Disclosures Genentech: Consultant Infectious diarrhea with a focus on Clostridium difficile Sarah Doernberg, MD, MAS Assistant professor and Medical Director of Antimicrobial Stewardship Division of Infectious Diseases, UCSF 4.20.16 Objectives Outline Clostridium difficile infection (CDI) To recognize patients at risk for CDI • Brief background, epidemiology, diagnosis, infection To understand management principles for treatment of mild, control severe, and fulminant CDI • Management—mild, uncomplicated disease To have a treatment approach to recurrent and relapsed CDI • Management—moderate-severe disease To have strategies to prevent CDI To generate a differential diagnosis for foodborne illness • Management—recurrent/relapsed disease To develop an approach to evaluating patients with diarrhea • Management—fulminant disease • Prevention Non-CDI infectious diarrhea 1 4/14/2016 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Epidemiology trends CDI Background Molecular testing era Anaerobic, spore-forming gram- Risk factors: positive bacillus • Antibiotics Toxins A + B • Age Epidemic strain Multiple strains • Hospitalization • Epidemic strain ID’d 2004 • Acid-suppression • 078 strain • IBD Fecal-oral spread • Tube feeds 12% of all HAIs • Host immune factors Carriage of C. difficile • Chemotherapy • < 3% for healthy adults in community • Female gender • 20% in hospitalized pts • Domestic animals? Retail food? • Up to 50% in LTCF http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6034a7.htm Magill SS et al., NEJM 2014 Diagnostic testing CDI overdiagnosis • 21% +PCR Polymerase chain reaction (PCR) • 44% + toxin • Newest gold standard • Toxin-/PCR+ • (culture very difficult, time consuming, research only) • ↓ bact load Glutamate dehydrogenase Ag (GDH) • ↓ abx • Sensitive but not specific • ↓ diarrhea • No CDI- • Tests for presence of bacteria, not toxin complications Enzyme immunoassay (EIA) • Less sensitive but may be a better predictor of outcomes Polange CR et al., JAMA Intern Med. 2015 Nov;175(11):1792-801. 2 4/14/2016 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Treatment scenario #1 63 y/o F recently treated for a UTI with levofloxacin, now having watery stools 4x/day, fever to 38.3, WBC 16K, Cr 1.7 (baseline 0.5). PCR positive for C. difficile toxin. With what should you treat her? A. Vancomycin 125 mg po qid B. Vancomycin 500 mg po qid C. Metronidazole 500 mg po tid MANAGEMENT D. Fidaxomicin 200 mg po bid CDI treatment depends on severity RCTs metronidazole vs. vancomycin 120 Mild to moderate: Does not meet criteria for severe p = 0.005 NS p = 0.02 NS 100 • Diarrhea ≥ 3 stools/24 hours Severe 80 • Not well validated MTZ 60 Vanco • IDSA/SHEA guidelines: Severe disease = Peak WBC > 15K or 40 Cr > 50% above baseline or “advanced age” (65? 75?) 20 Severe, complicated 0 • Severe plus hypotension, shock, ileus, and/or megacolon Cure, all Cure, mild-mod Cure, severe Recurrence • Similar findings for recent study of metronidazole vs vancomycin vs tolevamer • Cure not differential with regard to levels of severity • Higher recurrence across the board (20%) • Only vancomycin is FDA-approved Zar F A et al. Clin Infect Dis. 2007;45:302-307; Leffler DA and Lamont JT. NEJM 2015; 372:1539-1548; Johnson S et al., Clin Infect Zar F A et al. Clin Infect Dis. 2007;45:302-307 ; Cohen et al., Infection Control and Hospital Epidemiology, 2010; 31: Dis 2014;59(3):345-54 431-455 3 4/14/2016 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
