Management of UTI. Disclosures. Uncomplicated UTI UTI CLASSIFICATION. Where do UTI bugs come from? Food Sex

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Ashley Morris
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shareholder April 5, 2014 UTI CLASSIFICATION Uncomplicated UTI Uncomplicated UTI Acute cystitis or pyelonephritis in healthy ambulatory woman with no

1 Management of UTI Thomas M. Hooton, M.D. University of Miami Miami, Florida Disclosures Fimbrion a biotech company with mission to develop novel approaches to treat and prevent UTI Co-founder and shareholder April 5, 2014 UTI CLASSIFICATION Uncomplicated UTI Uncomplicated UTI Acute cystitis or pyelonephritis in healthy ambulatory woman with no history suggestive of GU anatomic or functional abnormalities Response to treatment is predictable using an appropriate antimicrobial for a recommended duration Complicated UTI Everybody else High frequency, high morbidity, frequent abx use Where do UTI bugs come from? Food Sex

CASE 1 26 y/o healthy woman 2-day history of burning on urination, frequency, urine pink No fever, back pain, abdominal pain No previous UTI or STD Are Voided Urine Cultures Routinely Indicated?

2 CASE 1 26 y/o healthy woman 2-day history of burning on urination, frequency, urine pink No fever, back pain, abdominal pain No previous UTI or STD Are Voided Urine Cultures Routinely Indicated? Diagnosis Uncomplicated UTI: Cystitis - no Pyelonephritis - yes Complicated UTI - yes Voided Urine Cultures for Cystitis Study to assess value of MSU in AUC MSU vs. cath In 200 women Hooton et al 2013 Results fairly predictable (less so with resistance) Little additive value to clinical highly predictive Delay in getting results Cost and inconvenience Labs ignore growth <10*4 cfu/ml miss 30% of UTIs Gram-positive flora not predictive

3 MSU Cultures in AUC IF you order a MSU Are you going to withhold treatment? Understand what the laboratory is likely to report Are you going to treat if the culture is negative? Do you believe in low colony count cystitis? UTI and Delayed Treatment Randomized, controlled trial 5 management approaches 309 non-pregnant women yrs Immediate antibiotics Antibiotics delayed until sx reassessment 48 h Antibiotics prescribed based on sx score Antibiotics prescribed based on dipstick results Antibiotics prescribed only if MSU + Little P, et al. BMJ 2010;340:c199 UTI and Delayed Treatment No significant diff in duration or severity of sx Immediate antibiotics: 97% abx Antibiotics delayed until sx reassessment 48h 77% Antibiotics prescribed based on sx score 90% Antibiotics prescribed based on dipstick results 80% Midstream urine, rx only if + 81% Conclusions: All approaches achieved similar sx control No advantage of routine urine culture Little P, et al. BMJ 2010;340:c199 Treatment Considerations TREATMENT Worldwide increase in antimicrobial resistance among bacterial pathogens ESBL infections more common Complicates the empiric treatment of AUC Antimicrobial stewardship is indicated, especially to preserve FQs FLUOROQUINOLONE RESISTANCE The Surveillance Network (TSN) US outpatients Urinary E. coli resistance (n = 12,253,679) Ciprofloxacin 3% 17% TMP-SMX 18% 24% Nitrofurantoin 0.8% 1.6% Ceftriaxone 0.2% 2.3% Sanchez GV, et al. Antimicrob Agents Chemother. 2012;56:

