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Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline (2019)

Published 2019

Unabridged version of this guideline [pdf]
Algorithm associated with this guideline [pdf]

Panel Members

Jennifer Anger, MD, MPH; Una Lee, MD; A. Lenore Ackerman, MD, PhD; Roger Chou, MD; Bilal Chughtai, MD; J. Quentin Clemens, MD; Duane Hickling, MD, MSCI; Anil Kapoor, MD; Kimberly S. Kenton, MD, MS; Melissa R. Kaufman, MD, PhD; Mary Ann Rondanina, Ann Stapleton, MD; Lynn Stothers, MD; Toby C. Chai, MD

Purpose

Over the past few decades, our ability to diagnose, treat, and manage recurrent urinary tract infection (rUTI) long-term has evolved due to additional insights into the pathophysiology of rUTI, a new appreciation for the adverse effects of repetitive antimicrobial therapy (“collateral damage”), rising rates of bacterial antimicrobial resistance, and better reporting of the natural history and clinical outcomes of acute cystitis and rUTI. For the purposes of this guideline, the Panel considers only recurrent episodes of uncomplicated cystitis in women. This guideline does not apply to pregnant women, patients who are immunocompromised, those with anatomic or functional abnormalities of the urinary tract, women with rUTIs due to self-catheterization or indwelling catheters or those exhibiting signs or symptoms of systemic bacteremia, such as fever and flank pain. This guideline also excludes those seeking prevention of urinary tract infections (UTIs) in the operative or procedural setting. In this document, the term UTI will refer to acute bacterial cystitis unless otherwise specified. This document seeks to establish guidance for the evaluation and management of patients with rUTIs to prevent inappropriate use of antibiotics, decrease the risk of antibiotic resistance, reduce adverse effects of antibiotic use, provide guidance on antibiotic and non-antibiotic strategies for prevention, and improve clinical outcomes and quality of life for women with rUTIs by reducing recurrence of UTI events.

Methodology

The systematic review utilized to inform this guideline was conducted by a methodology team at the Pacific Northwest Evidence–based Practice Center. Scoping of the report and review of the final systematic review to inform guideline statements was conducted in conjunction with the rUTI Panel. A research librarian conducted searches in Ovid MEDLINE (1946 to January Week 1 2018), Cochrane Central Register of Controlled Trials (through December 2017) and Embase (through January 16, 2018). Searches of electronic databases were supplemented by reviewing reference lists of relevant articles. An update literature search was conducted on September 20, 2018.

Guideline Statements

Evaluation

1. Clinicians should obtain a complete patient history and perform a pelvic examination in women presenting with rUTIs. (Clinical Principle)

2. To make a diagnosis of rUTI, clinicians must document positive urine cultures associated with prior symptomatic episodes. (Clinical Principle)

3. Clinicians should obtain repeat urine studies when an initial urine specimen is suspect for contamination, with consideration for obtaining a catheterized specimen. (Clinical Principle)

4. Cystoscopy and upper tract imaging should not be routinely obtained in the index patient presenting with a rUTI. (Expert Opinion)

5. Clinicians should obtain urinalysis, urine culture and sensitivity with each symptomatic acute cystitis episode prior to initiating treatment in patients with rUTIs. (Moderate Recommendation; Evidence Level: Grade C)

6. Clinicians may offer patient-initiated treatment (self-start treatment) to select rUTI patients with acute episodes while awaiting urine cultures. (Moderate Recommendation; Evidence Level: Grade C)

Asymptomatic Bacteriuria

7. Clinicians should omit surveillance urine testing, including urine culture, in asymptomatic patients with rUTIs. (Moderate Recommendation; Evidence Level: Grade C)

8. Clinicians should not treat ASB in patients. (Strong Recommendation; Evidence Level: Grade B)

Antibiotic Treatment

9. Clinicians should use first-line therapy (i.e., nitrofurantoin, TMP-SMX, fosfomycin) dependent on the local antibiogram for the treatment of symptomatic UTIs in women. (Strong Recommendation; Evidence Level: Grade B)

10. Clinicians should treat rUTI patients experiencing acute cystitis episodes with as short a duration of antibiotics as reasonable, generally no longer than seven days. (Moderate Recommendation; Evidence Level: Grade B)

11. In patients with rUTIs experiencing acute cystitis episodes associated with urine cultures resistant to oral antibiotics, clinicians may treat with culture-directed parenteral antibiotics for as short a course as reasonable, generally no longer than seven days. (Expert Opinion)

Antibiotic Prophylaxis

12. Following discussion of the risks, benefits, and alternatives, clinicians may prescribe antibiotic prophylaxis to decrease the risk of future UTIs in women of all ages previously diagnosed with UTIs. (Moderate Recommendation; Evidence Level: Grade B)

Non–Antibiotic Prophylaxis

13. Clinicians may offer cranberry prophylaxis for women with rUTIs. (Conditional Recommendation; Evidence Level: Grade C)

Follow–up Evaluation

14. Clinicians should not perform a post-treatment test of cure urinalysis or urine culture in asymptomatic patients. (Expert Opinion)

15. Clinicians should repeat urine cultures to guide further management when UTI symptoms persist following antimicrobial therapy. (Expert Opinion)

Estrogen

16. In peri– and post–menopausal women with rUTIs, clinicians should recommend vaginal estrogen therapy to reduce the risk of future UTIs if there is no contraindication to estrogen therapy. (Moderate Recommendation; Evidence Level: Grade B)

