6/4/2018. Conflicts Disclosure. Objectives. Introduction. Classifications of UTI. Host Defenses. Management of Recurrent Urinary Tract Infections

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1 Conflicts Disclosure Presenter has no conflicts of interest to disclose Management of Recurrent Urinary Tract Infections COLIN M. GOUDELOCKE, M.D. JUNE 14, 2018 Objectives Attendees will review the identification and management of acute lower urinary tract infection with emphasis on appropriate antibiotic stewardship Attendees will review the evaluation of and preventative strategies for recurrent lower urinary tract infections Attendees with review the concept of asymptomatic bacteriuria and the appropriate management of this common entity Introduction UTI are responsible for over 7 million outpatient visits annually in the US 1/3 women report an infection by age 24 Of women who have UTI, 80% will have a recurrent infection over the next 18 months of observation Classifications of UTI Complicated UTI associated with a structural or functional abnormality of the urinary tract Recurrent UTI greater than 3 infections over one year or 2 infections over 6 months Bacterial Persistence failure to eradicate bacteria in the urine 2 weeks after culture-specific antibiotic therapy Bacterial Reinfection infection with a different organism or after sterile urine culture Host Defenses Glycosaminoglycan (GAG) layer Tamm-Horsefall proteins Urinary and vaginal ph Commensal Flora 1

2 Diagnosis of Infection Urinalysis Nitrite: Sensitivity of 60% (not all pathogens reduce nitrate); Specificity is 95% (for bacteriuria only) Leukocyte esterase: Good negative predictive value of 90% but low specificity as it is only a marker of inflammation, not infection Urine culture: very useful but may: Exclude symptomatic patients with low colony counts Include asymptomatic patients with bacteriuria C-reactive protein: may be elevated in a acute but not chronic infections Necessity of Urine Cultures Diagnosis of UTI is often based on symptoms Difficulties with obtaining uncontaminated specimens Useful to associate specific symptoms to bacteriuria Once established, routine culture likely unnecessary unless symptoms persist after therapy Acute Infection Treatment Nitrofurantoin 100 mg twice daily for 5 days Trimethoprim-sulfamethoxazole 160/800 mg twice-daily for 3 days Fosfomycin 3 g in a single dose (though inferior efficacy to above) β-lactam agents, including amoxicillin-clavulanate, cefdinir, cefaclor and (possibly) cephalexin when other recommended agents cannot be used; but generally inferior efficacy and more adverse events Amoxicillin or ampicillin should not be used for empirical treatment Fluoroquinolones We have determined that fluoroquinolones should be reserved for use in patients who have no other treatment options for acute bacterial sinusitis, (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and uncomplicated urinary tract infections (UTI) because the risk of these serious side effects generally outweighs the benefits in these patients. For some serious bacterial infections the benefits of fluoroquinolones outweigh the risks, and it is appropriate for them to remain available as a therapeutic option. -The U.S. Food and Drug Administration (FDA) Safety Announcement Are Antibiotics the Future? WHO considers antibiotic resistance to be one of top 3 global health problems Most patients with UTI treated with placebo are symptom-free within a week Gágyor et al used NSAID to reduce use of antibiotic for uncomplicated UTI NSAID arm had symptoms for one day longer 2/3 of women were treated without use of antibiotic (though symptom burden was higher) Antibiotic treatment for patients with acute dysuria remains the standard of care but so far 5 RCT show no benefit beyond modestly faster improvement of symptoms (about 1 day) Imaging in Recurrent UTI US is the prime modality in upper tract imaging in adult recurrent UTI CT should be reserved only for select patients Urosepsis Suspicious findings on US requiring confirmation Functional studies VCUG MAG-3 Renal Scan 2

3 Cystoscopy in Recurrent UTI Can identify common etiologies for bacterial persistence (stone, foreign body, diverticulum, tumor). Can base selection on risk factors for anatomic abnormality including surgical history Strategies to Prevent Recurrent UTI Anatomic or Functional Abnormalities Patients with anatomic or functional abnormalities should have these addressed to prevent recurrent infections especially if bacterial persistence is demonstrated: Bladder foreign bodies or calculi Urethral diverticulum or bladder diverticulum that empties poorly Upper urinary tract obstruction Bladder outlet obstruction Chronic urinary retention Native Flora Vaginal microbiome is dominated by Lactobacillus species and pivotal in maintaining urogenital health Replacement of these species by anaerobic species is associated with a host of urogenital symptoms and diseases including UTI Thomas-White et al demonstrated using sterile suprapubic aspiration that Lactobacillus species are found in urine of healthy women and a more diverse microflora was associated with symptoms including OAB Important goal of treatment of recurrent UTI likely is restoration of normal native microbiome in the vagina and bladder Antibiotic Prophylaxis Long-term use of antibiotic prophylaxis does not reduce overall infection rates Prophylaxis is associated with a short-term reduction in the frequency of infection Trimethoprim, nitrofurantoin, and cephalexin are associated with minimal long term effects on native gut and vaginal flora A course of prophylaxis (3 months) may reduce exposure to broader spectrum antibiotics, helping to preserve native vaginal and bladder flora Post-coital prophylaxis may be useful in those patients who regularly associate infections with intercourse Probiotics in Recurrent UTI Studies have focused on species of Lactobacillus given its dominance in normal flora L. rhamnosus (GR-1) and L. reuteri (RC-14) seem to be the most efficacious L. casei shirota and L. crispatus have also shown promising efficacy Lactobacillus GG has shown mixed results in trials of oral therapy Probiotic RepHresh Pro-B Probium Culturelle Pro-Well Species L. reuteri RC-14, L. rhamnosus GR-1 L. Acidophilus LA-14 B. Bifidum Bb-04 Lactobacillus GG Hyperbiotics Pro-15 L. reuteri*, L. casei*, L. rhamnosus* * No species strain listed 3