4 REGIMENS FOR ACUTE CYSTITIS REVISION of IDSA GUIDELINES TMP-SMX DS TMP 100 mg Ciprofloxacin 250 mg Ciprofloxacin XR 500 mg Levofloxacin 250 mg Cefpodoxime proxetil 100 mg Nitrofurantoin 100 mg Amoxicillin/clavulanate 500 mg Fosfomycin q 12 h x 3d q 12 h x 3d q 12 h x 3d q 24 h x 3d q 24 h x 3d q 12h x 3d q 12 h x 5d q 12 h x 7d 3 gm sachet single dose Conclusion No single best agent for acute cystitis Consider collateral damage Limit FQ use Thus, for empiric treatment, consider: effectiveness; antimicrobial resistance; potential for collateral damage ; adverse effects; allergy history Gupta K, et al. Clinical Infect Diseases 2011;Vol 52, e103-e120 What Is Optimal Treatment for AUC? Recommended Antimicrobials Nitrofurantoin 100 mg bid X 5 days (AI) TMP/SMX 160/800 mg (one DS tablet) bid X 3 days (avoid if resistance >20% or if use in previous 3 months) (AI) Fosfomycin 3 gm single dose (lower efficacy than other recommended agents; avoid if pyelonephritis suspected) (AI) Pivmecillinam 400 mg bid x 5 days (lower efficacy vs. other recommended agents; avoid if pyelonephritis suspected) (AI) Follow-Up MSU? What are you going to do if: Asymptomatic, 10*5 E. coli Asymptomatic, 10*2 E. coli Symptomatic, 10*4 E. coli Gupta K, et al. Clinical Infect Diseases 2011;Vol 52, e103-e120 Other Considerations Are there other things we might do to reduce use of antimicrobials? NATURAL HX OF CYSTITIS Pivmecillinam vs. placebo for AUC 227 women in placebo group % Cured Clinical Micro Day 8-10 (n=212) 26% 34% Day (n=94) 51% 70% Ferry SA, et al. Scand J Primary Health Care 2007;25:49

5 Antimicrobial-Sparing Strategies Bleidorn J, et al. Study of symptomatic uncomplicated UTI Ibuprofen vs. Ciprofloxacin Randomized controlled pilot trial, n=80 BMC Med May 26;8:30. Antimicrobial-Sparing Strategies 80 healthy women aged 18 to 85 years 1 dysuria or frequency No complicating factors Randomly assigned to receive either ibuprofen mg x 3 days, OR cipro mg (+1 placebo) x 3d Bleidorn J. BMC Med May 26;8:30. Antimicrobial-Sparing Strategies Complete symptom resolution Day 7 Ibuprofen 27/36 (75%) Cipro 20/33 (61%) p=0.31 Bleidorn J. BMC Med May 26;8:30 UTI and Anti-Inflammatories Introduction of uropathogenic E. coli (UPEC) into the bladders of C3H mice results in 2 distinct outcomes: acute infection with resolution development of chronic cystitis lasting months Chronic cystitis is preceded by local and systemic acute inflammation at 24 hours postinfection severe pyuria bladder inflammation with mucosal injury, and a distinct serum cytokine signature Hannan TJ, et al. PLoS Pathog 2010: 6(8): e UTI and Anti-Inflammatories Treatment of C3H mice with dexamethasone prior to UPEC infection suppresses the development of chronic cystitis Hannan TJ, et al. PLoS Pathog 2010: 6(8): e C3H/HeN mice pretreated orally with an NSAID (indomethacin) a COX-2 specific inhibitor (SC-236), but not a COX-1 specific inhibitor (SC-560), had significantly reduced pyuria at 24 hpi and reduced incidence of chronic cystitis Hannan TJ, et al. Manuscript in preparation UTI and Anti-Inflammatories A work in progress NSAID not recommended routinely Further trials warranted

