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]
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