1. Progress in Diagnosing and Treating Clostridium difficile in IBD patients Alan C. Moss MD, FEBG, FACG, AGAF Associate Professor of Medicine Director of Translational Research

2. Disclosures Consultant; Janssen, Theravance, Bayer, Roche Research Support; Pfizer, NIDDK, Salix, Shire

3. Case - 58 yr. old male patient Extensive ulcerative colitis since 2005 in remission on mesalamine 2.4g/day August 2014 – Diverticulitis Rx antibiotics for 10 days “Flare-up” of colitis; increased mesalamine to 4.8g/d Stool negative for C.difficile Persistent diarrhea, abdominal cramps Rx prednisone 30mg PCR test comes back “positive” for C.difficile Rx Metronidazole

4. Case - Sigmoidoscopy Day 5 of metronidazole; Still having 4-6 stool /day, cramps

5. Clinical Dilemmas with C. difficile Infection (CDI) in IBD  C. difficile PCR test results in patients with IBD  Which antibiotic to use in IBD?  Should I stop the immunosuppressants?  Are fecal transplants safe in treating recurrent C. difficile in patients with IBD?

6. C.difficile Testing in IBD

7. Conundrum of C.difficile infection (CDI) in IBD Active IBD C.difficile Infection Diarrhea Abdominal pain Altered microbiome Elevated calprotectin Endoscopic lesions Diarrhea Abdominal pain Altered microbiome Elevated calprotectin Endoscopic lesions 7% Regnault H, Dig Liver Dis. 2014 Oct 4. pii: S1590-8658 Martinelli M, Inflamm Bowel Dis. 2014 Dec;20(12):2219-25

8. Clinical Specificity of PCR Testing Positive predictive value of PCR test for C.diff.; PPV 42-98% - versus toxigenic culture ‘clinical’ specificity unclear – colonization vs. infection PCR detects <10 pg of genomic DNA Switch from EIA to PCR testing – doubling of “+” results Prevalence of C.diff in 2,500 in-patients with IBD; 4%+ EIA, 5%+ PCR (9%+ EIA, 13%+ PCR in non-IBD) Burnham C, Clin Microbiol Rev. 2013 Jul;26(3):604-30 Shakir F, Gastroenterol Hepatol (N Y). 2012 May;8(5):313-7 Deshpande A, Curr Med Res Opin. 2012 Sep;28(9):1553-60

9. ELISA in PCR+ Stool Samples in IBD Lamouse-Smith, J Pediatr Gastroenterol Nutr. 2013 Sep;57(3):293-7 ? PCR+ / ELISA - samples = colonizers

10. C.difficile Infection Treatment in IBD

11. Antibiotics for Severe C.diff Infection in IBD 114 hospitalized patients with IBD 20 UC patients with severe CDI 65% got vancomycin with / or after metronidazole Not controlled for UC severity Horton A, Antimicrob Agents Chemother. 2014 Sep;58(9):5054-9 Khanna R, Inflamm Bowel Dis. 2013 Sep;19(10):2223-6

12. Suggested Approach to C.difficile Infection (CDI) in IBD Horton A, Antimicrob Agents Chemother. 2014 Sep;58(9):5054-9 Khanna R, Inflamm Bowel Dis. 2013 Sep;19(10):2223-6 Issa M, Clin Gastroenterol Hepatol. 2007 Mar;5(3):345-51. Ananthakrishnan, A, Alim Pharm Ther 2012; 35 (7): 789-795 Determine Disease & Infection Severity* Vancomycin 125mg QID Metronidazole for first infection Non-severe disease Vancomycin 500mg QID ‘Complicated’ disease Vancomycin with taper Fecal transplant Rifaximin / Fidoxamicin Severe disease Recurrent infection

13. What is ‘Severe’ CDI with IBD?* ‘Severe’ IBD with CDI Serum albumin < 3 g/dL Haemoglobin < 9 g/dL Serum creatinine >1.5 mg/dL 3-9 fold greater risk of colectomy or death ‘Severe’ CDI WBC count of >15,000 cells/mm Age >60 years Temperature > 100.9 F Albumin <2.5 mg/dl Pseudomembranes ICU admission Zar F, Clin. Infect. Dis. 45:302–307. doi:10.1086/519265 Ananthakrishnan, A, Alim Pharm Ther 2012; 35 (7): 789-795

14. Could a sigmoidoscopy help? Ben-Horin SJ Crohns Colitis. 2010 Jun;4(2):194-8 Only 13% of patients with CDI and IBD have pseudomembranes

15. Stop or Increase Immunosuppressants during IBD Flares with CDI?

16. Escalate or Stop IBD Treatment in CDI? IBD experts divided on what to do! ECCO retrospective study; 155 hospitalized patients with IBD and CDI 77% Rx metronidazole Risk factors for death, colectomy, megacolon, shock; >2 immunosuppressants during therapy Albumin <2.5mg/dl Ben-Horin S Inflamm Bowel Dis. 2011 Jul;17(7):1540-6 Ben-Horin S, Clin Gastroenterol Hepatol. 2009 Sep;7(9):981-7

17. Case – Follow-Up Metronidazole changed to Vancomycin Albumin 2.1, age >60, CRP 58 Still 4-6BM /day, blood Infliximab 10mg/kg infusion 2-4 BM /day, no blood CRP 10 Discharged on vancomycin taper In remission in office 2 weeks later

18. Thank You