November/December 2019

Urinary Tract Infections — Nonantibiotic Prophylaxis With High-Dose Cranberry Proanthocyanidins
By Sophie A. Fletcher, MD
Today’s Geriatric Medicine
Vol. 12 No. 6 P. 10

Robust science and clinical guidelines support 36 mg cranberry proanthocyanidins as an intervention to prevent recurrent urinary tract infections and drive optimal antibiotic stewardship efforts.

Call it the “silver tsunami” or the “gray wave”—the surge in this country’s aging population will touch every aspect of health care utilization and delivery. The US population of individuals aged 65 and older has topped 50 million for the first time and is projected to grow to more than 70 million in the next 25 years.1 Urinary tract infections (UTIs) are among the most common infections diagnosed in older adults. They’re also the most frequently occurring infection in long term care residents, accounting for more than one-third of all nursing home–associated infections.2 As the population ages, the overall UTI burden will go up too, requiring new approaches and multidisciplinary strategies to improve the diagnosis, treatment, and, most key, prevention strategies to optimize elder care.

By the Numbers
Across all age groups, more women than men have UTIs. Increasing age is itself a risk factor for UTIs, likely due to a multitude of factors such as added comorbidities, increasing rates of urinary incontinence and urinary retention, hospitalizations and accompanying urinary catheterizations, long-term medical institutionalization, age-associated changes in immune function, and exposure to nosocomial pathogens. More than 10% of women older than 65 report having had a UTI within the past 12 months. In women older than 85, more than 30% report having had a UTI in the past 12 months. Catheter use in long term care facilities tops the list as the primary contributor of UTIs in that setting.2

Challenging Diagnosis
In most populations, the diagnosis of a symptomatic UTI is relatively straightforward, but elderly patients and nursing home residents may not present with the typical symptoms. Instead, less specific symptoms such as disorientation or confusion may be present, with additional coexisting factors such as cognitive defects and chronic genitourinary issues further complicating the diagnosis.2 In that situation, those who work in elder care may have difficulty differentiating UTIs from other medical conditions.

Further compounding the problem, 25% to 50% of noncatheterized patients in long term care exhibit asymptomatic bacteriuria (AB). This is defined as the presence of bacteria in the urine without clinical signs or symptoms of a UTI. AB increases with age. Antibiotic therapy for AB doesn’t confer any long-term benefits in preventing symptomatic UTIs or improving mortality and may actually increase the incidence of adverse events and antibiotic resistance.3-5 Incorrect use of antibiotics in AB patients is potentially dangerous, with long-lasting negative effects. Multiple urological and infectious disease guidelines advise against treating AB with antibiotics, as does the American Geriatrics Society.4

Antibiotics and UTIs: A Slippery Slope
The call for regulations and policies to curb antibiotic overuse in long term care facilities primarily stems from the high rates of UTI recurrence, which account for up to 60% of all antibiotic prescriptions. The Centers for Disease Control and Prevention (CDC) reports that up to 75% of all antibiotics prescribed in older adults are unnecessary.6 When these agents lose their effectiveness, health care providers may be forced to use more toxic, less potent, and likely more expensive options. The CDC website notes that 2 million Americans get antibiotic-resistant infections annually, and 23,000 die from them. Furthermore, the increase in antibiotic resistance is a primary consequence of antibiotic overuse, as rates in E. coli, the most common UTI-associated pathogen, are rapidly rising.

Long-term antibiotic use is associated with adverse events and diminished care, making it increasingly unsustainable. Some antibiotics have side effects that are especially alarming in aging adults with multiple comorbidities. It’s known that azithromycin—albeit rarely—can lead to dangerous heart arrhythmias. Fluoroquinolones, the most commonly prescribed class of antibiotics, have been associated with an increased risk of tendinitis, peripheral neuropathy, and hypoglycemia. This has led the FDA to issue black box warnings on this class of antibiotics.7 Moreover, antibiotics may interact negatively with many of the other drugs older adults take, including such widely used medications as statins, blood thinners, and kidney and heart medications. As one of the most common infections in long term care facilities, UTIs are also among the top reasons for hospital readmissions among residents, further contributing to poor quality care and increased health care costs.8,9

An Opportunity for Nonantibiotic Intervention
Traditionally, guidelines and expert consensus panels have relied on the use of antibiotic prophylaxis to reduce UTI recurrence. Other recommendations have included behavioral changes such as increased hydration, perineal care, and improved catheter protocols. As awareness of the long-term negative implications of antibiotic use and their associated adverse events increases, the scientific community, health care providers, patients, and caregivers are searching for safe and sustainable alternatives.