Introduction

rUTI is a highly prevalent, costly, and burdensome condition affecting women of all ages, races, and ethnicities without regard for socioeconomic status, or educational level.2 The incidence and prevalence of rUTI depend on the definition used. Approximately 60% of women will experience symptomatic acute bacterial cystitis in their lifetime.3 An estimated 20-40% of women who have had one previous cystitis episode are likely to experience an additional episode, 25-50% of whom will experience multiple recurrent episodes.4,5 The exact numbers are unclear, as most epidemiologic studies utilize diagnosis codes that may overestimate true numbers due to overuse of UTI and rUTI codes in patients who have not yet undergone culture or evaluation.3 Regardless of the definition, the evaluation and treatment of UTI costs several billion dollars globally per year, reaching approximately $2 billion per year in the United States alone.6

Terminology and Definitions

For the purposes of this guideline, the Panel considers only recurrent episodes of uncomplicated cystitis in women. “Uncomplicated” means that the patient has no known factors that would make her more susceptible to develop a UTI, while “complicated” indicates that other complicating factors may put one at higher risk for UTI and decreased treatment efficacy. Such complicating factors may include an anatomic or functional abnormality of the urinary tract (e.g., stone disease, diverticulum, neurogenic bladder), an immunocompromised host, or infection with multi-drug resistant (MDR) bacteria. In this guideline, the term UTI will refer to culture-proven acute bacterial cystitis and associated symptoms unless otherwise specified. While most providers have confidence in making a diagnosis of acute cystitis, diagnostic criteria are imprecise and vary considerably. Strong evidence suggest that the diagnosis of acute cystitis should include the combination of laboratory confirmation of significant bacteriuria with endorsement of acute-onset symptoms referable to the urinary tract.7,8 Without symptoms, bacteriuria of any magnitude is considered asymptomatic bacteriuria (ASB).

While there are multiple definitions for rUTI,9 this Guideline endorses the two most commonly used definitions of two episodes of acute bacterial cystitis within six months or three episodes within one year. These definitions typically consider these episodes to be separate infections with the resolution of symptoms between episodes, and do not include those who require more than one treatment or multiple antibiotic courses for symptomatic resolution, as can occur with inappropriate initial or empiric treatment. Any patient experiencing episodes of symptomatic acute cystitis after previous resolution of similar symptoms meets the criteria for rUTI. However, it should be noted that those patients initially treated for uncomplicated bacterial cystitis who recur rapidly (i.e. within two weeks of initial treatment) after symptom resolution or display bacterial persistence without symptom resolution may be reclassified as complicated and require imaging, cystoscopy, or other further investigation for bacterial reservoirs. The definitions used in this guideline can be found in Table 1.

Table 1: Guideline DefinitionsThe index patient for this guideline is an otherwise healthy adult female with an uncomplicated recurrent urinary tract infection
TermDefinition
Acute bacterial cystitisA culture-proven infection of the urinary tract with a bacterial pathogen associated with acute-onset symptoms such as dysuria in conjunction with variable degrees of increased urinary urgency and frequency, hematuria, and new or worsening incontinence
Uncomplicated urinary tract infectionAn infection of the urinary tract in a healthy patient with an anatomically and functionally normal urinary tract and no known factors that would make her susceptible to develop a UTI
Complicated urinary tract infection

An infection in a patient in which one or more complicating factors may put her at higher risk for development of a UTI and potentially decrease efficacy of therapy. Such factors include the following:

  • Anatomic or functional abnormality of the urinary tract (e.g., stone disease, diverticulum, neurogenic bladder)
  • Immunocompromised host
  • Multi–drug resistant bacteria
Recurrent urinary tract infectionTwo separate culture-proven episodes of acute bacterial cystitis and associated symptoms within six months or three episodes within one year
Asymptomatic bacteriuriaPresence of bacteria in the urine that causes no illness or symptoms
The index patient for this guideline is an otherwise healthy adult female with an uncomplicated recurrent urinary tract infection

Index Patient

The index patient for this guideline is an otherwise healthy adult female with an uncomplicated rUTI. The infection is culture-proven and associated with acute-onset symptoms as discussed below. This guideline does not apply to pregnant women, patients who are immunocompromised, those with anatomic or functional abnormalities of the urinary tract, women with rUTIs due to self-catheterization or indwelling catheters or those exhibiting signs or symptoms of systemic bacteremia, such as fever and flank pain.4 This guideline also excludes those with neurological disease or illness relevant to the lower urinary tract, including peripheral neuropathy, diabetes, and spinal cord injury. Further, this guideline does not discuss prevention of UTI in operative or procedural settings.

Symptoms

In UTI, acute-onset symptoms attributable to the urinary tract typically include dysuria in conjunction with variable degrees of increased urinary urgency and frequency, hematuria, and new or worsening incontinence. Dysuria is central in the diagnosis of UTI; other symptoms of frequency, urgency, suprapubic pain, and hematuria are variably present. Acute-onset dysuria is a highly specific symptom, with more than 90% accuracy for UTI in young women in the absence of concomitant vaginal irritation or increased vaginal discharge.10,11

In older adults, the symptoms of UTI may be less clear. Given the subjective nature of these symptoms, careful evaluation of their chronicity becomes an important consideration when the diagnosis of UTI is in doubt. Acute-onset dysuria, particularly when associated with new or worsening storage symptoms, remains a reliable diagnostic criterion in older women living both in the community and in long-term care facilities.12–14 Older women frequently have nonspecific symptoms that may be perceived as a UTI, such as dysuria, cloudy urine, vaginal dryness, vaginal/perineal burning, bladder or pelvic discomfort, urinary frequency and urgency, or urinary incontinence, but these tend to be more chronic in nature. The lack of a correlation between symptoms and the presence of a uropathogen on urine culture was discussed in a systematic review of studies evaluating UTI in community-dwelling adults older than 65 years. Symptoms such as chronic nocturia, incontinence, and general sense of lack of well-being (e.g., fatigue, malaise, weakness), were common and not specific for UTI.15 While these guidelines do not include women with chronic symptoms common in urology, such as overactive bladder (OAB), guidelines from the American Geriatrics Society (AGS) and the Infectious Diseases Society of America (IDSA) agree that evaluation and treatment for suspected UTI should be reserved for acute-onset (<1 week) dysuria or fever in association with other specific UTI-associated symptoms and signs, which primarily include gross hematuria, new or significantly worsening urinary urgency, frequency and/or incontinence, and suprapubic pain.16–19

