Disclosures Grant/funding from: Antibacterial Research Leadership - PDF document

Disclosures § Grant/funding from: Antibacterial Research Leadership Group (NIH), Infectious Diseases Society of America § Consultant: Actelion, Genentech Cl Clostridium m difficile difficulties Sarah Doernberg, MD, MAS Assistant professor and Medical Director of Antimicrobial Stewardship Division of Infectious Diseases, UCSF 3.14.2018 Outline New guidelines hot off the press! § Brief background and epidemiology § Diagnosis § Management—mild, uncomplicated disease § Management—moderate-severe disease § Management—recurrent/relapsed disease § Management—fulminant disease § Prevention 3/14/18 1 3/14/18 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

One of CDC’s 3 “Urgent Threats” 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 500,000 • IBD § Fecal-oral spread • Tube feeds § 12% of all HAIs 3.8 billion • 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 https://www.cdc.gov/drugresistance/biggest_threats.html Epidemiology trends, inpatients Duration, number, and intensity of antibiotics affect risk for CDI Molecular testing era Epidemic strain Stevens V, et al. Clin Infect Dis 2011; 53: 42-48. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6034a7.htm 8 2 3/14/18 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Antibiotic use affects the population risk Spread of CDI in the hospital Endogenous Asymptomatic carriers 20% carriage Symptomatic cases 30% 25-33% Other (environmental • Risk for CDI if prior room occupant got antibiotics = HR 1.22 (1.02-1.45) contamination, etc) Walker AS et al. PLoS Med. 2012 Feb;9(2):e1001172.; Kamboj M et al. Infect Control Hosp Epidemiol. 2016 Jan; Brown K et al. JAMA Intern Med. 2015 Apr;175(4):626-33 37(1): 8–15; Curry SR et al. Clin Infect Dis. 2013 Oct 15; 57(8): 1094–1102; McDonald LC, Clin Infect Dis. 2013 Freedberg DE et al. JAMA Intern Med. 2016 Dec 1;176(12):1801-1808 Oct;57(8):1103-5 Diagnostic testing CDI overdiagnosis Glutamate dehydrogenase Ag (GDH) • Bacterial detection • 21% +PCR • Sensitive but not specific • Of these, 44% + toxin • Toxin-/PCR+ • ↓bacterial load Polymerase chain reaction (PCR): • ↓abx • Toxin-producing gene • ↓diarrhea • ↑Sensitivity • No CDI- complications Enzyme immunoassay (EIA) • Protein detection • ↓Sensitivity • ↑Specificity for disease Polange CR et al., JAMA Intern Med. 2015 Nov;175(11):1792-801. 3 3/14/18 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

New testing guidance § Develop institutional guidance on appropriate testing • No tests if on laxatives • Test only if new onset ≥ 3 stools/24 hours § Multistep algorithm preferred over PCR alone • GDH+toxin à PCR MANAGEMENT • PCR+toxin § If institution limits testing to high pretest probability testing, PCR alone okay McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085 3/14/18 Uncomplicated CDI treatment no longer Treatment scenario #1. 63 y/o F recently treated for a depends on severity! UTI with levofloxacin, now having watery stools 4x/day, fever to 38.3, WBC 11K, Cr 1.0. Other vitals stable. PCR § Mild to moderate: Does not meet criteria for severe positive for C. difficile toxin. With what should you treat • Diarrhea ≥ 3 stools/24 hours her? § Severe A. Vancomycin 125 mg po qid • Not well validated B. Vancomycin 500 mg po qid • IDSA/SHEA guidelines: Severe disease = Peak WBC > C. Metronidazole 500 mg po tid 15K or Cr ≥ 1.5 D. Fidaxomicin 200 mg po bid • Severe, complicated à Now “fulminant” ‒ Severe plus hypotension, shock, ileus, and/or megacolon Zar F A et al. Clin Infect Dis. 2007;45:302-307; McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085 4 3/14/18 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Initial uncomplicated CDI, severe or RCTs metronidazole vs. vancomycin non-severe 120 § VAN 125 mg po QID x 10 days (up to 14) (strong, 100 high) 80 § FDX 200 mg PO twice daily x 10 days (strong, MTZ 60 high) Vanco 40 • Favor in patients at high risk for recurrence 20 § If above agents are unavailable, can consider 0 metronidazole x 10-14 days (weak, high) 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 McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085 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 New evidence to support vancomycin 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 • aRR death vanco vs Cure Relapse metronidazole Strain • Any severity: 0.86; (0.74 Epidemic Same Same to 0.98) ¯ • Severe: 0.79 (0.65 to Non-epidemic Same 0.97) ­ ¯ Concomitant abx • NNT to prevent 1 death, ¯ Prior CDI Same severe CDI: 25 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 Stevens VW et al. JAMA Intern Med. 2017 Feb 6. doi: 10.1001/jamainternmed.2016.9045. 2013; 57(4): 555-561; Konijeti GG et al., CID 2014; 58:1507-1514. 5 3/14/18 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Real-world fidaxomicin experience Additional considerations § UK Trust § Stop unnecessary antibiotics Hospitals analyzed pre- § Shorten antibiotic courses and post- information s/p § Narrow antibiotic spectrum introduction of fidaxomicin § Stop acid-suppressive medications when § Each hospital possible (though low quality evidence) had a different approach to rx with fidaxomicin • Esp PPI (e.g. all patients vs. selected § No anti-peristaltic agents until acute sxs improve 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. Take-home 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 first § For initial treatment of non-fulminant CDI, episode was treated with VAN x 10 days. Her WBC VAN 125 mg po QID x 10-14 days for most count is 9 and Cr is 0.3. What should you treat her with? patients A. Metronidazole 500 mg po TID x 10 days § Role of fidaxomicin unclear B. VAN 125 mg PO QID x 10 days • Consider if ↑ risk of relapse or need CA C. VAN taper D. FDX 200 mg po BID x 10 days 6 3/14/18 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

First recurrence, non-fulminant CDI Evidence to support VAN taper § If metronidazole used initially à VAN 125 § Treatment outcomes from pts in placebo group with rCDI of 2 RCTs of probiotics (n = 163) mg po QID x 10 days (weak, low) § 29 got VAN tapers of varying stripes § If VAN used initially, two options: • Mean 21.5 +/- 10 days • VAN taper (weak, low) • 31% recurrence compared to 71% of the 10 pts • FDX 200 mg po BID x 10 days (weak, given standard VAN courses (p = 0.01) mod) • Also lower recurrences for VAN pulses § Small numbers, uncontrolled study McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085 McFarland LV et al. Am J Gastroenterol. 2002 Jul;97(7):1769-75 Vancomycin taper Risk for recurrent CDI § 125 mg po 4x daily x 14 days 100% 90% § 125 mg po 2x daily x 7 days 80% § 125 mg po 1x daily x 7 days 70% 60% § 125 mg po every other day x 8 days (4 doses) 50% No recurrence § 125 mg po every 3 days x 15 days (5 doses) Recurrence 40% 30% 20% 10% 0% 1st episode 2nd episode 3rd episode Kelly and LaMont, N Engl J Med. 2008;359(18):1932-40. Johnson S. J Infect 2009;58(6):403-10; Pepin J et al. Clin Infect Dis. 2005 Jun 1;40(11):1591-7 7 3/14/18 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]