6 CASE 2 57 y/o otherwise healthy woman Recurrent UTIs, many in past few years Many urologists, many tests UTI sx like before Cipro empiric did not work MSU grows out ESBL E. coli What to do? ESBL Strains Since 2000, CTX-M extended-spectrum ß-lactamase (ESBL)-producing strains of E. coli have emerged worldwide Important causes of community-onset urinary tract and bloodstream infections Mainly due to a single clone (ST131) Foreign travel to high-risk areas, such as the Indian subcontinent, appears to play a role in the spread ESBL Strains Increasing prevalence in both institutional and community-acquired UTI (ucuti and cuti) Resistant to beta lactams, and most resistant to FQ and TMP/SMX Mostly E. coli and K. pneumoniae Oral alternatives for cystitis in women: Fosfomycin good in vitro and clinical Nitrofurantoin good in vitro and some clinical Carbapenem (ertapenem) may be necessary Recurrent ESBL UTI A growing problem in healthy older women and patients with neurogenic bladder Minimize risk factors Delay treatment for questionable symptoms Minimize cultures don t look, don t treat Minimize antibiotics Does ESBL warrant prolonged treatment? 14 days ertapenem for ESBL cystitis/asb? CASE 3 23 year-old healthy woman Sexually active, uses BCP No other meds LMP 17 days ago History of recurrent UTIs, last one 3 months ago, treated with Bactrim, resolved rapidly, 3 in the year before this current one. Prevention of ruti Behavioral modification Cranberry Vaginal estrogen Probiotics Antimicrobials Mannosides Vaccines

Cranberry Barbosa-Cesnik C, et al. Cranberry Juice Fails to Prevent Recurrent Urinary Tract Infection: Results From a Randomized Placebo-Controlled Trial Clin Infect Dis.

: Among otherwise healthy college women with an acute UTI, those drinking 8 oz of 27% cranberry juice twice daily did not experience a decrease in the 6-month incidence of

Lactobacillus Probiotic Review Lactobacilli dominate vag flora and possess abx properties that regulate GU microbiota Incomplete cure and recurrence of GU infections lead

sizes/ unvalidated dosing strategies Barrons R. Clin Ther 2008;30:453-68 D-Mannose Attachment of E.

7 Cranberry Barbosa-Cesnik C, et al. Cranberry Juice Fails to Prevent Recurrent Urinary Tract Infection: Results From a Randomized Placebo-Controlled Trial Clin Infect Dis Jan;52(1): Cranberry CONCLUSIONS.: Among otherwise healthy college women with an acute UTI, those drinking 8 oz of 27% cranberry juice twice daily did not experience a decrease in the 6-month incidence of a second UTI, compared with those drinking a placebo. Clin Infect Dis Jan;52(1): Lactobacillus Probiotic Review Lactobacilli dominate vag flora and possess abx properties that regulate GU microbiota Incomplete cure and recurrence of GU infections lead to shift from lactobacilli to coliforms Lactobacillus-containing probiotics proposed to restore commensal vaginal flora UTI prevention remains inconclusive - small sample sizes/ unvalidated dosing strategies Barrons R. Clin Ther 2008;30: D-Mannose Attachment of E. coli to uroepithelium is necessary for pathogenesis attachment and invasion FimH adhesins on type 1 pili of E. coli attach to mannosylated receptors on epithelium So why not flood urine with mannose, a natural sugar, and prevent adherence? Well, you can D-Mannose Mannoside binds to FimH Basis for Mannosides Mannoside prevents FimH binding to the receptors of the bladder epithelium Mechanism of action of Mannosides Bladder Online or health food stores

8 Mannosides for UTI Block UPEC adherence/invasion into bladder epithelium, preventing formation of IBCs Optimized for oral bioavailability Single oral dose of lead mannoside resulted in a significant reduction in bacterial colonization 6 hours after rx - better than TMP-SMZ Prevent infection when given prophylactically Potentiate action of TMP-SMZ in CA-UTI Cusumano CK, et al. Sci Transl Med 2011;3:109ra115. When All Else Fails Antimicrobial management Self diagnosis/self treatment Post-coital prophylaxis Daily prophylaxis Stop and reassess at 3-6 months Collateral damage risks dampens enthusiasm THANK YOU

TMP/SMZ DS Ciprofloxacin Norfloxacin Ofloxacin Cefadroxil * 30 Amoxicilin 86* 19 25

TMP/SMZ DS Ciprofloxacin Norfloxacin Ofloxacin Cefadroxil * 30 Amoxicilin 86* 19 25 Evidence-Based Evaluation and Treatment of UTI UTI Prevalence Leslee L. Subak, MD Associate Professor Obstetrics, Gynecology & RS Epidemiology & Biostatistics University of California, San Francisco 50%