AUA & CUA Recurrent UTI (2019)

See Original Guideline

• This guideline only describes diagnosis and treatment of 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 infection with multi-drug resistant bacteria or presence of risk factor(s) for UTI and decreased treatment efficacy.
    • See from Table 1 from 2011 CUA Guideline on Recurrent UTI
• 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. This guideline does not apply to complicated UTI or those exhibiting signs or symptoms of systemic bacteremia, such as fever and flank pain.

Background

• ≈60% of females will experience at least 1 symptomatic episode of acute bacterial cystitis in their lifetime. Of these, 20-40% will experience at least 1 other episode, of which 25-50% of whom will experience multiple recurrent episodes.

Acute Bacterial Cystitis

Definition

• Diagnosis of acute bacterial cystitis requires (2):
  1. Laboratory confirmation of significant bacteriuria AND
  2. Acute-onset symptoms (lower urinary tract symptoms)
• In this guideline, the term UTI will refer to culture-proven acute bacterial cystitis and associated symptoms unless otherwise specified.

Diagnosis and Evaluation

History and Physical Exam

• History
  • Symptoms
    • Urinary tract infection symptoms include dysuria, central to the diagnosis of UTI, with variable degrees of:
      1. Increased urinary urgency and frequency
      2. Hematuria
      3. Suprapubic pain
      4. New or worsening incontinence
    • 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.
        • Older females 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
        • Acute-onset dysuria, particularly when associated with new or worsening storage symptoms, remains a reliable diagnostic criterion in older females living both in the community and in long-term care facilities.

Labs

• Urine culture/laboratory confirmation of significant bacteriuria
  • Urine culture remains the mainstay of diagnosis of an episode of acute cystitis
    • Clinical judgment is needed to determine when a culture result represents clinically significant bacteriuria considering the patient presentation, urine collection method, and the presence of other suggestive factors such as pyuria.
      • The definition for clinically significant bacteriuria of >10⁵ colony forming units (CFU)/mL represents an arbitrary cut-off.
      • Although > 10⁵ CFU/mL 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
  • Obtain repeat urine studies when an initial urine specimen is suspect for contamination, with consideration for obtaining a catheterized specimen
    • Urine culture contamination should be suspected when (3):
      1. Mixed cultures containing ≥2 organisms
      2. Low quantities (<103 CFU/mL) of a pathogenic organism in an asymptomatic patient
      3. Specimen exhibits growth of normal vaginal flora (e.g. Lactobacilli, Group B Streptococci, Corynebacteria, or non-saprophyticus coagulase-negative Staphylococci)
         • Growth of these organisms are thought to be contaminant and generally do not require treatment
    • Concomitant urinalysis can also be useful (presence of epithelial cells or mucus on microscopic urinalysis may also suggest contaminant).
    • When there is high suspicion for contamination, consider obtaining a catheterized specimen for further evaluation prior to treatment.
    • Urine specimens should not sit at room temperature for > 30 minutes to facilitate lab diagnosis of UTI.

Differential Diagnosis

• Differential Diagnosis of UTI (10):
  1. Interstitial cystitis/bladder pain syndrome
  2. Overactive Bladder
  3. Urinary calculi
  4. Infectious bacterial or fungal vaginitis
  5. Vulvar dermatitis
  6. Non-infectious vulvovestibulitis
  7. Vulvodynia
  8. Hypertonic pelvic floor muscle dysfunction
  9. Genitourinary syndrome of menopause
  10. CIS of the bladder (less commonly)
• A lack of correlation between microbiological data and symptomatic episodes should prompt a diligent consideration of alternative/comorbid diagnoses (many females with gross hematuria may be incorrectly treated for a UTI when they should be evaluated for bladder cancer; a negative culture would prompt further investigation of GH)