In its recently published guidelines for the management of recurrent UTIs, the American Urological Association highlights the use of cranberry prophylaxis, citing the benefits of proanthocyanidins (PAC), the bioactive ingredient contained in the fruit.10 Only the benefits of PAC from cranberry were highlighted as a consideration for nonpharmaceutical UTI prevention.

36 mg PAC and Proven Antiadhesion Activity
As reflected by the new guidelines, the role of cranberry in maintaining urinary tract health has been clarified by a growing body of scientific and clinical evidence. Cranberry intake has historically been used for UTI prevention based on a loose and often anecdotal understanding of the fruit’s mechanism of action. More recent evidence has clarified the role of soluble A-type PAC as an important inhibitor of P-fimbriated E. coli adhesion to uroepithelial cells, establishing bacterial antiadhesion activity (AAA) as the evidence-based mechanism of action.11 Furthermore, a dose-dependent, randomized, double-blind study determined that a minimum of 36 mg of the PAC ingredient is required to promote bacterial AAA and contribute to UTI prevention.12 Additional research has looked at the 36 mg bioactive PAC formula as a nonantibiotic alternative for UTI prophylaxis, finding it effective compared with the low-dose antibiotic trimethoprim.13 In a university study, the one 36 mg PAC supplement helped to prevent and reduce catheter-associated UTIs, without the side effects and resistance associated with antibiotics.14

Evaluating Cranberry Products Against the Standard: Variability in Products
There’s wide variability in the quality and ingredients contained in commercial cranberry supplements found in most grocery stores and pharmacies. Differences in formulations have led to misunderstanding and misconceptions around the value of PAC prophylaxis for recurrent UTIs. Furthermore, studies have revealed that many of these preparations contain fewer than 5 mg of PAC, not nearly enough of the bioactive ingredient to prevent bacterial adhesion to the bladder and to reduce UTI occurrence.15 Due to their limited bioactivity, such products are rendered unreliable and ineffective. These supplements are often inexpensively made from the whole berry or presscake—the name for the dried skins, stems, and seeds that have limited to no soluble bioactive PAC—instead of the PAC extracted from the pure juice concentrate. Many traditional cranberry products also contain sugar (negating their use by people with diabetes) or other added ingredients that are contraindicated in patients with certain comorbidities or in those taking concomitant medications.

Importantly, the American Urological Association’s guidelines caution that many products used in studies were formulated specifically for research purposes, and the availability of similar and appropriately manufactured commercial products may be limited. It’s imperative that those in elder care settings review the research and ingredients prior to initiating cranberry prophylaxis in this vulnerable population.

A New Approach
Evidence-based cranberry prophylaxis with 36 mg PAC represents an opportunity for a reset in health care providers’ approach to the management of UTIs. An impressive body of research has validated the minimum dose necessary for promoting bacterial AAA and clinical efficacy. Additionally, soluble A-type PAC can be tested via an internationally recognized standard, therefore allowing for comparison among formulations.16,17 In the current setting of widespread antibiotic resistance and redoubled efforts at optimal antibiotic stewardship—particularly with regard to the aging population—it’s time to rethink preventive strategies. Data back the implementation of a bioactive, medical-grade alternative for UTI prophylaxis, marking a powerful paradigm shift in caring for the aging population.

Putting Prevention Into Practice
Most would agree that any actions taken to improve antibiotic use will promote quality of life for older adults and elevate their standard of care; however, alternative options seem limited and their implementation daunting. Antibiotic overuse is a widespread issue that requires formalized policies and behavior modification. At the same time, antibiotic prescribing decisions are complex and often come with high levels of uncertainty and risk. Untreated UTIs can lead to significant complications. Incorporating 36 mg PAC into any daily regimen for ongoing UTI prevention can be simple and be a component of a larger UTI strategy focused on driving optimal antibiotic stewardship.