Diagnosis

Typically, for a diagnosis of cystitis, acute-onset symptoms should occur in conjunction with the laboratory detection of a uropathogen from the urine, typically E. coli (75-95%), but occasionally other pathogens such as other Enterobacteriaceae, P. mirabilis, K. pneumoniae, and S. saprophyticus. Other species are rarely isolated in uncomplicated UTI.20,21

Urine culture remains the mainstay of diagnosis of an episode of acute cystitis; urinalysis provides little increase in diagnostic accuracy.22 There are significant limitations that constrain the ability of this guideline to recommend strict cut-off definitions correlating with clinically meaningful results. Standard agar-based clinical culture has been used since the 19th century with few technical refinements; more recent studies demonstrate that a large proportion of urinary bacteria are not cultivatable using these standard conditions. The definition for clinically-significant bacteriuria of 105 colony-forming units (CFU)/mL was published more than 60 years ago and likely represents an arbitrary cut-off.23–27 The origin of this cut-off derives from evidence that the use of this threshold in asymptomatic individuals is relevant to reducing the overdetection of contaminating organisms. More than 95% of subjects with >105 CFU/mL bacteria in a clean-catch specimen had definite bacteriuria on a catheterized specimen, while only a minority of patients with lower bacterial counts exhibited bacterial growth from a catheterized urine sample.23 These data were obtained from asymptomatic women, however, and do not reflect the population in whom there is a suspicion of UTI.

In symptomatic women, however, several studies have identified subsets of women with pyuria and symptoms consistent with a UTI but colony counts <105 CFU/mL in voided urine.28–35 One study of more than 200 pre-menopausal, non-pregnant women who presented with at least two symptoms of acute cystitis compared colony counts in a midstream, clean-catch urine sample to specimens obtained by urethral catheterization. Approximately 40% of the women who had E. coli grow from a catheterized specimen had colony counts <105 CFU/mL in the voided sample.35 In multiple studies, a threshold of >102 CFU/mL E. coli from voided specimens had 88-93% positive predictive value for bladder bacteriuria in patients with a high suspicion of UTI.31,35 Lower midstream urine colony counts (>102 CFU/mL) have been associated with bladder bacteriuria on catheterization in symptomatic women with pyuria, suggesting that >102 CFU/mL of a single uropathogen may be a more appropriate cut-off in appropriately selected patients in whom there is strong suspicion of infection.36,37

Many laboratories, however, will not report colony counts <103 CFU/mL. In addition, it is likely that the strict use of a low threshold will lead to overdiagnosis. As such, clinical judgment determining when a culture result represents clinically significant bacteriuria must factor in the clinical presentation of a patient, the urine collection method used, and the presence of other suggestive factors such as pyuria. Although a 105 CFU/mL threshold for bacterial growth on midstream voided urine may help distinguish bladder bacteriuria from contamination in asymptomatic, pre-menopausal women, a lower 102 CFU/mL threshold may be appropriate in symptomatic individuals. Further, no specific threshold for urinary colony count has been demonstrated to identify those symptomatic patients at risk for progression to pyelonephritis or those who would benefit from more aggressive antimicrobial management.

Molecular Diagnostics

Sensitive culture-dependent and -independent techniques have revealed that the lower urinary tract, even in asymptomatic, healthy individuals, hosts a complex microbial community that is likely important in the maintenance of normal bladder function.22,38,39 Thus, in the strictest definition, all individuals are likely “bacteriuric.” In fact, it has been suggested that ASB may protect patients with rUTI from additional symptomatic episodes.40 Thus, more sensitive culture-based or molecular bacterial detection methods (e.g., high-throughput sequencing, polymerase chain reaction-based detection methods) are not necessarily beneficial in the diagnostic evaluation of patients with suspected bacterial cystitis. Sensitive detection of microorganisms will likely be associated with increased diagnostic confusion and dilemmas, including overdiagnosis and associated overtreatment. While there is some early evidence that molecular diagnostic methods to rapidly identify uropathogen antibiotic susceptibility may help to avoid delayed or inappropriate antimicrobial treatment,41 the impact of such tests on the accuracy of diagnosis is not documented and cannot yet be recommended for incorporation into clinical practice. While the current definitions of UTI rely on the unlikely principle that only those organisms detectable with agar-based culture are clinically concerning, the converse that all detectable organisms are pathogenic is also inaccurate. Thus, despite a growing desire for the accurate diagnosis of UTI in patients with suggestive symptoms, particularly those who lack positive urine cultures or who have vague lower urinary tract symptoms (LUTS), extreme caution must be taken to avoid reliance on this technology when its utility remains unproven and the potential for increased harm remains significant.