Asymptomatic Bacteruria

• Definition: bacteriuria of any magnitude without symptoms
• Management
  • DO NOT routinely treat asymptomatic bacteriuria
    • No evidence that treatment of asymptomatic bacteriuria improves outcomes
  • Indications for screening/treatment of asymptomatic bacteriuria (2):
    1. Pregnant females
    2. Patients undergoing elective urologic surgery
    3. [Neonatal candiduria, not technically bacteruria but should be treated even if asymptomatic]
  • Asymptomatic bacteriuria and struvite stones
    • Routine treatment of urease-producing bacteriuria in the absence of UTI symptoms or documented urinary tract stones is not recommended
    • There is no clear evidence that identification and treatment of asymptomatic bacteriuria caused by urease-producing organisms (recall that urease-producing organisms include proteus, pseudomonas, klebsiella, mycoplasma, and staphylococcus) prevents struvite stone formation. However, in certain patients with recurrent struvite stones, screening for and treating urease-producing bacteriuria may be indicated if other measures have not been able to prevent stone formation.

Recurrent UTI

Definitions

• Definition of Recurrent UTI: Either (2):
  1. ≥2 episodes of acute bacterial cystitis within 6 months or
  2. ≥3 episodes within 1 year
     • These episodes are considered to be separate infections with resolution of symptoms between episodes, and do not include those who require >1 course of antibiotics for symptomatic resolution, as can occur with inappropriate initial or empiric treatment
     • For diagnosis of recurrent UTI, each symptomatic episode must be associated with a document positive urine culture
• Patients with a long history of culture-proven symptomatic episodes of cystitis that occur at a lower frequency than this definition will likely benefit from management strategy similar to that for patients with rUTI.

Diagnosis and Evaluation

UrologySchool.com Summary

• Mandatory (1):
  1. History and Physical Exam
• Optional (1):
  1. PVR
• Not recommended
  • Cystoscopy
  • Upper tract imaging

Mandatory

• History and Physical Exam
  • History
    • Characterize LUTS (dysuria, frequency, urgency, nocturia, incontinence, hematuria, pneumaturia, fecaluria)
    • Baseline genitourinary symptoms between infections
    • UTI history: frequency of UTI, antimicrobial usage, and documentation of positive cultures and the type of cultured microorganisms, responses to treatment for each episode, the symptoms the patient considers indicative of a UTI, the relationship of acute episode to infectious triggers (e.g. sexual intercourse for post-coital UTIs), relationship of infections to hormonal influences (e.g., menstruation, menopause, exogenous hormone use), results of any prior diagnostic investigations
    • Bowel symptoms such as diarrhea, accidental bowel leakage, or constipation
    • Menopausal status; contraceptive method; and use of spermicides or estrogen- or progesterone-containing products
    • Back or flank pain; catheter usage; vaginal discharge or irritation
    • Risk factors for complicated UTI (see Urinary Tract Infections Chapter Notes)
    • Medications (immunosuppressive meds, recent use of antibiotics for any medical condition), PMHx, PSHx (may suggest complicated UTI), allergies, travel history
  • Physical Exam
    • Abdominal and pelvic examination
      • Prolapse, urethral tenderness, urethral diverticulum, Skene’s gland cyst, or other enlarged or infected vulvar or vaginal cysts
      • Any other infectious and inflammatory conditions (vaginitis, vulvar dermatitis, and vaginal atrophy (genitourinary syndrome of menopause)
      • Pelvic floor musculature for tone, tenderness, and trigger points
    • Focused neurological exam
      • May also be considered to rule out occult neurologic defects

Optional

• Post-void Residual
  • Indications
    • Can be considered for all patients
    • Should be performed in any patient with suspicion of incomplete emptying, such as those with (4):
      1. Significant anterior vaginal wall prolapse
      2. Underlying neurologic disease
      3. Diabetes
      4. Subjective sensation of incomplete emptying.

Not recommended (2):

• Cystoscopy and upper tract imaging
  • Low yield of anatomical abnormalities with cystoscopy and upper tract imaging in patients with uncomplicated rUTI.
    • However, if a patient does not respond appropriately to treatment of uncomplicated UTI, particularly rapid recurrence with the same organism repeatedly, the patient should be considered to have a complicated UTI, thereby necessitating further investigations of the urinary tract
  • In patients with gross hematuria in the presence of a positive urine culture and no risk factors for urothelial malignancy (e.g., age under 40, non-smoker, no environmental risk), cystoscopy is not necessary.
    • If any risk factors are present, cystoscopy should be performed.

