Key Questions: 1.What is the most appropriate endpoint for evaluating treatment success for recurrent urinary tract infection (UTI): microbiological cure, symptom improvement, reduction of future recurrences or other biologic markers? 2.What is the natural history of recurrent UTI in terms of recurrence rates, medical and genetic risk factors, and upper tract involvement?

3.What is the comparative effectiveness of diagnostic tests, including urine analysis, cutoff values in microbiological studies and antibiotic sensitivities, imaging tests, voiding efficiency (post void residual volumes), cystoscopy, and urine culture, in the screening, diagnosis and risk management of recurrent UTI? 4.How do current treatments for recurrent UTI (i.e., oral and intravesical antiseptics and antibiotics, duration of treatment and self-directed programs) affect health care utilization, hospitalization, symptom relief, microbiological outcomes and recurrence rates? 5.How do antibiotic prophylaxis and non-antibiotic prophylaxis methods, such as vaginal estrogens, probiotics, A-type proanthocyanidins (cranberry products, D-mannose, hyaluronic acid, herbals [e.g., goldenseal and uva ursi], vitamin C, hygiene, contraceptions and fluid intake) compare with each other in terms of adverse effects, health care utilization, hospitalization, symptom relief, and microbiological outcomes and recurrence rates? 6.How can physicians and patients manage side effects and multiple drug resistance associated with the available standard therapy for recurrent UTI treatment? 7.What is the comparative effectiveness of screening urinalysis and chemical strips in asymptomatic patients versus assessment at time of symptoms in terms of antibiotic stewardship, multiple drug resistance? 8.What is the effectiveness of vaccines and anti-infectives (e.g. methenamine) for the prevention of recurrent UTI? 9.What is the role of asymptomatic bacteriuria (ASB) in management of recurrent UTI? a.Does treatment of asymptomatic bacteriuria in women result in a reduction in morbidity, mortality? b.What signs and symptoms can be used to distinguish between ASB and acute bacterial cystitis? c.How can urinalysis or urine culture distinguish between ASB and acute cystits?

Relevant Patients

Adult women (age 18 and above)

As of 2006, urinary tract infections (UTIs) accounted for around 8.1 million visits to health care providers.1 While UTIs can occur in both men and women, they are much more common in women due to anatomical structure of the female body such as a shortened urethra and proximity of the urethra to vaginal and bowel flora. For women of all ages, UTIs are the most common bacterial infection in the United States.2 The lifetime risk of acquiring a UTI in women is 50% to 60%.3 Recurrent UTI is defined as two or more infections in six months or three or more infections in one year. It is estimated that recurrent UTI affects more than 25% of women with a history of UTI.4 This topic nomination is specifically looking at female patients with suspected recurrent UTIs.

Relevant Sub-populations

Elderly/Geriatric Women (ages 65 and older)

Postmenopausal Women

Women with renal stones, or structural or functional abnormalities of the genitourinary tract (complicated recurrent UTIs)

Diabetics

Immunosuppressed populations

While recurrent UTIs are somewhat common among healthy young women, epidemiology and pathophysiology studies have indicated that the incidence of UTI increases with increasing age.5 A study by Kodner et al. showed that 36% of women below the age of 55 in a primary care setting had a recurrence within one year, whereas 53% of women older than the age of 55 had a recurrence within one year of infection.4

Pelvic prolapse, lack of estrogen, loss of lactobacilli in the vaginal flora, increased periurethral colonization by E. coli, and a higher incidence of medical illnesses are hypothesized to be all contributing factors to the higher rates of UTIs seen in post-menopausal women.6

Women with diabetes are at a higher risk for infections compared to those without diabetes, which includes the risk for UTIs. The relative risk of UTI in those with diabetes compared to those without has been shown in multiple epidemiological studies to have a 1.21 to 2.2 increase.7 Diabetics also have an increased risk of recurrence of 25-45% compared to that of women in general, which is estimated to be around 25%.4

Health Related Benefits

Decrease in recurrence rates

Antibiotic stewardship to reduce epidemiologic push towards multiply resistant organisms

Reduced health care utilization

Available standard antimicrobial therapies are meeting increasing drug resistance, leading to an increased focus on researching non-antimicrobial, antiseptic and non-systemic treatment options.