Antimicrobial Stewardship and the Consideration of Collateral Damage

In the past 20 years, antimicrobial resistance among uropathogens has increased dramatically. For example, increases in extended-spectrum β-lactamase (ESBL)-producing isolates has been described among patients with acute simple cystitis worldwide.1,42,43 Uncomplicated UTI is one of the most common indications for antimicrobial exposure in otherwise healthy women. Fluoroquinolones have been linked to infection with methicillin-resistant S. aureus and increasing fluoroquinolone resistance in gram-negative bacilli, such as P. aeruginosa, while broad spectrum cephalosporins have been linked to subsequent infections with vancomycin-resistant Enterococci, ESBL–producing K. pneumoniae, β-lactam-resistant Acinetobacter species, and C. difficile.1

Adhering to a program of antimicrobial stewardship with attempts to reduce inappropriate treatment, decrease broad-spectrum antibiotic use, and appropriately tailor necessary treatment to the shortest effective duration, may significantly mitigate increasing fluoroquinolone and cephalosporin resistance.44 Non-adherence to guidelines for the treatment of acute cystitis, however, is more common in patients who have rUTIs than patients with an isolated episode of acute cystitis.45 When patients present with acute cystitis and a history of rUTIs, many providers will employ strategies of lengthening antimicrobial course, broadening antibiotic treatment, or increasing antibiotic doses for each episode, despite the absence of evidence to support such practices. Sometimes patients pressure providers to give non-guideline-based treatments with the hope that the number of recurrent episodes will be reduced or the time between acute cystitis episodes will be lengthened. These strategies have not been demonstrated to be efficacious and have the potential for harm to the individual and community, directly contradicting the principles of antibiotic stewardship.46,47 As antimicrobial resistance patterns vary regionally, the specific treatment recommendations for acute cystitis episodes and rUTI prophylaxis may not be appropriate in every community. Providers should combine knowledge of the local antibiogram with the selection of antimicrobial agents with the least impact on normal vaginal and fecal flora. An antibiogram provides a profile of the local results of antimicrobial sensitivity testing for specific microorganisms. Aggregate data from single hospital or healthcare systems are cumulatively summarized, usually annually, providing the percentage of a given organism sensitive to a particular antimicrobial.

In a study of more than 25 million emergency department visits during which a UTI was diagnosed, urinary symptoms were only identified in 32%. In the subset of older individuals (aged 65 to 84 years), this prevalence of symptoms fell to 24%.48 The prevalence of antibiotic-resistant bacteria, risk of continued rUTIs as well as progression to later pyelonephritis is enhanced by unnecessary antibiotic treatment of ASB without any demonstrable benefit. These data demonstrate the important role of rUTI overtreatment in promoting antimicrobial resistance. While the Panel recognizes that there are financial and time costs associated with obtaining urinary cultures, such studies remain an important aspect of care, as culture-directed, not empiric, therapies are associated with fewer UTI-related hospitalizations and lower rates of intravenous antibiotic use.49 The diligence of obtaining cultures for each symptomatic episode, which is associated with reduced rates of overtreatment and more appropriate antibiotic selection, is thought to be beneficial through minimizing collateral damage and the potential need for further treatment in the event of inappropriate empiric therapy.

Collateral damage describes ecological adverse effects of antimicrobial therapy, such as alterations of the normal gut microbiome that can help select drug-resistant organisms and promote colonization or infection MDR organisms.1 The effects of specific antibiotics on the normal fecal flora promote drug resistance and increased pathogenicity. E. coli isolates continue to demonstrate high in vitro susceptibility to nitrofurantoin, fosfomycin, and mecillinam.32,50 These antimicrobials have minimal effects on the normal fecal microbiota.51–53 In contrast, antimicrobials that alter the fecal flora more significantly, such as trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolones, promote increased rates of antimicrobial resistance.53,54

Continued intermittent courses of antibiotics in rUTI patients are associated with significant adverse events, which may include allergic reactions, organ toxicities, future infection with resistant organisms, and C. difficile infections, particularly in older adults. Thus, substantial effort should be made to avoid unnecessary treatment unless there is a high suspicion of an acute cystitis episode.55 Even with short courses of more targeted antibiotics, multiple treatments over time may in aggregate impact both the individual and community. Indeed, asymptomatic women with a history of rUTIs randomized to treatment for ASB in a placebo-controlled trial were more likely to have additional symptomatic cystitis episodes in a year of follow-up than those randomized to placebo.40 In a longer study of over two years of follow up, women with rUTIs treated with the goal of eradicating residual bacteriuria demonstrated a higher prevalence of antibiotic resistance, a higher incidence of pyelonephritis, and a poorer quality of life in comparison to those in the non-treatment group.56

Education and Informed Decision Making

The prevalence of antibiotic-resistant bacteria is enhanced by the unnecessary antibiotic treatment of ASB.56 Given the subjectivity of patient-reported symptoms and the lack of clear diagnostic criteria on laboratory testing, the diagnosis of UTI is highly imprecise. While no evidence exists to support the concept of withholding antimicrobials to patients with rUTIs, providers must bear in mind that continued intermittent courses of antibiotics are associated with significant adverse events, particularly in older patients. Substantial effort should be made to avoid unnecessary treatment unless there is a high suspicion of UTI.

For uncomplicated patients with episodes of acute cystitis, there is minimal risk of progression to tissue invasion or pyelonephritis. Additionally, urinary tract symptoms do not reliably indicate risk or presence of “bacteremic bacteriuria” (“urosepsis”) or pyelonephritis. In a representative study of older patients with bacteremia who had the same bacterial species cultured from the urine, ascertainment of the patients’ symptoms at the time of infection revealed that only one of 37 participants aged 75 and older had symptoms consistent with UTI, such as dysuria.57 Multiple randomized placebo-controlled trials have demonstrated that antibiotic treatment for acute cystitis offers little but mildly faster symptomatic improvement compared to placebo in patients with acute dysuria and significant bacteriuria.58–61 However, the incidence of pyelonephritis in these patients is low and is not substantially different in individuals receiving antibiotics versus those treated with supportive care of analgesics and hydration.62 As deferring treatment is associated with a small risk of progression to pyelonephritis,59 antibiotic treatment of suspected UTI remains common practice, but expectant management with analgesics while awaiting culture results is likely underutilized. Indeed, this evidence suggests that supportive care can be reasonably attempted with antibiotic treatment reserved for those patients in whom it would be anticipated to impact prognosis.