Management

Conservative

• Options (2):
  1. Education
  2. Behaviour modification
     1. Education and Informed Decision Making
        • Discuss the option of delaying antibiotics while awaiting culture results as there is minimal risk of progression to tissue invasion or pyelonephritis for uncomplicated patients with episodes of acute cystitis.
          • Antibiotic treatment for acute cystitis results in mildly faster symptomatic improvement but only modestly decrease the risk of pyelonephritis.
          • Patients with urosepsis or pyelonephritis often do not have UTI-related symptoms.
     2. Behaviour modification (2):
        1. Changing mode of contraception (avoid barrier contraceptives and spermicidal products (has deleterious effect on lactobacillus colonization and/or the vaginal microbiome))
        2. Increasing water intake in those consuming < 1.5L/day
           • Unclear if there is a benefit in women that normally consume over this amount
     3. Changes that DO NOT play a role in rUTI prevention:
        1. Hygiene practices (e.g., front to back wiping)
        2. Pre- and post-coital voiding
        3. Avoidance of hot tubs
        4. Tampon use
        5. Douching

Intervention

• Options (3):
  • Antibiotics
  • Non-antibiotic prophylaxis
    • Cranberry
    • Vaginal estrogen (if post-menopausal)

Antibiotics

• Acute cystitis
  • Obtain urinalysis, urine culture and sensitivity with each symptomatic acute cystitis episode prior to initiating treatment in patients with rUTIs
    • Continued documentation of cultures during symptomatic periods prior to starting antibiotics helps to provide a baseline against which interventions can be evaluated, to determine the appropriate pathway within the treatment algorithm, and to allow for the tailoring of therapy based on bacterial sensitivities.
    • In select patients with rUTIs with symptoms of recurrence, presumptive treatment with antibiotics can be initiated prior to finalization of the culture based on prior speciation, susceptibilities, and local antibiogram
  • Use first-line therapy (See Table 3 (statement 9, no direct link) from Original Guideline) dependent on the local antibiogram for treatment of symptomatic UTIs in women
    • Options (3):
      • Fosfomycin 3g PO x 1
      • TMP-SMX one tab DS PO BID x 3 days
      • Nitrofurantoin 100mg PO BID x 5 days
    • A systematic review found no differences between fluoroquinolones, β-lactams (e.g., penicillins and its derivatives, cephalosporins), nitrofurantoin or TMP-SMX in the efficacy or risk of discontinuation due to adverse events
    • TMP-SMX is not recommended for empiric use in areas where local resistance rates > 20%]
    • Table 3 from guideline suggests that nitrofurantoin does not cover enterococcus but CW11 Table 12-5/CW12 Table 55-6 suggets that it does
  • Clinicians should treat rUTI patients experiencing acute cystitis episodes with as short a duration of antibiotics as reasonable, generally < 7 days
    • 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 7 days. Many such infections will be caused by organisms producing ESBLs.
      • Generally, such organisms are susceptible only to carbapenems. However, clinicians should order fosfomycin susceptibility testing, as many MDR uropathogens, including ESBL-producing bacteria, retain susceptibility to Fosfomycin thereby providing an oral option.
  • Do not perform a post-treatment test of cure (urinalysis or urine culture) in asymptomatic patients
    • Extrapolating from the asymptomatic bacteruria literature, repeat urine culture after successful UTI treatment may lead to overtreatment
    • Omit surveillance urine testing, including urine culture, in asymptomatic patients with rUTIs.
      • While pregnant women and patients undergoing invasive urologic procedures do benefit from treatment, substantial evidence supports that other populations, including women with diabetes mellitus and long-term care facility residents, do not require or benefit from additional evaluation or antibiotic treatment
  • Repeat urine cultures to guide further management when UTI symptoms persist following antibiotic therapy
    • After initiating antibiotic therapy for UTI, clinical cure (i.e. UTI symptom resolution) is expected within 3-7 days. Although there is no evidence, it is reasonable to repeat a urine culture if symptoms persist > 7 days
• Antibiotics to reduce UTI episodes in patients with rUTI (self-start vs. prophylaxis)
  1. Self-start antibiotics: patient-initiated treatment for acute episodes while awaiting urine cultures.
     • For reliable patients, consider shared decision-making with regards to deferring therapy prior to obtaining results from the urine culture.
     • Despite the original concept behind self-start therapy that allowed for women to treat their UTI without obtaining a culture. given more recent goals to reduce overuse of antibiotics and the development of antibacterial resistance, obtaining culture data for symptomatic recurrences is recommended, when feasible.
  2. Antibiotic prophylaxis (continuous vs. post-coital)
     1. Continuous: After discussion of the risks and benefits, clinicians may prescribe continuous antibiotic prophylaxis to decrease the risk of future UTIs in women of all ages previously diagnosed with UTIs.
        • Antibiotic prophylaxis reduces the number of clinical recurrences but increases risk of adverse events. Once the antibiotics are stopped, UTIs recur at the baseline rate.
        • The dosing options for continuous prophylaxis include the following:
          • Nitrofurantoin monohydrate/macrocrystals 50mg daily
          • Nitrofurantoin monohydrate/macrocrystals 100mg daily
          • Cephalexin 125mg once daily
          • Cephalexin 250mg once daily
          • TMP 100mg once daily
          • TMP-SMX 40mg/200mg once daily
          • TMP-SMX 40mg/200mg thrice weekly
          • Fosfomycin 3g every 10 days
        • Potential adverse effects of gastrointestinal disturbances and skin rash are commonly associated with antibiotics, including TMP, TMP-SMX, cephalexin, and Fosfomycin
        • Potentially serious risks with nitrofurantoin include pulmonary and hepatic toxicity.
          • The rate of possible serious pulmonary or hepatic adverse events has been reported to be 0.001% and 0.0003%, respectively.
        • The use of fluoroquinolones (e.g. ciprofloxacin) for prophylactic antibiotic use is not recommended in current clinical practice.
          • Fluoroquinolone agents have potentially adverse side effects including QTc prolongation, tendon rupture, and increased risk of aortic rupture
        • The duration of prophylaxis can vary from 3-12 months, with periodic assessment
     2. Post-coital
        • In women with UTIs temporally related to sexual activity, a single dose of antibiotic prophylaxis taken before or after sexual intercourse is effective and safe
          • Options:
            • TMP-SMX 40mg/200mg
            • TMP-SMX 80mg/400mg
            • Nitrofurantoin 50-100mg
            • Cephalexin 250mg

