Clostridium difficile Sarah Doernberg, MD, MAS Assistant professor - PDF document

Clostridium difficile Sarah Doernberg, MD, MAS Assistant professor and Medical Director of Antimicrobial Stewardship Division of Infectious Diseases, UCSF 2.19,2018 Outline  Brief background and epidemiology  Diagnosis  Management—mild, uncomplicated disease  Management—moderate-severe disease  Management—recurrent/relapsed disease  Management—fulminant disease  Prevention 1 2/7/2018

One of CDC’s 3 “Urgent Threats” 500,000 3.8 billion https://www.cdc.gov/drugresistance/biggest_threats.html CDI Background  Anaerobic, spore-forming gram-  Risk factors: positive bacillus • Antibiotics  Toxins A + B • Age  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 Magill SS et al., NEJM 2014 2 2/7/2018

Epidemiology trends, inpatients Molecular testing era Epidemic strain http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6034a7.htm Duration, number, and intensity of antibiotics affect risk for CDI Stevens V, et al. Clin Infect Dis 2011; 53: 42-48. 6 3 2/7/2018

Antibiotic use affects the population risk Brown K et al. JAMA Intern Med. 2015 Apr;175(4):626-33 Spread of CDI in the hospital Endogenous ? Asymptomatic carriers carriage Symptomatic cases 30% 25-33% Walker AS et al. PLoS Med. 2012 Feb;9(2):e1001172.; Kamboj M et al. Infect Control Hosp Epidemiol. 2016 Jan; 37(1): 8–15; Curry SR et al. Clin Infect Dis. 2013 Oct 15; 57(8): 1094–1102; McDonald LC, Clin Infect Dis. 2013 Oct;57(8):1103-5 4 2/7/2018

Diagnostic testing Glutamate dehydrogenase Ag (GDH) • Bacterial detection • Sensitive but not specific Polymerase chain reaction (PCR): • Toxin-producing gene • ↑ Sensitivity Enzyme immunoassay (EIA) • Protein detection • ↓ Sensitivity • ↑ Specificity for disease CDI overdiagnosis • 21% +PCR • Of these, 44% + toxin • Toxin-/PCR+ • ↓ bacterial load • ↓ abx • ↓ diarrhea • No CDI- complications Polange CR et al., JAMA Intern Med. 2015 Nov;175(11):1792-801. 5 2/7/2018

Case  63 year old F s/p spinal fusion c/b hardware infection. She received a 6 week course of antibiotics for this and is admitted for redo spinal fusion. She has been constipated and has daily orders for senna, colace and miralax.  On HD# 8, she develops 2 loose stools and tests positive for C. difficile. She is afebrile with a normal WBC and is started on PO metronidazole. She has no further episodes of loose stools during the remainder of hospitalization. Overdiagnosis case  63 year old F s/p spinal fusion c/b hardware infection. She received a 6 week course of antibiotics and is admitted for redo spinal fusion. She has been constipated and has daily orders for senna, colace and miralax.  On HD# 8, she develops 2 loose stools and tests positive for C. difficile. She is afebrile with a normal WBC and is started on PO metronidazole. She has no further episodes of loose stools during the remainder of hospitalization. 6 2/7/2018

MANAGEMENT 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 D. Fidaxomicin 200 mg po bid 7 2/7/2018

CDI treatment depends on severity  Mild to moderate: Does not meet criteria for severe • Diarrhea ≥ 3 stools/24 hours  Severe • Not well validated • IDSA/SHEA guidelines: Severe disease = Peak WBC > 15K or Cr > 50% above baseline or “advanced age” (65? 75?)  Severe, complicated • Severe plus hypotension, shock, ileus, and/or megacolon Zar F A et al. Clin Infect Dis. 2007;45:302-307; Cohen et al., Infection Control and Hospital Epidemiology, 2010; 31: 431-455 RCTs metronidazole vs. vancomycin 120 p = 0.005 NS p = 0.02 NS 100 80 MTZ 60 Vanco 40 20 0 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 Dis 2014;59(3):345-54 8 2/7/2018