Due to the significant variation in diagnosis and treatment schedules, a guideline will be created from the AHRQ evidence report providing physicians and patients with the guidance necessary to inform health care decisions. A guideline discussing comparative effectiveness of the diagnostic tools and available treatments will also reduce the use of ineffective therapies and the costs associated with the treatment of recurrent UTI.

Health Related Harms, risks, side effects

Risk of missed diagnosis

Risk of over treatment

Side-effects associated with systemic antibiotic treatment including vaginal and gastro-intestinal infections, colonization with multiply resistant organisms

While physicians continue to look for novel diagnostic tools, the risk of a missed diagnosis is a often causes significant over treatment of this common symptom. Additionally, while there are multiple options for both antimicrobial and non-antimicrobial treatment following a diagnosis of recurrent UTI, all treatments using antibiotics are subject to change over time due to increasing antibiotic resistance. Current systemic treatment options are associated with various side effects, such as antibiotic associated colitis, hypersensitivity, hematopoietic abnormalities, nephrotoxicity, to name a few. 8 Given that a majority of diagnoses are in the elderly population, such side effects have a tremendous impact on overall health. In addition, there is tremendous variation by providers on the use of microbiologic follow-up and whether there are sub-populations who would benefit from surveillance. .

1.Schappert SM, Rechtsteiner EA. Ambulatory medical care utilization estimates for 2006. National health statistics reports; no 8. Hyattsville, MD: National Center for Health Statistics 2008;

http://www.cdc.gov/nchs/data/nhsr/nhsr008.pdf . 2.Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clinical Infectious Disease. 2011;52(5):e103 e120; http://cid.oxfordjournals.org/content/52/5/e103.full

3.Litwin MS, Saigal CS, editors. Urologic Diseases in America. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Washington, DC: US Government Printing Office, 2012; NIH Publication No. 12-7865;

http://www.niddk.nih.gov/about-niddk/strategic-plans-reports/Documents/urologic/Urologic_Diseases_in_America.4.13.12.pdf . 4.Kodner CM, Thomas Gupton EK. Recurrent Urinary Tract Infections in Women: Diagnosis and Management. American Family Physician 2010; 82(6): 638-43; http://www.aafp.org/afp/2010/0915/p638.html . 5.Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. The American Journal of Medicine. 2002; 113(1):5-13; http://www.amjmed.com/article/S0002-9343(02)01054-9/fulltext .

6.Raz R, Gennesin Y, Wasser J, Stoler Z, Rosenfeld S, Rottensterich E, Stamm WE. Recurrent Urinary Tract Infections in Postmenopausal Women. Clinical Infectious Diseases 2000; 30(1): 152-156;

http://cid.oxfordjournals.org/content/30/1/152.full . 7.Chen SL, Jackson SL, Edward JB. Diabetes Mellitus and Urinary Tract Infection: Epidemiology, Pathogenesis and Proposed Studies in Animal Models. J Urol 2009; 182; S51-S56;

http://www.jurology.com/article/S0022-5347(09)01952-1/fulltext . 8.Antibiotics for urinary tract infections in older people. Choosing Wisely; An initiative of the ABIM Foundation. Published October 2013. http://www.choosingwisely.org/patient-resources/antibiotics-for-urinary-tract-infections-in-older-people/. .

UTIs can affect the kidneys, ureters, bladder and urethra. Women are more susceptible to UTI due to the anatomical structure of the female body.1 UTIs occur when bacteria enter the body through the urethra and multiply. The symptoms of UTI may include a strong persistent urge to urinate; a burning sensation when urinating; passage of frequent small amounts of urine; urine that is cloudy, red, pink, or brown colored; strong smelling urine; and pelvic pain.

Risk factors for UTI specific to women include sexual activity; certain types of birth control, such as diaphragms and the use of spermicidal agents; and menopause.1 One of the strongest risk factors reported for recurrent UTI is frequency of sexual intercourse.2 Other risk factors for recurrent UTI include voiding dysfunction, age at first UTI, maternal and family history of UTI, and new sex partner in the past year.