In a large clinical trial, a substantial proportion of women agreed to placebo randomization63 without other treatments to ameliorate symptoms. This suggests that many women may be willing to attempt temporizing measures with symptomatic and non-antimicrobial management when the benefits and potential harms of intermittent antimicrobial treatment are adequately discussed. It is reasonable to consider an approach to the diagnosis and treatment of rUTI as one of shared decision-making, in which patients are educated about the inaccuracy of diagnostic testing, the benefits and potential risks of antimicrobial use, and the alternatives to standard antibiotic treatment. It is likely that far fewer patients will opt for more aggressive treatments when counseled appropriately. Many patients and providers do not know that uncomplicated cystitis typically is self-limited and rarely progresses to more severe disease.15,63,64 If this were explained, the goals of care could be more clearly defined as the amelioration of symptoms, the prevention of long-term complications, and the more appropriate use of antibiotics to those situations in which it is likely to improve outcomes.10

The Panel also supports discussion with patients regarding certain modifiable behaviors, including changing mode of contraception and increasing water intake, that have been shown to reduce the risk of rUTI. Sexually active women may consider changing their mode of contraception if using either barrier contraceptives or spermicidal products.65 The increased risk of UTI associated with spermicidal use is likely due to the deleterious effect on lactobacillus colonization and/or the vaginal microbiome.66 Increased water intake should be recommended to those consuming less than 1.5 L per day as a recent study showed that increased water intake was also associated with a lower likelihood of having at least 3 UTI episodes over 12 months (<10% versus 88%) and a greater interval between UTI episodes (143 versus 84.4 days, p<0.001).67 Unfortunately, there are many commonly held myths surrounding rUTI lifestyle modification. Case-control studies clearly demonstrate that changes in hygiene practices (e.g., front to back wiping), pre- and post-coital voiding, avoidance of hot tubs, tampon use, and douching do not play a role in rUTI prevention.65,68 This reframing of the discussion surrounding UTI is likely to benefit both individual patients and the health care system as a whole.

Methodolgy

The systematic review utilized to inform this guideline was conducted by a methodology team at the Pacific Northwest Evidence-based Practice Center. Determination of the guideline scope and review of the final systematic review to inform guideline statements was conducted in conjunction with the rUTI Panel.

Panel Formation

The rUTI Panel was created in 2017 by the American Urological Association Education and Research, Inc. (AUAER). This guideline was developed in collaboration with the Canadian Urological Association (CUA) and the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction (SUFU). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Chairs who in turn appointed the additional panel members with specific expertise in this area in conjunction with CUA and SUFU. Additionally, the Panel included patient representation. Funding of the Panel was provided by the AUA with contributions from CUA and SUFU; panel members received no remuneration for their work.

Searches and Article Selection

A research librarian conducted searches in Ovid MEDLINE (1946 to January Week 1 2018), Cochrane Central Register of Controlled Trials (through December 2017) and Embase (through January 16, 2018). Searches of electronic databases were supplemented by reviewing reference lists of relevant articles. An update search was conducted for additional publications on September 20, 2018.

The methodology team developed criteria for inclusion and exclusion of studies based on the Key Questions and the populations, interventions, comparators, outcomes, timing, types of studies and settings (PICOTS) of interest. For populations, inclusion focused on women with rUTIs (defined as >3 UTIs in a 12-month period or >2 UTIs in a 6-month period; studies were also included in which rUTI was not defined, but the mean or median number of UTIs in a 12 months period was >3). Exclusions included pregnant women, women with rUTIs due to self-catheterization or indwelling catheters, and prevention of UTI in operative or procedural settings. Subgroups of interest were based on age, history of pelvic surgery, and the presence of diabetes mellitus. For interventions, evaluations included diagnostic tests for rUTI (urine dipstick, urinalysis with microscopy, urine culture, urine or serum biomarkers), antibiotics for treatment of acute UTI and prevention, cranberry, lactobacillus, estrogen, and other preventive treatments. For studies on treatment and prevention of UTI, outcomes were UTI recurrence, UTI related symptoms, recurrence rate, hospitalization, antimicrobial resistance, and adverse effects associated with interventions. The Panel included randomized and non-randomized clinical trials of treatments for acute UTI and preventive interventions in women with rUTIs, studies on the diagnostic accuracy of tests for rUTI, and prospective studies on the association between risk factors and progression to symptomatic UTI in women with ASB. For questions related to treatment of acute UTI, methodologists included systematic reviews, supplemented by primary studies published after the reviews.

Using the pre-specified criteria, two investigators independently reviewed titles and abstracts of all citations. The methodology team used a two-phase method for screening full-text articles identified during review of titles and abstracts. In the first phase, investigators reviewed full-text articles to identify systematic reviews for inclusion. In the second phase they reviewed full-text articles to address key questions not sufficiently answered by previously published systematic reviews, or recent publications to update previously published systematic reviews. Database searches resulted in 6,153 potentially relevant articles. After dual review of abstracts and titles, 214 systematic reviews and individual studies were selected for full-text dual review, and 65 studies in 67 publications were determined to meet inclusion criteria and were included in this review. An additional 10 publications were identified in the updated literature search and added to the review.

