1. GI tract infections in IBD: Detection and treatment of Clostridium difficile, CMV and enteric pathogens: Case studies David G. Binion, MD Bruce E. Sands, MD, MS

2. Case 2: Severe Pouch Inflammation 32 yo woman undergoing a 3 stage colectomy and J pouch reconstruction for refractory ulcerative colitis Diagnosed with UC at age 22, maintained on mesalamine, then worsening of disease 3 years ago. Escalation to immunomodulator and infliximab with no improvement Colectomy for steroid dependent, poorly controlled disease; end ileostomy (6 months earlier). J pouch and diverting loop ileostomy (2 months earlier

3. Case 2: Severe Pouch Inflammation Pt employed as dental hygienist in VA Hospital and domicillary Admitted with 2 weeks of worsening rectal discharge, pelvic and abdominal pain; fevers. Admitted to surgical service Exam –Febrile to 101, tachycardic –Abdomen: distended, hypoactive bowel sounds, tender –Stenosis at the anal cuff/pouch anastomosis

4. Case 2: Severe Pouch Inflammation What diagnostic tests on admission? Pouchoscopy CT scan of abdomen and pelvis

5. Endoscopic appearance of the J pouch and proximal ileum Hamlin P J et al. Postgrad Med J 2004;80:233-235 J pouch with diverting loop ileostomy Ileum above J pouch downstream from diverting loop ileostomy

6. Case 2: Severe Pouch Inflammation J pouch with diverting loop ileostomy (contrast passes into the ostomy) Dilated bowel loops in diverted, downstream small bowel Bowel wall thickening Ascites

7. Case 2: Severe Pouch Inflammation Stool sample sent from pouchoscopy C difficile is detected What are data regarding C difficile infection of small bowel and J pouch?

8. Case 2: Severe Pouch Inflammation C difficile enteritis: An early complication in IBD patients following colectomy Rare but associated with significant morbidity with mortality rates ranging from 60-83% Institutional series of six patients (2004-2006). C difficile enteritis manifested with high volume watery ileostomy output, ileus, fever with leukocytosis. No mortality with prompt diagnosis and therapy Miller, D.L et al. Arch Surg, 1989; 124: p. 1082. Jacobs, A., et al. Medicine, 2001; 80: p. 88-101. Hayetian, F.D., et al. Arch Surg, 2006; 141: p. 97-9. Lundeen S et al. J Gastroentest Surg 2007; 11:138-142 Surawicz C. et al. Am J Gastroenterol 2013; 108: 478-498.

9. Case 2: Severe Pouch Inflammation How can we treat diverted bowel? Oral metronidazole Intravenous metronidazole Oral vancomycin Vancomycin enema Injection of vancomycin into loop ileostomy Intravenous vancomycin Lundeen S et al. J Gastroentest Surg 2007; 11:138-142 Surawicz C. et al. Am J Gastroenterol 2013; 108: 478-498. Zuckerbraun B. et al. Ann Surgery 2011; 254: 423-7.

10. Case 2: Severe Pouch Inflammation How can we treat diverted bowel? Metronidazole is rapidly absorbed and will enter distal GI tract after biliary excretion (normal bowel) Metronidazole in bloodstream will cross into lumen of inflamed mucosa Vancomycin oral delivery will not enter distal, diverted small bowel Vancomycin enema is effective; strictured anal cuff/pouch anastomosis made this initially Injection (lavage) of vancomycin flushes into the afferent limb of loop ileostomy Lundeen S et al. J Gastroentest Surg 2007; 11:138-142 Surawicz C. et al. Am J Gastroenterol 2013; 108: 478-498. Zuckerbraun B. et al. Ann Surgery 2011; 254: 423-7.

11. Case 2: Severe Pouch Inflammation How can we treat diverted bowel? Patient responded to vancomycin flushes into the loop ileostomy Dilation of the anastomotic stricture allowed for vancomycin enema therapy to be initiated Recurrence of C difficile after initial therapy stopped after 2 weeks. Prolonged vancoymcin used until time of the loop ileostomy takedown Lundeen S et al. J Gastroentest Surg 2007; 11:138-142 Surawicz C. et al. Am J Gastroenterol 2013; 108: 478-498. Zuckerbraun B. et al. Ann Surgery 2011; 254: 423-7.