What about fidaxomicin? Additional considerations • Bottom line vs. vanco: Similar cure (~88%), lower recurrence (13- Stop unnecessary antibiotics 15% vs. 25-27% ) • Unclear role in multiply recurrent or severe disease Shorten antibiotic courses Cure Relapse Narrow antibiotic spectrum Strain Stop acid-suppressive medications when possible Epidemic Same Same • Esp PPI Non-epidemic Same Do not use anti-peristaltic agents until acute symptoms of Concomitant abx CDI improve =/ Prior CDI Same • Unlikely cost effective under any circumstance Fidaxomicin Vancomycin Metronidazole $2800 $250-680 $22 Louie TJ, et al. NEJM 2011;364:422-431; Cornely et al, Lancet Infect Dis 2012;12:281-8 ; Petrella LA, et al. Clin Infect Dis 2012;55(3):351-7; Mullane et al., CID 2011;53(5):440-7; Corneley et al., CID 2012;55:s154-s161.; Bartsch SM et al., CID 2013; 57(4): 555-561; Konijeti GG et al., CID 2014; 58:1507-1514. Take-home Treatment scenario #2 You are referred a 62 y/o F in clinic who has takes chronic For mild-moderate disease, can choose metronidazole, more amoxicillin acid for suppression of cellulitis and has developed her movement towards PO vancomycin in recent years second bout of C. difficile colitis. Her WBC count is 9 and Cr is 0.3. For severe disease, choose vancomycin What should you treat her with? • Higher cure, but same relapse A. Metronidazole 500 mg po TID Role of fidaxomicin unclear B. Vancomycin 125 mg PO QID • Consider if high risk of relapse or need CA C. Vancomycin taper • ? Use in multiply recurrent disease • ? Role in severe disease 4 4/14/2016 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Treatment scenario #3 Risk for recurrent CDI This patient returns one month after you have treated her with a 14-day course of PO metronidazole complaining of ongoing 100% diarrhea. A repeat stool toxin is positive. What do you do? 90% A. Metronidazole 500 mg po TID x 14 days 80% 70% B. Vancomycin 125 mg PO QID x 14 days 60% C. Vancomycin taper No recurrence 50% D. Fidaxomicin 200 mg PO BID x 10 days Recurrence 40% E. Other 30% 20% 10% 0% 1st episode 2nd episode 3rd episode Johnson S. J Infect 2009;58(6):403-10; Pepin J et al. Clin Infect Dis. 2005 Jun 1;40(11):1591-7 Stool transplant Vancomycin taper “Fecal microbiota transplantation” (FMT) First performed in 1958 for pseudomembranous 125 mg po 4x daily x 14 days colitis 125 mg po 2x daily x 7 days Colonization resistance 125 mg po 1x daily x 7 days 125 mg po every other day x 8 days (4 doses) Purified stool via NJ tube, scope, enema 125 mg po every 3 days x 15 days (5 doses) • Most resolve with 1, some (<25%) require ≥ 2 Related donors or banked stool • Need to screen for transmissible diseases Multiple RCTs have now been done Guidance document available (Bakken et al) Kassam et al., Arch Intern Med. 2012;172(2):191-3. Gough et al., CID 2011;53(10):994-1002; Bakken JS et al Clin Gastroenterol Hepatol 2011; 9: 1044-49 Kelly and LaMont, N Engl J Med. 2008;359(18):1932-40. 5 4/14/2016 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
FMT leads to better cure rates Poop pill? • Similar results for Open-label, single group feasibility study of patients with recurrent or refractory CDI RCT vs vanco taper • Good results when N = 20 given by NGT as well No SAEs 14/20 (70%; 95% CI, 47%-85%) had sustained (8 wk) resolution after 1 treatment • Nonresponders were re-treated (~7 days later) • Overall response: 90% (95% CI, 68%-98%) Youngster I, et al. JAMA 2014;312(17):1772-8. www.npr.org Van Nood E, et al. NEJM 2013; 368: 407-15; Cammarota et al, Alim Pharm Ther 2015:41:835; Youngster I et al., CID 2014;58:1515-1522 FMT adverse events Take-home Recurrent CDI is a challenge Common Rare/serious Treat first episode with same agent, adjust for severity Diarrhea Procedure-related harms Subsequently, use vanco (taper if multiply recurrent) Cramping • Perforation Primary FMT indications • Aspiration Belching • Recurrent or relapsing FMT (usu > 2 episodes) Norovirus Nausea • Moderate CDI not responding to Rx Bacteremia Bloating • More to follow on severe/complicated IBD flare Drekonja D et al. Ann Intern Med 2015;162(9):630-8. 6 4/14/2016 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
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