4 Vaginal Estrogen in Recurrent UTI Treatment of atrophic vaginitis (AV) with vaginal estrogen therapy results in shift of vaginal flora to Lactobacillus dominant Similarly, treatment of AV results in lower ph that more closely matches that seen in premenopausal women which may promote the colonization by Lactobacillus species Vaginal estrogen therapy reduces the incidence of urinary tract infection There is no demonstrated improvement in UTI with oral estrogen therapy Cranberry in Recurrent UTI Proanthocyanidins (PAC) found in cranberries are thought to keep E. coli from binding to bladder cells Studies on pure juice are mixed and it is often poorly tolerated The amount of PAC across 7 different cranberry extracts varied by 30-fold D-Manose in Recurrent UTI D-mannose binds and blocks FimH adhesin, which is found on the type 1 fimbria of enteric bacteria and so acts as a competitive inhibitor of bacterial adherence Randomized trial of over 300 patients found that D-mannose 2g day reduced recurrence of UTI similar to nitrofurantoin prophylaxis (60% vs 15% vs 20% for no prophylaxis vs d-mannose vs nitrofurantoin) Side effects were considerably decreased compared with antibiotic prophylaxis GAG Layer Replacement in Recurrent UTI Surface (umbrella) cells of the urothelium are covered by a hydrophillic, charged disaccharide layer called the glycosaminoglycan (GAG) layer The components include hyaluronic acid (HA), heparin sulfate, and chondroitin sulfate The layer creates a permeability as well as antimicrobial barrier for the bladder Attenuation of the GAG layer increased bacterial adherence by 100x GAG replacement therapy has been used extensively in treatment of Bladder Pain Syndrome Studies have demonstrated benefit for recurrent UTI from HA, heparin and chondroitin sulfate administered intravesically Understanding Bacteriuria Significant Bacteriuria In 1956, a threshold of 10 5 colony counts was chosen arbitrarily as the dividing line to attempt to distinguish from contamination To date, no colony count has been demonstrated that predicts those likely to become ill or likely to show benefit from antibiotic treatment Boscia et al (1986) looked at older men and women who were bacteriuric and nonbacteriuric during the survey. Frequency, urgency, suprapubic pain, malaise, weakness and fatigue all were NOT associated with episodes of bacteriuria. Dysuria was excluded. 4

5 Significant Bacteriuria Urinary tract symptoms do not appear to predict risk of urosepsis or pyelonephritis and Woodford et at (2011) showed that in older patients with bacteremia with identical urinary isolate, only 1/37 patients >75 years reported history of dysuria Pyuria appears commonly in older patients with bacteriuria. There is no evidence that presence of pyuria in these patients predicts benefit from antibiotic therapy Pyuria accompanying bacteriuria is not an indication for antimicrobial treatment (IDSA Guidelines for the Treatment of Asymptomatic Bacteriuria (2005)) Asymptomatic Bacteriuria Pregnant women and those undergoing urinary tract procedures likely to disrupt the mucosa benefit from treatment of asymptomatic bacteriuria Strong evidence against any benefit from treatment of asymptomatic bacteriuria exists for elderly men and women (at home or institutionalized), catheterized patients, premenopausal women and women with diabetes. Asymptomatic Bacteriuria No evidence suggests that treatment of bacteriuria results in improved outcomes for delirium, falls, or confusion For non-catheterized residents of long-term facilities, delirium is not a reason to send laboratory tests for UTI (IDSA Clinical Practice Guidelines for Evaluation of Fever and Infection in Older Adult Residents of Long-Term Care Facilities) Juthani-Mehta et al (2005) found the most common reasons for suspecting UTI were AMS (39%), change in behavior (19%) and change in character of urine (16%). Only 8% were for dysuria. Range of bacteriuria in nursing home residents is 15-50% Harm to Native Microbiome Cai et al (2012) randomized 673 women (mean age 39) to treatment or observation of asymptomatic bacteriuria Treated women were more likely to have a symptomatic UTI at 1 year At 27 months, treated women were more likely to have recurrent UTI, poorer quality of life, and more common pyelonephritis Clear evidence demonstrates that urine is not normally sterile and that antibiotic use disrupts this normal microflora Conclusions Appropriate management of acute lower urinary tract infection plays an important role in preventing the development of recurrent UTI An effective diagnostic regimen for recurrent UTI depends on identifying specific anatomic or functional abnormalities that may contribute to recurrent infection, particularly through bacterial persistence Multiple strategies exist to treat recurrent UTI, many focusing on restoring the normal vaginal and urinary microbiome Inappropriate treatment of asymptomatic bacteriuria provides no substantial benefit and may result in significant harm and the development of recurrent UTI Thank You 5