UTI 101 Antimicrobial agents duration and prophylaxis April

UTI 101: Antimicrobial agents, duration and prophylaxis April 30, 2012 Jennifer J. Schimmel, MD Baystate Medical Center Division of Infectious Diseases and Antimicrobial Stewardship

Objectives • Describe the agents used for treating bacterial urinary tract infections (UTI’s) and understand how to choose the most appropriate agent • Understand the appropriate duration of therapy and monitoring • Understand the options for prophylaxis of recurrent UTI

Background • UTI is one of the most common infections in the elderly in the community and in long-term care • Two problems: overdiagnosis and overtreatment • Subsequent issues: – C. difficile – Antibiotic resistance • What’s important? – Proper diagnosis – Appropriate antibiotic choice and duration

Defining the Problems • Lower UTI: infection in bladder and/or urethra • Uncomplicated UTI: lower UTI AND – Not pregnant – No urinary tract abnormalities – No indwelling urinary device • Complicated UTI: – – Upper UTI (systemic symptoms, extension beyond urethra/bladder) Functional or structural urinary tract abnormality UTI in men Urinary catheter (CA-UTI) – Older female patients • Many have functional or structural abnormalities

Microbiology in Nursing Homes • New Haven, CT • 5 Nursing Homes May 2005 -2007 • 551 patients, presumed UTI Das R et al. ICHE 2009; 30(11): 1116 -1119.

Case 1 • 75 year old woman s/p recent vertebral fracture, in NH for past 2 weeks, no prior UTI’s • Now several days of urinary frequency, urgency, burning • No fevers or back pain • U/a with significant pyuria • Started empirically on ciprofloxacin

What to use empirically? • Take into account most likely uropathogens • Patient Factors – Other medications/interactions – Allergies – Other past infections – Other medical problems (renal insufficiency, C. diff, etc) • Threshold for failure • Local epidemiology • Cost

Antibiogram • Helps to determine best choices for empiric therapy

Case 1: Culture Data What can you do now? Collect date: 04/15/12 08: 35 Result Status: Auth (Verified) Result Date: 04/17/12 09: 33 SPECIMEN DESCRIPTION : URINE CLEAN CATCH/MIDSTREAM SPECIAL REQUESTS : NONE CULTURE : >100, 000 COL/ML ESCHERICHIA COLI TEST PERFORMED AT BAYSTATE MEDICAL CENTER, SPRINGFIELD, MA. 01199 REPORT STATUS : FINAL 04/17/2012 ORGANISM >100, 000 COL/ML ESCHERICHIA COLI METHOD MIN. INHIB. CONC. (MCG/ML) AMPICILLIN RESISTANT AMPICILLIN/SULBACTAM INTERMEDIATE AMOXICILLIN/CLAVULAN SUSCEPTIBLE CEFAZOLIN SUSCEPTIBLE CEFEPIME SUSCEPTIBLE CEFTRIAXONE SUSCEPTIBLE CIPROFLOXACIN SUSCEPTIBLE ERTAPENEM SUSCEPTIBLE GENTAMICIN SUSCEPTIBLE LEVOFLOXACIN SUSCEPTIBLE MEROPENEM SUSCEPTIBLE NITROFURANTOIN SUSCEPTIBLE PIPERACILLIN/TAZOBAC SUSCEPTIBLE TRIMETH/SULFAMETHOX SUSCEPTIBLE TETRACYCLINE SUSCEPTIBLE

Seeking the perfect antibiotic… • Needs to get into urinary tract – And sometimes the prostate • • Treat specific organism Narrowest spectrum possible Minimize adverse effects Avoid drug interactions No allergy Compliance Cost • Oral option?

Case 2 • 75 year old woman with well-controlled Crohn’s disease on mesalamine, admitted with syncopal event • Found to have conduction abnormality • Allergy to penicillin (unknown) • Has pacemaker placed (perioperative Clindamycin) • 2 days after procedure still has unexplained leukocytosis with WBC 13 • no obvious source of infection, no urinary symptoms, no diarrhea, CXR unremarkable, u/a with 1 wbc

Case 2 • Urine culture pending at the time of discharge to rehab • What would be the next best step? A) Discharge on 5 days of Levofloxacin for possible UTI B) Follow off antibiotics C) Keep her in the hospital and repeat u/a tomorrow D) Treat with Ceftriaxone 1 g IV and additional antibiotics base on culture data E) Treat with Tobramycin 5 mg/kg and additional antibiotics based on culture data

C. diff-o-genicity • High risk – Carbapenems – 2 nd – 4 th generation cephalosporins – Fluoroquinolones – Clindamycin • Medium risk – – Penicillins 1 st generation cephalosporins Macrolides Aztreonam Mullane et al. Clin Infect Dis. 2011; 53: 440 -447. • Low risk – – – – – Aminoglycosides Vancomycin Daptomycin Nitrofurantoin Linezolid Trimethoprim/ sulfamethoxazole Tetracyclines Rifampin Colistin Fosfomycin

Recommendations from the Guidelines

Uncomplicated UTI: Lower Tract Gupta K et al. Clinical Infectious Diseases 2011; 52(5): e 103 -120.

