Clostridium difficile Disclosures: Consultant for Actelion, prior - PDF document

Clostridium difficile Disclosures: Consultant for Actelion, prior research studies with Cerexa, Merck, Cubist Sarah Doernberg, MD, MAS Assistant Professor, University of California, San Francisco Medical Director, Adult Antimicrobial Stewardship Objectives Outline  To recognize patients at risk for C. difficile infection (CDI)  Brief background and epidemiology  To understand diagnostic testing for CDI  Diagnosis  To understand management principles for treatment of mild,  Management—mild, uncomplicated disease severe, and fulminant CDI  Management—moderate-severe disease  To have a treatment approach to recurrent and relapsed CDI  Management—recurrent/relapsed disease  To have strategies to prevent CDI  Management—fulminant disease  To understand concepts in emerging therapies for CDI  Prevention 1 3/15/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

One of CDC’s 3 “Urgent Threats” CDI Background  Anaerobic, spore-forming gram-positive  Risk factors: bacillus • Antibiotics  Toxins A + B • Age  Multiple strains • Hospitalization • Epidemic strain ID’d 2004 • Acid-suppression 500,000 • 078 strain • IBD  Fecal-oral spread • Tube feeds 3.8 billion  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 https://www.cdc.gov/drugresistance/biggest_threats.html Epidemiology trends, inpatients Epidemiology snapshot Molecular testing era  453,000 estimated cases in the USA in year 2011 • 147 cases/100,000 people  66% healthcare-associated Epidemic strain • 24% hospital-onset  Female > male (rate ratio = 1.26 [1.25 to 1.27])  White > non-white (RR = 1.7 [1.6 to 2.0])  ↑ 65 > ↓ 65 (RR = 8.7 [8.2 to 9.3])  13% recurred (21% if HAI)  3% died within 30 days (9% if HAI)  $$ millions in excess costs estimated http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6034a7.htm Lessa FC, et al. N Engl J Med 2015; 372(9):825-34. 2 3/15/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Duration, number, and intensity of Antibiotic use affects the population risk antibiotics affect risk for CDI Stevens V, et al. Clin Infect Dis 2011; 53: 42-48. 9 Brown K et al. JAMA Intern Med. 2015 Apr;175(4):626-33 Spread of CDI in the hospital Diagnostic testing Glutamate dehydrogenase Ag (GDH) • Bacterial detection • Sensitive but not specific Endogenous Polymerase chain reaction (PCR): ? Asymptomatic carriers carriage • Toxin-producing gene Symptomatic cases 30% • ↑ Sensitivity 25-33% Enzyme immunoassay (EIA) • Protein detection • ↓ Sensitivity • ↑ Specificity for disease 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 3 3/15/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

CDI overdiagnosis What is wrong with this picture?  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 • 21% +PCR redo spinal fusion. She has been constipated and has daily orders for senna, colace and miralax. • Of these, 44% + toxin • Toxin-/PCR+ • ↓ bacterial load  On HD# 8, she develops 2 loose stools and tests positive for C. • ↓ abx difficile. She is afebrile with a normal WBC and is started on PO • ↓ diarrhea metronidazole. She has no further episodes of loose stools during • No CDI- the remainder of hospitalization. complications Polange CR et al., JAMA Intern Med. 2015 Nov;175(11):1792-801. 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. MANAGEMENT 4 3/15/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

CDI treatment depends on severity 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  Mild to moderate: Does not meet criteria for severe what should you treat her? • Diarrhea ≥ 3 stools/24 hours A. Vancomycin 125 mg po qid  Severe B. Vancomycin 500 mg po qid • Not well validated C. Metronidazole 500 mg po tid • IDSA/SHEA guidelines: Severe disease = Peak WBC > 15K or D. Fidaxomicin 200 mg po bid 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 New evidence to support vancomycin 120 p = 0.005 NS p = 0.02 NS 100 • aRR death vanco vs 80 metronidazole, any MTZ 60 severity Vanco • Any severity: 0.86; 40 95% CI, 0.74 to 0.98; 20 • Severe CDI: 0.79; 95% 0 CI, 0.65 to 0.97 Cure, all Cure, mild-mod Cure, severe Recurrence • NNT to prevent 1 death, • Similar findings for recent study of metronidazole vs vancomycin vs tolevamer severe CDI: 25 • 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 Stevens VW et al. JAMA Intern Med. 2017 Feb 6. doi: 10.1001/jamainternmed.2016.9045. 5 3/15/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

What about fidaxomicin? Real-world fidaxomicin experience • Bottom line vs. vanco: Similar cure (~88%), lower  UK Trust recurrence (13-15% vs. 25-27% ) Hospitals analyzed pre- • Unclear role in multiply recurrent or severe disease and post- Cure Relapse information s/p introduction of Strain fidaxomicin Epidemic Same Same  Each hospital  had a different Non-epidemic Same approach to rx   Concomitant abx with fidaxomicin (e.g. all patients =/  Prior CDI Same vs. selected populations) • A and B: Fidaxomicin used first-line for all Fidaxomicin Vancomycin Metronidazole • C, E, F, G: Selected episodes • D: Recurrences only $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 Goldenberg SD et al. Euro J Clin Microbiol and Infect Dis 2016; 35L 251-9. 2013; 57(4): 555-561; Konijeti GG et al., CID 2014; 58:1507-1514. Additional considerations Take-home  Stop unnecessary antibiotics  For mild-moderate disease, can choose metronidazole, more movement towards PO vancomycin in recent years  Shorten antibiotic courses  For severe disease, choose vancomycin  Narrow antibiotic spectrum • Higher cure, but same relapse  Stop acid-suppressive medications when possible  Role of fidaxomicin unclear • Esp PPI  Do not use anti-peristaltic agents until acute symptoms of CDI • Consider if high risk of relapse or need CA improve • ? Use in multiply recurrent disease • ? Role in severe disease 6 3/15/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Treatment scenario #2: You are seeing a 62 y/o F who has takes Risk for recurrent CDI 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 100% her with? 90% A. Metronidazole 500 mg po TID 80% B. Vancomycin 125 mg PO QID 70% C. Vancomycin taper 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 Vancomycin taper 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.  125 mg po 4x daily x 14 days What do you do?  125 mg po 2x daily x 7 days A. Metronidazole 500 mg po TID x 14 days  125 mg po 1x daily x 7 days B. Vancomycin 125 mg PO QID x 14 days  125 mg po every other day x 8 days (4 doses) C. Vancomycin taper  125 mg po every 3 days x 15 days (5 doses) D. Fidaxomicin 200 mg PO BID x 10 days E. Other Kelly and LaMont, N Engl J Med. 2008;359(18):1932-40. 7 3/15/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]