Safety and Reliability
There are virtually no drawbacks associated with a 36 mg PAC protocol for UTI prophylaxis. The approach is safe, as there are no side effects, drug interactions, or worry over antibiotic resistance. While dietary supplements fall outside FDA’s regulatory process, and federal law doesn’t require claims made in the labeling of dietary supplements be proven by the manufacturer, a reliable medical-grade product can be used with confidence. A superior manufacturer will verify labeling claims as accurate—with each production lot—before those claims appear on products.

To ensure a supplement is reliable for clinical use, the maker must have rigorous manufacturing standards, full transparency of ingredients, proof of consistency and efficacy of dosage and, above all else, clinical evidence with high-quality research supporting its use in various patient populations. Health care providers and patients should be able to readily access a product’s portfolio of evidence related to these standards for full confidence in its efficacy, ie, 36 mg of soluble A-type PAC to elicit clinically significant AAA for UTI prophylaxis.

Effectiveness
A recent observational trial conducted by the author and colleagues at one skilled nursing facility found that residents on a protocol of 36 mg of standardized and bioactive PAC extracted from pure cranberry concentrate with 100% AAA (ellura by Trophikos) were UTI-free for six months. Importantly, no residents had an adverse event while taking the product.18 Based on this outcome, larger trials are warranted to further define the role of this approach to recurrent UTI prophylaxis in long term care residents.

‘Slow-Motion Catastrophe’
A recently published review in the Mayo Clinic Proceedings describes antimicrobial resistance as a “slow-motion catastrophe.” With antibiotic prescribing as arguably the largest contributor to resistance, the authors report that from 2010 to 2015, the global consumption of antibiotics increased 65%.19 The authors cite areas where antibiotic stewardship interventions can have the most impact. The report goes on to focus on overdiagnosis, ie, attribution of a condition that’s not present, and overtreatment, or overprescribing antibiotics with a broader spectrum or for longer than indicated.

Of note, the Mayo Clinic Proceedings report says “antibiotic-related reflexes” are a factor in overprescribing. It advises that clinicians slow down and practice more mindful medicine, “because mindfulness and reflection increase diagnostic and therapeutic accuracy.” It’s fair to say that clinicians can receive pressure from patients and their families to prescribe antibiotics, especially at first sign of symptoms. Older adults, for example, experiencing symptoms such as change in behavior and urine odor with no confirmed UTI, shouldn’t be prescribed an antibiotic without additional tests, whenever possible. These symptoms could be associated with other medical issues.

Clinicians should take the opportunity instead to have a conversation with patients and caregivers about the inappropriate use of antibiotics and possible urogesic agents that may help with treating UTI-like symptoms when no infection is present.

Conclusion
UTIs, afflicting millions of Americans a year, are increasingly resistant to antibiotics, making diagnosis and treatment far from routine. The incidence of these infections is increasing, leading to more hospitalizations, more severe illness, and prolonged discomfort.20 The New York City Department of Health has found that one-third of uncomplicated UTIs caused by E. coli were resistant to Bactrim, and at least one-fifth of them were resistant to five other common treatments.21 At the same time, the number of new antibiotics being developed and available to clinicians remains at an all-time low due to regulatory issues, scientific-technical challenges, and unfavorable marketing economics that serve to disincentivize pharmaceutical companies.19

To promote superior antibiotic stewardship in the treatment of UTIs in long term care facilities and in all aspects of geriatric medicine, a better strategy for UTI prevention is long overdue. Health care providers must commit to prevention and self-care policies that start with actions to prevent and reduce UTIs altogether. A pharmaceutical-grade supplement that contains proven effective 36 mg PAC is a tool that can be simply and safely implemented into routine care to prevent recurrent UTIs, thus improving the quality of life for elderly patients. Experts are unanimous: Clinicians urgently need alternatives and adjuncts to antibiotics due to the lack of new antibiotics and the rapid speed at which bacteria are becoming resistant.

— Sophie A. Fletcher, MD, is a staff urologist for Sutter Medical Group of the Redwoods and the Sutter Health Foundation in Santa Rosa, California, and is an expert in female urology, voiding dysfunction, neurourology, female pelvic medicine, and reconstructive surgery. Fletcher is chair of the ellura Medical Advisory Board for Trophikos and is credited as the first US physician to implement the first commercial 36 mg proanthocyanidins formula in practice.