New evidence to support vancomycin • aRR death vanco vs metronidazole • Any severity: 0.86; (0.74 to 0.98) • Severe: 0.79 (0.65 to 0.97) • NNT to prevent 1 death, severe CDI: 25 Stevens VW et al. JAMA Intern Med. 2017 Feb 6. doi: 10.1001/jamainternmed.2016.9045. What about fidaxomicin? • Bottom line vs. vanco: Similar cure (~88%), lower recurrence (13-15% vs. 25-27% ) • Unclear role in multiply recurrent or severe disease Cure Relapse Strain Epidemic Same Same  Non-epidemic Same   Concomitant abx =/  Prior CDI Same 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. 9 2/7/2018

Real-world fidaxomicin experience  UK Trust Hospitals analyzed pre- and post- information s/p introduction of fidaxomicin  Each hospital had a different approach to rx with fidaxomicin (e.g. all patients vs. selected populations) • A and B: Fidaxomicin used first-line for all • C, E, F, G: Selected episodes • D: Recurrences only Goldenberg SD et al. Euro J Clin Microbiol and Infect Dis 2016; 35L 251-9. UCSF guidelines Clinical definition Criteria Treatment Initial, mild ‐ mod, Outpatient Not meeting criteria Metronidazole 500 mg po q8h x for severe 10 ‐ 14 days If no response @ 5 days, switch to vancomycin 125 mg po q6h x 10 ‐ 14 days Initial, mild ‐ mod, Inpatient Not meeting criteria Vancomycin 125 mg po q6h x 10 ‐ for severe 14 days If unable to obtain upon discharge, okay to complete the course with metronidazole 500 mg po q8h Initial, severe WBC ≥ 15 OR Cr ≥ 1.5x Vancomycin 125 mg po q6h x 10 ‐ baseline without 14 days hypotension, shock, ileus, and/or megacolon http://idmp.ucsf.edu/news/updated-ucsfmcvasfzsfgh-guidelines-c-difficile-infection 10 2/7/2018

Additional considerations  Stop unnecessary antibiotics  Shorten antibiotic courses  Narrow antibiotic spectrum  Stop acid-suppressive medications when possible • Esp PPI  Do not use anti-peristaltic agents until acute symptoms of CDI improve Take-home  For mild-moderate disease, can choose metronidazole, more movement towards PO vancomycin in recent years  For severe disease, choose vancomycin • Higher cure, but same relapse  Role of fidaxomicin unclear • Consider if high risk of relapse or need CA • ? Use in multiply recurrent disease • ? Role in severe disease 11 2/7/2018

Treatment scenario #2: You are seeing a 62 y/o F who has takes chronic amoxicillin/clavulanic acid for suppression of Enterococcal osteomyelitis and has developed her second bout of C. difficile colitis. Her WBC count is 9 and Cr is 0.3. What should you treat her with? A. Metronidazole 500 mg po TID B. Vancomycin 125 mg PO QID C. Vancomycin taper Risk for recurrent CDI 100% 90% 80% 70% 60% No recurrence 50% Recurrence 40% 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 12 2/7/2018

Treatment scenario #3. This patient returns one month after you have treated her with a 14-day course of PO metronidazole complaining of ongoing diarrhea. A repeat stool toxin is positive. What do you do? A. Metronidazole 500 mg po TID x 14 days B. Vancomycin 125 mg PO QID x 14 days C. Vancomycin taper D. Fidaxomicin 200 mg PO BID x 10 days E. Other Vancomycin taper  125 mg po 4x daily x 14 days  125 mg po 2x daily x 7 days  125 mg po 1x daily x 7 days  125 mg po every other day x 8 days (4 doses)  125 mg po every 3 days x 15 days (5 doses) Kelly and LaMont, N Engl J Med. 2008;359(18):1932-40. 13 2/7/2018

↓↓↓ Fecal diversity with rCDI FMT basics  Colonization resistance  Related donors or banked stool • Need to screen for transmissible diseases  Multiple RCTs have now been done  Guidance document available (Bakken et al) Chang JY et al. JID 2008; 197: 435-8; 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 FMT trial trends  6 published • 3 vs. abx management • 3 vs. FMT refinements  Over time, ↓ efficacy in RCTs  ↑ response to comparator abx  Might matter whether active recurrence vs. prior recurrence?  Might need multiple FMTs  Vanco taper might be better than we thought?  Commercially-prepared FMT in development Johnson S and Gerding DN. Clin Infect Dis (2016) 64 (3): 272-274; van Nood E et al. N Engl J Med 2013; 368:407-415; Orenstein R et al. Clin Infect Dis (2015) 62 (5): 596-602. 14 2/7/2018