintercourse practices such as not voiding after vaginal intercourse, but lack of hydration is actually a greater risk factor. In a high-quality randomized trial in 2018 by Hooten et al, premenopausal women with recurrent UTIs and low-volume fluid intake were intervened to increase their water intake by at least 1.5 liters daily. This trial showed that the improved hydration reduced UTIs and the frequency of antibiotic use during UTIs.8 The importance of hydration likely has something to do with reducing the adherence of UPEC to the bladder/urethra wall. The manual flushing of bacteria is, thus, preventative. Just a word of caution that it is also important to be mindful of overhydration as a possibility in our most compliant patients, which can lead to hyponatremia. Lastly, there is some evidence that voiding within 15 minutes of vaginal intercourse may lower the risk of getting a UTI, especially in those without any history of past UTIs.9
Cranberry likely reduces UTIs due to its PAC content. The proanthocyanidins may reduce the adherence of UPEC to the bladder wall, thereby reducing infection risk. The study by Xia’s group showed that cranberry-containing capsues or tablets in 10 studies led to a relative risk (RR) of 0.8, meaning the relative risk of UTI was reduced by 20%. Cranberry juice had a RR of 0.65, meaning the relative risk of UTI was reduced by 35% and suggesting that juice is the better form for risk reduction.
In certain subpopulations such as children with recurrent UTIs, there was a 45% risk reduction taking cranberry products. And women with recurrent UTIs had a 32% risk reduction of UTIs taking cranberry products. Patients with indwelling catheters taking cranberry products to prevent recurrent UTIs had a 51% risk reduction of recurrent UTIs.
Investigators analyzed the dosing, frequency, and type of cranberry preparation (juice or tablet). The key factor in dosing seemed related to PAC content within the preparations. The recommended intake of PACs to decrease the number of recurrent UTIs, based on this review, is not lower than 36 mg daily regardless of type of preparation (ie, juice, tablet, capsule).
The appeal of cranberry juice is 2-fold. Its PAC content can be coupled with its hydration effect, thus possibly helping on both fronts of increasing hydration and reducing adhesion of UPEC. In reality, however, drinking daily cranberry juice might not be as fun as Mr. Nathan Apodaca made it seem in his famous viral TikTok video during the height of the Covid-19 pandemic.10 So capsules or tablets may be more practical for some.
The limitations of the study are the wide variety of dosing that the comparison studies used and also that in real-world settings cranberry is not often used as a monotherapy but rather in conjunction with other therapies. In addition, the lack of uniformity of what constitutes a UTI also added a limitation to the quality of the evidence.
Early education on preventing recurrent UTIs is essential, as the risk of recurrence in women is 27% within 6 months of having their first UTI. For example, education on reducing exposure of colon flora to vaginal regions, improving hydration, increasing perineal hydration and moisture, lubricating, and addressing other factors would help prevent recurrence.
This study was very helpful in solidifying dosing (>36 mg proanthocyanidins daily) and supplement selection for daily cranberry consumption in populations at risk of recurrent UTIs. It also highlights the appeal of studying more integrative protocols containing other proven UTI prevention treatments such as D-mannose, Arctostaphylos uva-ursi, Zea Mays (corn silk), and probiotics. What also needs to be looked into (and which the researchers did not mention) is the role of biofilm in the recurrence of UTIs.
Last but not least, this study shone a light on the importance of prudent antibiotic prescribing, especially in the era of telehealth. We must use all our tools and be precise with antibiotic prescribing, or refer out for this if needed.
This is the paper that is under current review. This should be: Foxman B, Brown P. Epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs. Infect Dis Clin North Am. 2003 Jun;17(2):227-41. doi: 10.1016/s0891-5520(03)00005-9. PMID: 12848468.