Nitrofurantoin (Macrobid, Macrodantin) • Minimal “collateral” damage • DRUG INTERACTIONS – Minimal – Concomitant administration of a magnesium trisilicate antacid may decrease the absorption of nitrofurantoin – Nitrofurantoin may reduce the effect of quinolone antibiotics – Fluconazole: increased risk of pulmonary and hepatic toxicity • Avoid if creatinine clearance less than 60 – Due to potentiation of adverse effects • Common side effects: nausea, headache • Other serious adverse effects: – – – Peripheral neuropathy Pulmonary hypersensitivity Hepatoxicity Decreased renal function Hemolytic anemia

Fosfomycin • Issues: Minimal resistance Minimal collateral damage High urinary levels Prolonged bactericidal effect Minimal drug interactions Not always available Susceptibility data not routinely available – Role for treatment of resistant organisms such as ESBL’s, VRE, MRSA – Maybe less effective than other short-course regimens – – – –

Trimethoprim/Sulfamethoxazole TMP/SMX (Bactrim) • DRUG INTERACTIONS Warfarin Methotrexate Fluconazole (incr QT) TCA, antipsychotics, antiarrhythmics – Antihyperglycemics – – • Common side effects: nausea, vomiting, rash • Other serious adverse effects: – – – Bone marrow suppression Hepatic necrosis Severe rash Hyperkalemia Hypoglycemia (esp with renal and liver disease) • Increased creatinine…may be falsely elevated

Quinolones: Ciprofloxacin and Levofloxacin • Highly efficacious in a 3 day regimen • Numerous issues with collateral damage: C. difficile and resistance • Save for other uses • Black Box Warning: tendonitis/tendon rupture esp. over age 60, steroids, transplant • Interactions: – calcium, aluminum, magnesium, iron, and zinc (antacids, nutritional supplements, multivitamin and mineral supplements), sucralfate – Warfarin – Antihyperglycemics • Other issues: – QT prolongation esp. in elderly – Decreased seizure threshold

Upper Tract Infection: Acute Pyelonephritis • Not requiring hospitalization (and resistance less than 10%): – Ciprofloxacin 500 mg PO BID for 7 days – Ciprofloxacin 1000 mg ER for 7 days – Levofloxacin 750 mg for 5 days – Bactrim DS BID for 14 days (if pathogen susceptible) – Alternative initial IV antibiotic: Ceftriaxone 1 g IV or Aminoglycoside – Alternative: Oral b-lactam (initial IV dose Ceftriaxone) and 10 -14 days • Hospitalized: – IV regimen: • Fluoroquinolone • Aminoglycoside +/- ampicillin • 2 nd or 3 rd generation cephalosporin +/- aminoglycoside • Extended spectrum penicillin +/- aminoglycoside • Carbapenem Gupta K et al. Clinical Infectious Diseases 2011; 52(5): e 103 -120.

Catheter-Associated UTI (CA-UTI) • Most common health care-associated infection worldwide • 40% of hospital-acquired infections • 5 -10% of LTCF residents with long-term indwelling catheters – Almost all have bacteriuria – Single organism in short-term catheter – Multiple organisms in long-term catheterization Hooton TM et al. Clinical Infectious Diseases 2010; 50: 625 -663.

CA-UTI • E. coli (30%), Klebsiella species, Serratia species, Citrobacter species, Enterobacter species, Pseudomonas aeruginosa, coagulasenegative staphylococci, Enterococcus species • Long-term catheters: the organisms above and: Proteus mirabilis, Morganella morganii, Providencia stuartii

CA-UTI • Duration: – Prompt resolution of symptoms: 7 days – Delayed response: 10 -14 days – Not severely ill: 5 day Levofloxacin may be considered – Women aged 65 or under with CA-UTI and no upper tract symptoms, with removal of catheter: consider 3 days of therapy • Other issues – De-escalation/narrowing of therapy as soon as possible – If catheter in place for >2 weeks and is still needed, catheter should be replaced • More rapid resolution of symptoms • Decrease risk of subsequent CA-bacteriuria and CA-UTI Hooton TM et al. Clinical Infectious Diseases 2010; 50: 625 -663.