Data Abstraction

For each study that met inclusion criteria, a single investigator abstracted information on study design, year, setting (inpatient or outpatient), country, sample size, eligibility criteria, dose and duration of the intervention, population characteristics (age, race, UTI history, diabetes, prior genitourinary surgery, and other treatments), results, and source of funding. For included systematic reviews, a single investigator abstracted study characteristics (number and design of included studies, definition of rUTI, study settings, study dates, treatment and follow up duration), population characteristics (age, diabetes history, surgical history, prior treatments), interventions, methods and ratings for the risk of bias, synthesis methods, and results. The methodology team calculated relative risks and 95% confidence intervals if necessary for included outcomes, from data reported in the studies. All data abstractions were reviewed by a second investigator for accuracy. Discrepancies were resolved through discussion and consensus.

Risk of Bias Assessment

Two investigators independently assessed risk of bias using predefined criteria. Disagreements were resolved by consensus. For clinical trials, we adapted criteria for assessing risk of bias from the U.S. Preventive Services Task Force.69 Criteria included use of appropriate randomization and allocation concealment methods, clear specification of inclusion criteria, baseline comparability of groups, blinding, attrition, and use of intention-to-treat analysis. Methodologists assessed systematic reviews using AMSTAR 2 (Assessing the Methodological Quality of Systematic Reviews) criteria.70 Studies were rated as “low risk of bias,” “medium risk of bias,” or “high risk of bias” based on the presence and seriousness of methodological shortcomings.

Studies rated “low risk of bias” are generally considered valid. “Low risk of bias” studies include clear descriptions of the population, setting, interventions, and comparison groups; a valid method for allocation of patients to treatment; low dropout rates and clear reporting of dropouts; blinding of patients, care providers, and outcome assessors; and appropriate analysis of outcomes.

Studies rated “medium risk of bias” are susceptible to some bias, though not necessarily enough to invalidate the results. These studies do not meet all the criteria for a rating of low risk of bias, but any flaw present is unlikely to cause major bias. Studies may be missing information, making it difficult to assess limitations and potential problems. The “medium risk of bias” category is broad, and studies with this rating vary in their strengths and weaknesses. Therefore, the results of some medium risk of bias studies are likely to be valid, while others may be only possibly valid.

Studies rated “high risk of bias” have significant flaws that may invalidate the results. They have a serious or “fatal” flaw in design, analysis, or reporting; large amounts of missing information; discrepancies in reporting; or serious problems in the delivery of the intervention. The results of high risk of bias studies could be as likely to reflect flaws in study design and conduct as true difference between compared interventions. Methodologists did not exclude studies rated high risk of bias a priori, but high risk of bias studies were considered to be less reliable than low or medium risk of bias studies, and methodologists performed sensitivity analyses without high risk of bias studies to determine how their inclusion impacted findings.

Data Synthesis and Rating the Body of Evidence

The methodology team constructed evidence tables with study characteristics, results, and risk of bias ratings for all included studies, and summary tables to highlight the main findings.

For interventions to prevent rUTIs, investigators performed meta-analysis using the random effects DerSimonian and Laird model in RevMan 5.3.5 (Copenhagen, Denmark) when there were at least three studies that could be pooled. Investigators stratified analyses of antibiotics by the specific antibiotic and stratified analyses of estrogen according to whether they were administered systemically or topically. Sensitivity analysis was performed by excluding high risk of bias trials. For antibiotic treatment of acute UTI, investigators reported pooled estimates from systematic reviews. Heterogeneity is reported via I2 calculations. Investigators did not update meta-analyses from prior reviews with the results of new trials, but examined whether the findings of new trials were consistent with the reviews. For other Key Questions, there were too few studies to perform meta-analysis.

Determination of Evidence Strength

The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and includes not only individual study quality but consideration of study design, consistency of findings across studies, adequacy of sample sizes, and generalizability of samples, settings, and treatments for the purposes of the guideline. Investigators graded the strength of evidence for key comparisons and outcomes for each Key Question, using the approach described in the Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) Methods Guide for Comparative Effectiveness and Effectiveness Reviews.71 Strength of evidence assessments were based on the following domains:

  • Study limitations, based on the overall risk of bias across studies (low, medium, or high)
  • Consistency of results across studies (consistent, inconsistent, or unable to determine when only one study was available)
  • Directness of the evidence linking the intervention and health outcomes (direct or indirect)
  • Precision of the estimate of effect, based on the number and size of studies and confidence intervals for the estimates (precise or imprecise)
  • Reporting bias, based on whether the studies defined and reported primary outcomes and whether we identified relevant unpublished studies (suspected or undetected)

The AUA categorizes body of evidence strength as Grade A (well-conducted and highly-generalizable randomized controlled trials [RCTs] or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data). By definition, Grade A evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is evidence about which the Panel has a moderate level of certainty, and Grade C evidence is evidence about which the Panel has a low level of certainty.72

AUA Nomenclature: Linking Statement Type to Evidence Strength

The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, magnitude of benefit or risk/burdens, and the Panel’s judgment regarding the balance between benefits and risks/burdens (Table 2). Strong Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is substantial. Moderate Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is moderate. Conditional Recommendations are non-directive statements used when the evidence indicates that there is no apparent net benefit or harm or when the balance between benefits and risks/burden is unclear. All three statement types may be supported by any body of evidence strength grade. Body of evidence strength Grade A in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances and that future research is unlikely to change confidence. Body of evidence strength Grade B in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence could change confidence. Body of evidence strength Grade C in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence is likely to change confidence. Body of evidence strength Grade C is only rarely used in support of a Strong Recommendation. Conditional Recommendations also can be supported by any evidence strength. When body of evidence strength is Grade A, the statement indicates that benefits and risks/burdens appear balanced, the best action depends on patient circumstances, and future research is unlikely to change confidence. When body of evidence strength Grade B is used, benefits and risks/burdens appear balanced, the best action also depends on individual patient circumstances and better evidence could change confidence. When body of evidence strength Grade C is used, there is uncertainty regarding the balance between benefits and risks/burdens, alternative strategies may be equally reasonable, and better evidence is likely to change confidence.

Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinions with consensus achieved using a modified Delphi technique if differences of opinion emerged.73 A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence.

Table 2: AUA Nomenclature Linking Statement Type to Level of Certainty, Magnitude of Benefit or Risk/Burden, and Body of Evidence Strength
Evidence Strength A
(High Certainty)
Evidence Strength B
(Moderate Certainty)
Evidence Strength C
(Low Certainty)

Strong Recommendation
(Net benefit or harm substantial)

Benefits > Risks/Burdens (or vice versa)
Net benefit (or net harm) is substantial
Applies to most patients in most circumstances and future research is unlikely to change confidence

Benefits > Risks/Burdens (or vice versa)
Net benefit (or net harm) is substantial
Applies to most patients in most circumstances but better evidence could change confidence

Benefits > Risks/Burdens (or vice versa)
Net benefit (or net harm) is substantial
Applies to most patients in most circumstances but better evidence is likely to change confidence (rarely used to support a Strong Recommendation)

Moderate Recommendation
(Net benefit or harm moderate)

Benefits > Risks/Burdens (or vice versa)
Net benefit (or net harm) is moderate
Applies to most patients in most circumstances and future research is unlikely to change confidence

Benefits > Risks/Burdens (or vice versa)
Net benefit (or net harm) is moderate
Applies to most patients in most circumstances but better evidence could change confidence

Benefits > Risks/Burdens (or vice versa)
Net benefit (or net harm) appears moderate
Applies to most patients in most circumstances but better evidence is likely to change confidence

Conditional Recommendation
(No apparent net benefit or harm)

Benefits = Risks/Burdens
Best action depends on individual patient circumstances
Future research unlikely to change confidence

Benefits = Risks/Burdens
Best action appears to depend on individual patient circumstances
Better evidence could change confidence

Benefits = Risks/Burdens
Alternative strategies may be equally reasonable
Better evidence likely to change confidence

Clinical Principle

A statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature

Expert Opinion

A statement, achieved by consensus of the Panel, that is based on members clinical training, experience, knowledge, and judgment for which there is no evidence

Peer Review and Document Approval

An integral part of the guideline development process at the AUA is external peer review. The AUA conducted a thorough peer review process to ensure that the document was reviewed by experts in the diagnosis and treatment of UTIs in women. In addition to reviewers from the AUA PGC, Science and Quality Council (SQC), and Board of Directors (BOD), the document was reviewed by representatives from CUA and SUFU as well as external content experts. Additionally, a call for reviewers was placed on the AUA website from November 19-30, 2018 to allow any additional interested parties to request a copy of the document for review. The guideline was also sent to the Urology Care Foundation to open the document further to the patient perspective. The draft guideline document was distributed to 114 peer reviewers. All peer review comments were blinded and sent to the Panel for review. In total, 50 reviewers provided comments, including 38 external reviewers. At the end of the peer review process, a total of 622 comments were received. Following comment discussion, the Panel revised the draft as needed. Once finalized, the guideline was submitted for approval to the AUA PGC, SQC and BOD as well as the governing bodies of CUA and SUFU for final approval.

Evaluation and Testing

Guideline Statement 1

Clinicians should obtain a complete patient history and perform a pelvic examination in women presenting with rUTIs. (Clinical Principle)

Discussion


Guideline Statement 2

To make a diagnosis of rUTI, clinicians must document positive urine cultures associated with prior symptomatic episodes. (Clinical Principle)

Discussion


Guideline Statement 3

Clinicians should obtain repeat urine studies when an initial urine specimen is suspect for contamination, with consideration for obtaining a catheterized specimen. (Clinical Principle)

Discussion


Guideline Statement 4

Cystoscopy and upper tract imaging should not be routinely obtained in the index patient presenting with a rUTI. (Expert Opinion) 

Discussion


Guideline Statement 5

Clinicians should obtain urinalysis, urine culture and sensitivity with each symptomatic acute cystitis episode prior to initiating treatment in patients with rUTIs. (Moderate Recommendation; Evidence Level: Grade C)

Discussion


Guideline Statement 6

Clinicians may offer patient-initiated treatment (self-start treatment) to select rUTI patients with acute episodes while awaiting urine cultures. (Moderate Recommendation; Evidence Level: Grade C)

Discussion


Asymptomatic Bacteriuria

Guideline Statement 7

Clinicians should omit surveillance urine testing, including urine culture, in asymptomatic patients with rUTIs. (Moderate Recommendation; Evidence Level: Grade C) 

Discussion


Guideline Statement 8

Clinicians should not treat ASB in patients. (Strong Recommendation; Evidence Level: Grade B) 

Discussion


Antibiotic Treatment

Guideline Statment 9

Clinicians should use first-line therapy (i.e., nitrofurantoin, TMP-SMX, fosfomycin) dependent on the local antibiogram for the treatment of symptomatic UTIs in women. (Strong Recommendation; Evidence Level: Grade B) 

Discussion


Guideline Statement 10

Clinicians should treat rUTI patients experiencing acute cystitis episodes with as short a duration of antibiotics as reasonable, generally no longer than seven days. (Moderate Recommendation; Evidence Level: Grade B) 

Discussion


Guideline Statement 11

In patients with rUTIs experiencing acute cystitis episodes associated with urine cultures resistant to oral antibiotics, clinicians may treat with culture-directed parenteral antibiotics for as short a course as reasonable, generally no longer than seven days. (Expert Opinion) 

Discussion


Antibiotic Prophylaxis

Guideline Statement 12

Following discussion of the risks, benefits, and alternatives, clinicians may prescribe antibiotic prophylaxis to decrease the risk of future UTIs in women of all ages previously diagnosed with UTIs. (Moderate Recommendation; Evidence Level: Grade B) 