Non-antibiotic prophylaxis (2):

1. Cranberry prophylaxis
   • MOA: thought to be related to proanthocyanidins present in cranberries and their ability to prevent the adhesion of bacteria to the urothelium
   • Indications
     • Can be offered for women with rUTIs
   • Oral juice and tablet formulations are available
2. Vaginal estrogen
   • Indications
     • Recommended in peri-and post-menopausal women with rUTIs, if there is no contraindication to estrogen.
       • Oral or other formulations of systemic estrogen therapy have not been shown to reduce UTI and are associated with different risks and benefits.
       • Given low systemic absorption, risks generally associated with systemic estrogen (cardiovascular disease, thrombosis, breast cancer) are minimal with vaginal estrogen.
   • Patients with rUTI and are already on systemic estrogen therapy should still be placed on vaginal estrogen. There is no substantially increased risk of adverse events.
   • Vaginal estrogen therapy has not been shown to increase risk of cancer recurrence in women undergoing treatment for or with a personal history of breast cancer. Therefore, vaginal estrogen therapy should be considered in prevention of UTI women with a personal history of breast cancer in coordination with the patient’s oncologist.

• Lactobacillus is not recommended as a prophylactic agent for rUTI given the lack of data

Questions

1. What is the definition of recurrent UTIs?
2. What is an uncomplicated UTI?
3. List 10 factors that classify a UTI as complicated.
4. What are the 3 antibiotic regimens to treat recurrent UTIs?
5. Urine culture demonstrating growth of which bacteria would be considered contaminant?
6. What is the workup of a patient with recurrent UTIs?
7. What is the differential diagnosis of a UTI?
8. Take a history and describe the physical exam in a patient with recurrent UTI
9. What are the indications to treat asymptomatic bacteriuria?
10. When should a urine culture be repeated in patients that have started treatment for UTI?
11. What conservative recommendations can be made to reduce risk of recurrent UTI?
12. Describe 3 first-line antibiotic therapies for uncomplicated symptomatic UTI
13. Describe 3 options for continuous antibiotic prophylaxis in the context of recurrent UTI
14. What are drug-specific adverse events related to fluoroquinolone use?
15. What is the role of cranberry or lactobacillus in the treatment of recurrent UTI?