12. Case 2: Severe Pouch Inflammation Long-term results after takedown of diverting ileostomy

13. Case 3: Is this C difficile? 38 yo woman with 10 year history of Crohn’s colitis on azathioprine and adalimumab therapy in durable remission becomes sick with first colitis flare in 4 years. C difficile infection at time of diagnosis. Patient contacts office with complaint of 10 loose bowel movements per day, nocturnal bowel movements, abdominal pain Patient was visiting elderly relative in hospital and long- term care facility over the past month It is Friday afternoon. Stool testing cannot be brought to lab until Monday What should we do?

14. Case 3: Is this C difficile? Oral vancomycin is started – 125 mg four times per day Patient improves over initial 3 days Stool sample is brought in while patient is on therapy, and is negative How accurate is stool analysis if the patient is on therapy?

15. Case 3: Diagnostic Tests for C difficile Gene TargetChemistry/Manufacturer Sensitivity Specificity PPV NPV Gold standard tcdB Prodesse (Gen-Probe Prodesse, Waukesha, WI, USA)77.3 99.2 99.2 99.4 TC tcdB BD GeneOhm (BD Diagnostics, LaJolla, CA, USA)96.4 99.1 99.6 91.4 Composite tcdB Cepheid (Sunnyvale, CA, USA)97.1 93.0 72.3 99.4 CCCNA tcdB BD GeneOhm 88.5 95.4 88.5 95.4 TC tcdB BD GeneOhm 83.6 98.2 89.5 97.1 TC tcdC FRET 86 97 90 96 TC tcdB SYBR green 93.3 97.4 75.7 99.4 Composite tcdB Taqman-FAM 87.1 96.5 60.0 99.2 CCCNA

16. Sunkesula V et al. Clin Infect Dis. 2013;57:494-500 Proportion PCR positive Time to conversion of CDI test to negative while on therapy by treatment (vanco n=20)

17. Case 3: Is this C difficile? Nucleic acid testing for C difficile is a major advance in the laboratory diagnosis of CDI, but it cannot be the basis for withholding therapy in situations where pre-test suspicion is high Once on therapy, sensitivity of PCR based detection of C difficile decreases rapidly Once initiated, commit to treatment. No rationale for retesting for C difficile during initial treatment time period Surawicz C. et al. Am J Gastroenterol 2013; 108: 478-498.

18. What’s new in treatment … Surawicz CM, Brandt LJ, Binion DG et al. Am J Gastroenterol 2013; 108: 478-498.

19. Metronidazole vs. oral vancomycin for C. difficile: Picking your first therapy: Surawicz CM, Brandt LJ, Binion DG et al. Am J Gastroenterol 2013; 108: 478-498.

20. Louie et al. N Engl J Med 364 (5):422-431, 2011. Fidaxomicin and vancomycin for initial C. difficile infection: 30 day recurrence

21. Recurrent C difficile in IBD Prolonged antibiotic therapy (oral vancomycin) Fecal microbiome transplant (FMT) –Associated with IBD flare –Resolution of recurrent CDI in IBD De Leon L, Watson JB, Kelly CR. Clin Gastroenerol Hepatol 2013; 11: 1036-1038. Zainah H, Silverman A. Case Rep Inf Dis 2012; 2012: 810943

22. Case 4: Bloody diarrhea in terminal ileal Crohn’s disease 66 yo woman with 40 year history of Crohn’s ileitis, who had required an ileocectomy 30 year prior is admitted to the hospital with severe bloody diarrhea, tachycardia, dehydration and abdominal pain. No prior history of Crohn’s colitis on colonoscopies. Last colonoscopy performed 2 years prior showed healthy anastomosis, diverticuli. Oral mesalamine maintenance therapy Visits with individuals in hospital and nursing home regularly. Diaper changing of new granddaughter.

23. Case 4: Bloody diarrhea in terminal ileal Crohn’s disease Physical exam obese abdomen, tender to deep palpation. Tachycardic with HR 110 On admission CRP 9.65 mg/dl WBC 20.3, 9% bands What is your differential diagnosis? Which diagnostic tests to perform?

24. Endoscopic appearance of the colon Transverse colon Salmonella enteritidis Source – peanut butter

25. Endoscopic appearance of C difficile infection IBD non-IBD Issa M et al. Clin Gastroenterol Hepatol. 2007;5: 345-51.