Discussion


Non-Antibiotic Prophylaxis

Guideline Statement 13

Clinicians may offer cranberry prophylaxis for women with rUTIs. (Conditional Recommendation; Evidence Level: Grade C) 

Discussion


Follow-Up Evaluation

Guideline Statement 14

Clinicians should not perform a post-treatment test of cure urinalysis or urine culture in asymptomatic patients. (Expert Opinion)

Discussion


Guideline Statement 15

Clinicians should repeat urine cultures to guide further management when UTI symptoms persist following antimicrobial therapy. (Expert Opinion) 

Discussion


Estrogen

Guideline Statement 16

In peri- and post-menopausal women with rUTIs, clinicians should recommend vaginal estrogen therapy to reduce the risk of future UTIs if there is no contraindication to estrogen therapy. (Moderate Recommendation; Evidence Level: Grade B) 

Discussion


Future Directions

A better understanding of rUTI pathophysiology will greatly aid in our ability to design more effective, mechanistically-based treatments. Critical expansion of our understanding of both host and pathogen factors that result in rUTI is mandated. Additionally, refinement of how UTI is defined must be considered. Indeed, delineating differences between ASB with concomitant non-specific LUTS secondary to storage dysfunction or diverse conditions such as IC/BPS and OAB versus true rUTI may eventually rely on development of innovative urine or serum biomarkers that can differentiate between these entities.202 Relying on results from the urinary dipstick test, including leukocyte esterase and nitrate, lacks the necessary level of sensitivity and specificity for diagnostic accuracy. In this context, defining initiatives for partnering with our primary care colleagues and patients to provide education regarding rUTI definitions, evaluation, and treatment will provide an impactful narrative for the future.

Urine culture results, even those from extended quantitative urine culture techniques, do not reflect any aspect of the host response. Investigations of more defined host biomarkers, such as cytokines or serum inflammatory markers, may allow more precise analysis of the host response which reflects a true UTI. Further refinements of bacterial molecular genetic technologies may help point-of-care testing with faster identification of potential uropathogens. By extension, the types and content of bacteria which inhabit the urinary tract as part of the native microbiome will change our understanding of how host-bacterial interactions contribute to development of rUTI.

Emerging data regarding the microbiome of the human bladder, bowel, and vagina, including the contribution of both traditional and viable but non-culturable bacteria, viruses, bacteriophages, fungi, and helminths, will define a more accurate portrait of the healthy balance, as well as pathogenic dysbiosis that may contribute to rUTIs. Depletion or alteration of the normal host microbiome and host innate barriers and innate immune system may lead to development of rUTI. A better understanding of the relationship between the urinary microbiome and bladder health may fundamentally transform our earlier belief that urine is “sterile.” Indeed, the reconstitution of our native immune system, potentially by changing the microbiome of the gut with the use of probiotics and even fecal transplants, may be a pathway to resolution of rUTI for select patients. Modulation of the host response to bacterial infection is a key dynamic for which limited information currently exists.

A worldwide crisis has emerged due to rapid expansion of MDR bacteria, foreshadowing the devastating implications of the eventual inefficacy of many of our broad-spectrum antimicrobial agents.176 Current concepts of antibiotic stewardship have provoked a further initiative to develop agents outside the traditional pipeline of antibiotics. On a more immediate time frame is the need for comprehensive randomized controlled trials for non-antibiotic prevention therapies, including probiotics and cranberry formulations. The influence of our environments including the foods we eat, how they are prepared, and their source may become increasingly important as the area of food science expands. Future efforts may uncover other food sources with preventative mechanisms.

Implementation of novel technologies, such as vaccines for urinary pathogens, may represent a future direction for prevention strategies. Use of mannosides as therapeutic entities to prevent bacterial adhesion to the urothelium may represent a narrow-spectrum treatment strategy associated with few systemic manifestations.203 Modulation of host responses, such as the use of non-steroidal anti-inflammatory agents, have been suggested as a useful adjunct in both preclinical and clinical studies.204,205

We must also expand our perspective of rUTI to include prevention. There currently exists an NIH-funded research consortium addressing this mission- the Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium.206 The PLUS consortium is dedicated to promoting prevention of LUTS (including UTIs) across the woman’s life spectrum, including UTIs, utilizing a socioecologic construct.207 Critical to these investigative efforts is the discovery of methods to suppress symptoms without use of antibiotics and direct studies that support a broader view of rUTI from the host-pathogen perspective. The PLUS consortium also seeks to identify modifiable risk factors for acute cystitis which can be tested in a prospective prevention trial. Through multiple efforts, which include identifying modifiable socioecological risk factors, understanding host responses involved in UTI and understanding pathogen virulence factors, we will discover new methods in diagnosis and treatment of rUTI.

Abbreviations

1. AHRQAgency for Healthcare Research and Quality
2. AMRAntimicrobial resistance
3. ASBAsymptomatic bacteriuria
4. ASMAmerican Society for Microbiology
5. AUAAmerican Urological Association
6. CUACanadian Urological Association
7. EPCEvidence–based Practice Center
8. ESBLExtended–spectrum –lactamase
9. IDSAInfectious Diseases Society of America
10. IVUIntravenous urography
11. LUTSLower urinary tract symptoms
12. MDRMulti–drug resistant
13. OABOveractive bladder
14. PACProanthocyanidins
15. PGCPractice Guidelines Committee
16. RCTRandomized controlled trial
17. rUTIRecurrent urinary tract infection
18. SQCScience & Quality Council
19. SUFUSociety of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction
20. TMP‐SMXTrimethoprim–sulfamethoxazole
21. UTIUrinary tract infection

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