Answers

1. What is the definition of recurrent UTIs?
   • ≥2 UTI within 6 months or ≥3 UTI within 12 months
2. What is an uncomplicated UTI?
   • A UTI in a female patient has no known factors that would make her more susceptible to develop a UTI
3. List 10 factors that classify a UTI as complicated.
   • UTI with multidrug resistant bacteria
   • Anatomic abnormality: cystocele, diverticulum, fistula
   • Iatrogenic: indwelling catheter, nosocomial infection, surgery
   • Voiding dysfunction: VUR, neurologic disease, pelvic floor dysfunction, high PVR, incontinence
   • Obstruction: Bladder outlet obstruction, ureteral stricture, UPJO
   • Other: pregnant, urolithiasis, diabetes, immunosuppression, UTI in men
4. What are the 3 antibiotic regimens to treat recurrent UTIs?
   1. Self-start
   2. Prophylaxis
   3. Post-coital
5. Urine culture demonstrating growth of which bacteria would be considered contaminant?
   1. Lactobacilli
   2. Corynebacteria
   3. Group B Streptococci
   4. Non-saprophyticus coagulase-negative Staphylococci
6. What is the workup of a patient with recurrent UTIs?
   • History, physical exam (no role for cystoscopy or imaging in initial workup)
7. What is the differential diagnosis of a UTI?
   1. Interstitial cystitis/bladder pain syndrome
   2. OAB
   3. Genitourinary syndrome of menopause
   4. Urinary calculi
   5. Infectious bacterial or fungal vaginitis
   6. Vulvar dermatitis
   7. Non-infectious vulvovestibulitis
   8. Vulvodynia
   9. Hypertonic pelvic floor muscle dysfunction
   10. CIS of the bladder
8. Take a history and describe the physical exam in a patient with recurrent UTI
   • History: characterize LUTS, baseline GU symptoms between infections, UTI history, bowel symptoms, menopausal status, contraceptive method
   • Physical exam: abdominal and pelvic exam, focused neurologic exam, +/- PVR
9. What are the indications to treat asymptomatic bacteriuria?
   1. Pregnant women
   2. Patient undergoing elective urologic surgery
10. When should a urine culture be repeated in patients that have started treatment for UTI?
    • If symptoms persist > 7 days
11. What conservative recommendations can be made to reduce risk of recurrent UTI?
    1. Avoid barrier contraceptives and spermicidal products
    2. Drink >1.5L water/day
    3. Changes that DO NOT play a role in rUTI prevention: hygiene practices (e.g., front to back wiping), pre- and post-coital voiding, avoidance of hot tubs, tampon use, and douching
12. Describe 3 first-line antibiotic therapies for uncomplicated symptomatic UTI
    1. Nitrofurantoin 100mg BID x 5 days
    2. TMP-SMX 1 tab DS BID x 3 days
    3. Fosfomycin 3g x 1 dose
    • Note that ciprofloxacin is not considered first-line
13. Describe 3 options for continuous antibiotic prophylaxis in the context of recurrent UTI
    1. Nitrofurantoin 100mg daily
    2. Cephalexin 250mg daily
    3. Fosfomycin 3g q10days
14. What are drug-specific adverse events related to fluoroquinolone use?
    1. Prolonged QT syndrome
    2. Aortic rupture
    3. Tendon rupture
15. What is the role of cranberry or lactobacillus in the treatment of recurrent UTI?
    • Cranberry can be offered, lactobacillus is not recommended

References

• Anger, Jennifer, et al. "Recurrent uncomplicated urinary tract infections in women: AUA/CUA/SUFU guideline." The Journal of urology 202.2 (2019): 282-289.