References
1. The nation’s older population is still growing, Census Bureau reports. The United States Census Bureau website. https://www.census.gov/newsroom/press-releases/2017/cb17-100.html. Updated June 22, 2017. Accessed May 27, 2019.

2. Genao L, Buhr GT. Urinary tract infections in older adults residing in long-term care facilities. Ann Longterm Care. 2012;20(4):33-38.

3. Nicolle LE. Asymptomatic bacteriuria: review and discussion of the IDSA guidelines. Int J Antimicrob Agents. 2006;28(Suppl 1):S42-S48.

4. Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis. 2005;40(5):643-654.

5. Cai T, Nesi G, Mazzoli S, at al. Asymptomatic bacteriuria treatment is associated with a higher prevalence of antibiotic resistant strains in women with urinary tract infections. Clin Infect Dis. 2015;61(11):1655-1661.

6. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA. 2016;315(17):1864-1873.

7. FDA updates warnings for fluoroquinolone antibiotics on risks of mental health and low blood sugar adverse reactions. FDA website. https://www.fda.gov/news-events/press-announcements/fda-updates-warnings-fluoroquinolone-antibiotics-risks-mental-health-and-low-blood-sugar-adverse. Updated July 10, 2018. Accessed June 1, 2019.

8. Meddings J, Saint S, Krein SL, et al. Systematic review of interventions to reduce urinary tract infection in nursing home residents. J Hosp Med. 2017;12(5):356-368.

9. Montoya A, Mody L. Common infections in nursing homes: a review of current issues and challenges. Aging health. 2011;7(6):889-899.

10. Anger J, Lee U, Ackerman AL, et al. Recurrent uncomplicated urinary tract infections in women: AUA/CUA/SUFU guidelines. https://www.auanet.org/guidelines/recurrent-uti. Published 2019. Accessed May 5, 2019

11. Howell AB, Reed JD, Krueger CG, Winterbottom R, Cunningham DG, Leahy M. A-type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry. 2005;66(18):2281-2291.

12. Howell AB, Botto H, Combescure C, 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.

13. Uberos J, Nogueras Ocana M, Fernandez-Puentes V, et al. Cranberry syrup vs trimethoprim in the prophylaxis of recurrent urinary tract infections among children: a controlled trial. Open Access J Clin Trials. 2012;4:31-38.

14. Thomas D, Rutman M, Cooper K, Abrams A, Finkelstein J, Chughtai B. Does cranberry have a role in catheter-associated urinary tract infections? Can Urol Assoc J. 2017;11(11):E421-E424.

15. Chughtai B, Thomas D, Howell A. Variability of commercial cranberry dietary supplements for the prevention of uropathogenic bacterial adhesion. Am J Obstet Gynecol. 2016;215(1):122-123.

16. 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.

17. Sintara M, Li L, Cunningham DG, Prior RL, Wu X, Chang T. Single-laboratory validation for determination of total soluble proanthocyanidins in cranberry using 4-dimethylaminocinnamaldehyde. J AOAC Int. 2018;101(3):805-809.

18. Sorensen J, Taylor M, Carlson S, Fletcher S. 36 mg bioactive PAC supplement — ellura® — for the prevention of recurrent urinary tract infections (rUTIs) in skilled nursing facility residents — an observational pilot study. https://cdn.shopify.com/s/files/1/1991/9753/files/EMAIL_Bayview_ellura_pilot_study.pdf?135

19. Lesho EP, Laguio-Vila M. The slow-motion catastrophe of antimicrobial resistance and practical interventions for all prescribers. Mayo Clin Proc. 2019;94(6):1040-1047.

20. Simmering JE, Tang F, Cavanaugh JE, Polgreen LA, Polgreen PM. The increase in hospitalizations for urinary tract infections and the associated costs in the United States, 1998-2011. Open Forum Infect Dis. 2017;4(1):ofw281.

21. Richtel M. Urinary tract infections affect millions. Treatments are faltering. The New York Times. July 13, 2019. https://www.nytimes.com/2019/07/13/health/urinary-infections-drug-resistant.html