Case 3 • 68 yo woman with poorly-controlled diabetes, dysuria, fever and chills • Prior history of UTI’s with resistant Klebsiella • No allergies • WBC 18 K • Cr 2. 6 • U/a with >182 wbc, 2 rbc, 1 sq epith cell

Limited Therapeutic Options URINE CULTURE Final Organism 1 KLEBSIELLA PNEUMO SSP PNEUMO. COLONY COUNT >100, 000 CFU/ml RESULT COMMENT: ** DRUG RESISTANT ORGANISM ** Drug Resistant Organism KLEBSIELLA PNEUMO. SSP PNEUMO. MULTIPLE DRUG RESISTANCE TRIMETHOPRIM/SULFAMETHOXAZOLE R >=320 AMPICILLIN R >=32 AMPICILLIN/SULBACTAM R >=32 CEFAZOLIN R >=64 CEFOXITIN R >=64 CEFTAZIDIME R >=64 CEFTRIAXONE R >=64 CEFEPIME R >=64 CIPROFLOXACIN R >=4 GENTAMICIN R >=16 LEVOFLOXACIN R >=8 IMIPENEM R >=16 NITROFURANTOIN R >=512 TOBRAMYCIN R >=16 AMIKACIN R >=64 PIPERACILLIN/TAZOBACTAM R >=12 8 • What are the antibiotic options in this case? a) b) c) d) e) None Colistin Gatifloxacin Ertapenem Other ideas?

New FDA Antibiotic Approvals Boucher HW et al. Clinical Infect Diseases 2009; 48: 1 -12. Increasing Resistant Organisms

Answers • Colistin • Tigecycline • Fosfomycin

Case 3, Part 2 • Patient is treated with colistin, has resolution of her symptoms, leukocytosis and eventually improved renal function. • Which of the following should be done? A) Repeat u/a 7 days after therapy completed B) Repeat urine culture 7 days after therapy completed C) A and B D) Repeat u/a and culture are not indicated

Test of Cure • Not routinely recommended

Case 4 • 70 year old woman with 4 E. coli UTI’s in the past 6 months, urologist notes a mild cystocele and atrophic vaginal mucosa on exam • What do you recommended? A) Nothing B) Bactrim DS BID indefinitely C) Cranberry juice 8 oz daily D) Topical estrogen D) Cipro 500 mg weekly

Recurrent UTI: Risk Factors • Post-menopausal: – estrogen deficiency – urogenital surgery – incontinence, cystocele, post-void residuals • Men: – Prostatic disease • Both Men and Women: – Obstruction: stones, tumor • Complicated UTI: – MDRO, obstruction, stasis, foley catheter, stent, diabetes, pregnancy, renal failure, transplant, immunosuppression Franco AV. Best Pract & Res Clin Obstet & Gynec 2005; 19(6): 861 -73.

What else other than antibiotics? • Fluids to promote a dilute urine flow • Topical estrogen – In some postmenopausal women it can normalize the vaginal flora and reduce recurrent UTI • Methenamine • Adhesion blockers (D-mannose) – Not evaluated in clinical trials • Drinking cranberry juice or cranberry tablets – Clinical Data Cochrane Review 2008 – Recent studies – Pilot Study in LTC

Mayo Clinic Proceedings 2012 Feb; 87(2): 143 -50 Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial. Stapleton AE, Dziura J, Hooton TM, Cox ME, Yarova-Yarovaya Y, Chen S, Gupta K. Source Department of Medicine, University of Washington, Seattle, USA. Abstract OBJECTIVE: To compare the time to urinary tract infection (UTI) and the rates of asymptomatic bacteriuria and urinary P-fimbriated Escherichia coli during a 6 -month period in women ingesting cranberry vs placebo juice daily. PATIENTS AND METHODS: Premenopausal women with a history of recent UTI were enrolled from November 16, 2005, through December 31, 2008, at 2 centers and randomized to 1 of 3 arms: 4 oz of cranberry juice daily, 8 oz of cranberry juice daily, or placebo juice. Time to UTI (symptoms plus pyuria) was the main outcome. Asymptomatic bacteriuria, adherence, and adverse effects were assessed at monthly visits. RESULTS: A total of 176 participants were randomized (120 to cranberry juice and 56 to placebo) and followed up for a median of 168 days. The cumulative rate of UTI was 0. 29 in the cranberry juice group and 0. 37 in the placebo group (P=. 82). The adjusted hazard ratio for UTI in the cranberry juice group vs the placebo group was 0. 68 (95% confidence interval, 0. 33 -1. 39; P=. 29). The proportion of women with P-fimbriated urinary E coli isolates during the intervention phase was 10 of 23 (43. 5%) in the cranberry juice group and 8 of 10 (80. 0%) in the placebo group (P=. 07). The mean dose adherence was 91. 8% and 90. 3% in the cranberry juice group vs the placebo group. Minor adverse effects were reported by 24. 2% of those in the cranberry juice group and 12. 5% in the placebo group (P=. 07). CONCLUSION: Cranberry juice did not significantly reduce UTI risk compared with placebo. The potential protective effect we observed is consistent with previous studies and warrants confirmation in larger, well-powered studies of women with recurrent UTI. The concurrent reduction in urinary P-fimbriated E coli strains supports the biological plausibility of cranberry activity. Juthani-Mehta M et al. Journal of the American Geriatric Socety 2010; 58(10): 2028 -2030.