Recurrent UTI is defined as two or more UTIs within six months of initial diagnosis or three or more UTIs within twelve months of initial diagnosis. Recurrent UTI is caused by bacterial reinfection or bacterial persistence. Persistence or relapse is defined as when the bacteria have not been eradicated in the urine two weeks after appropriate treatment. Reinfection is a recurrence with a different organism, the same organism in more than two weeks, or a sterile intervening culture.3

In a study surveying 2,000 women, 10.8% aged 18 or older reported at least one presumed UTI within the past 12 months.4 A majority of those cases occurred among women with a history of two or more UTI episodes in their lives. It was then estimated that for women, by the age of 24, one-third will have at least one physician-diagnosed UTI. The total annual cost in the United States is currently estimated to be over $2.6 billion.4 The estimated total cost over 20 years is around $25.5 billion.5

The AUA guideline that will be produced from the proposed evidence report has the potential to standardize evaluation and treatment algorithms, decrease the substantial cost associated with the diagnosis and treatment of recurrent UTI, provide guidance regarding antibiotic stewardship as well as evaluate other treatment options. Various available tests are associated with considerable costs, but with generally accepted poor specificity and impact on the natural history.

1.Mayo Clinic: Urinary Tract Infection (UTI) 2015;

http://www.mayoclinic.org/diseases-conditions/urinary-tract-infection/basics/definition/con-20037892 . 2.Kodner CM, Thomas Gupton EK. Recurrent Urinary Tract Infections in Women: Diagnosis and Management. American Family Physician 2010; 82(6): 638-43; http://www.aafp.org/afp/2010/0915/p638.html . 3.Dason S, Dason JT, Kapoor A. Guidelines for the diagnosis and management of recurrent urinary tract infection in women. Canadian Urological Association Journal. 2011;5(5):316-322;

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202002/ . 4.Suskind AM, Saigal CS, Hanley JM, Lai J, Setodji CM, Clemens JQ. Incidence and Management of Uncomplicated Recurrent Urinary Tract Infections in a National Sample of Women in the United States. Urology 2016; 90; 50-55;

http://www.goldjournal.net/article/S0090-4295(16)00085-6/fulltext . 5.Foxman B, Barlow R, D Arcy H, Fillespie B, Sobel JD: Urinary Tract Infection. Annals of Epidemiology 2000; 10(8): 509-515;

http://www.annalsofepidemiology.org/article/S1047-2797(00)00072-7/fulltext .

The AUA intends to use this systematic report developed by AHRQ as the basis for an evidence-based guideline. The creation of an evidence report on this topic would allow the AUA to create a clinical practice guideline in a relatively short timeframe as the data collection, extraction and analysis would have already been completed in adherence with the highest standards of systematic review. AUA guidelines are scientifically rigorous and evidence-based, and with a staff of six full-time professionals as well as extensive consultant support, the AUA Guidelines Department is well positioned to develop high-quality guidelines in a timely, efficient and effective manner.

The AUA continues its dedication to providing quality, evidence-based education through the dissemination of pocket guides and other educational products to both urologic specialists and primary care physicians who most commonly treat the patients described herein. Additionally, the AUA Guidelines Department works closely with the Urology Care Foundation, committed to patient education and advocacy, to develop patient guides from its clinical practice guidelines. The development of a clinical practice guideline on recurrent UTI would enable the AUA to develop additional material with a strong focus on the importance of patient counseling and education, which is essential for a condition that relies heavily on shared decision making when discussing treatment options.

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American Urological Association

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The AUA has previously partnered with AHRQ in the development of evidence reports on the Management of Female Overactive Bladder (OAB), Urinary Retention, Medical Recurrent Nephrolithiasis, Cryptorchidism, and Bladder Cancer. Following the publication of guidelines on each of these topics, the AUA has increased its previous dissemination efforts to include production of high-quality videos for the purposes of continuing medical education (CME), patient and medical provider trifolds, Clinical Problem Solving Protocols, and a compendium of all AUA guidelines in both App and Pocket-Guide formats. The AUA is also pleased to partner with additional organizations to enhance dissemination efforts to include both the urology community as well as primary care. Using the AHRQ produced recurrent UTI evidence report, the AUA is prepared to continue such efforts for the topic of recurrent UTI.