Objectives Recognize patients at risk for C. difficile infection (CDI) Clostridium difficile infections Contrast diagnostic testing for CDI Describe treatment strategies for mild, severe, and fulminant CDI and fecal transplant Devise a treatment approach to recurrent and relapsed CDI List current and emerging strategies to prevent CDI Peter Chin-Hong, MD, MAS Professor, University of California, San Francisco Special thanks to: Sarah Doernberg, MD, MAS Outline One of CDC’s 3 “Urgent Threats” Brief background and epidemiology Diagnosis Management—mild, uncomplicated disease Management—moderate-severe disease 500,000 Management—recurrent/relapsed disease 3.8 billion Management—fulminant disease Prevention https://www.cdc.gov/drugresistance/biggest_threats.html 1 10/10/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
CDI Background Anaerobic, spore-forming gram-positive • < 3% for healthy adults in community bacillus • 20% in hospitalized pts Toxins A + B • up to 50% in LTCF Multiple strains Risk factors: • Epidemic strain ID’d 2004 • Antibiotics • 078 strain • Age Fecal-oral spread • Hospitalization EPIDEMIOLOGY 12% of all HAIs • Acid-suppression, IBD, Tube feeds Carriage of C. difficile • Host immune factors, Chemotherapy Magill SS et al., NEJM 2014 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 10/10/2017 [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 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; 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 Oct;57(8):1103-5 Asians have high CDI-related mortality DIAGNOSIS Mao EJ, Kelly CR, Machan JT. 2015. Racial differences in Clostridium difficile infection rates are attributable to disparities in health care access. Antimicrob Agents Chemother 59:6283–6287 3 10/10/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
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. What is wrong with this picture? Overdiagnosis 63 year old Chinese F s/p spinal fusion c/b hardware infection. 63 year old Chinese F s/p spinal fusion c/b hardware infection. She received a 6 week course of antibiotics for this and is admitted She received a 6 week course of antibiotics for this and is admitted for redo spinal fusion. She has been constipated and has daily for redo spinal fusion. She has been constipated and has daily orders for senna, colace and miralax. orders for senna, colace and miralax . On HD# 8, she develops 2 loose stools and tests positive for C. 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 difficile. She is afebrile with a normal WBC and is started on PO metronidazole. She has no further episodes of loose stools during metronidazole. She has no further episodes of loose stools during the remainder of hospitalization. the remainder of hospitalization. 4 10/10/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Treatment scenario #1. 73 y/o Filipina 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 TREATMENT 5 10/10/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
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 • 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 Zar F A et al. Clin Infect Dis. 2007;45:302-307; Cohen et al., Infection Control and Hospital Epidemiology, 2010; 31: 431-455 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, any Strain severity Epidemic Same Same • Any severity: 0.86; 95% CI, 0.74 to 0.98; Non-epidemic Same • Severe CDI: 0.79; 95% Concomitant abx CI, 0.65 to 0.97 =/ Prior CDI Same • NNT to prevent 1 death, 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. 6 10/10/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
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 Treatment scenario #2: 62 y/o Korean male who has takes Risk for recurrent CDI chronic amoxicillin/clavulanic acid for suppression of Enterococcal osteomyelitis and has developed his second bout of C. difficile colitis. His WBC count is 9 and Cr is 0.3. What should you treat 100% him 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 7 10/10/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Vancomycin taper Treatment scenario #3. This patient returns one month after you have treated him 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. Fecal diversity ↑ and abxR ↓ post ↓↓↓ Fecal diversity with rCDI FMT 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- Millan B et al. Clin Infect Dis 2016;62:1479-1486 1002; Bakken JS et al Clin Gastroenterol Hepatol 2011; 9: 1044-49 8 10/10/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
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