What about for CA-UTI? • Reduce indwelling catheter use • Remove catheters the as soon as they are no longer clinically necessary • Catheters – Care • Insertion with aseptic technique/sterile equipment • Closed drainage systems, with drainage bag and tube always below bladder level – Antimicrobial coating • May delay onset of CA-bacteriuria in short-term Hooton TM et al. Clinical Infectious Diseases 2010; 50: 625 -663.

What about for CA-UTI? • Methenamine not recommended in long-term catheterization – Data unconvincing that it is effective – May be effective with intermittent catheterization and short-term catheterization (studied in specific population) • Methenamine hippurate 1 g BID • Methenamine mandelate 1 g 4 times daily – And it may help to acidify urine when using these agents (Vit C? ) • Cranberry – 3/4 double-blind placebo controlled trials: no effect – Studies are poor, mostly negative • Antimicrobial prophylaxis can reduce CA-ASB, but not CA-UTI – Not recommended because of cost, potential for adverse effects and development of antimicrobial resistance Hooton TM et al. Clinical Infectious Diseases 2010; 50: 625 -663.

In Summary • Decide if treatment is necessary • Appropriate antibiotic and duration – Choice based on patient (allergies/comorbidities/prior history), epidemiologic factors, organism – Minimize adverse effects, minimize development of resistance, avoid C. difficile • Narrowest spectrum possible • If empiric therapy is more broad than needed, narrow after culture data • Prophylaxis – Several options that do not affect antimicrobial resistance – Avoid antimicrobial agents if possible – If such an agent is chosen, would re-evaluate after several months

Questions?

• • • • References Barbosa-Cesnik C et al. Cranberry Juice Fails to Prevent Recurrent Urinary Tract Infection: Results from a Randomized Placebo-Controlled Trial. Clinical Infectious Diseases 2011; 52(1); 23 -30. Beerepoot MAJ et al. Cranberries vs Antibiotics to Prevent Urinary Tract Infections. Archives of Internal Medicine 2011; 171(14): 1270 -78. Beveridge LA et al. Optimal Management of Urinary Tract Infections in Older People. Clinical Interventions in Aging 2011; 6: 173 -180. Boucher HW et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clinical Infect Diseases 2009; 48: 1 -12. Das R et al. Antimicrobial Susceptibility of Bacteria Isolated from Urine Samples Obtained from Nursing Home Residents. ICHE 2009; 30(11): 1116 -1119. Franco AV. Recurrent Urinary Tract Infections. Best Pract & Res Clin Obstet & Gynec 2005; 19(6): 861 -73 Gupta K et al. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society of Microbiology and Infectious Diseases. Clinical Infectious Diseases 2011; 52(5): e 103120. Hooton, TM. Uncomplicated Urinary Tract Infection. NEJM 2012; 366: 1028 -37. Hooton TM et al. Diagnosis, Prevention, and Treatment of Catheter-Associated Urinary Tract Infection in Adults: 2009 Internation Clinical Practice Guidelines from the Infectious Diseases Society of America. Clinical Infectious Diseases 2010; 50: 625 -663. Jepson RG et al. Cranberries for preventing urinary tract infections. Cochrane Review 2008. Juthani-Mehta M et al. Feasibility of Cranberry Capsule Administration and Clean-Catch Urine Collection in Long-Term Care Residents. Journal of the American Geriatric Socety 2010; 58(10): 2028 -2030. Mcmurdo MET et al. Does Ingestion of Cranberry Juice Reduce Urinary Tract Infections in Older People in Hospital? A Double-Blind Placebo-Controlled Trial. Age and Aging 2005; 34: 256 -261. Mullane et al. Clin Infect Dis. 2011; 53: 440 -447. Nicolle LE et al. Infectious Diseases Society of America Guidelines for the Diagnosis and Treatment of Asymptomatic Bacteriuria in Adults. Clinical Infectious Diseases 2005; 40: 643 -54. Stapleton AE et al. Recurrent Urinary Tract Infection and Urinary Escherichia coli in Women Ingesting Cranberry Juice Daily: A Randomized Controlled Trial. Mayo Clinic Proceedings 2012; 87(2): 143 -50.