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Prevention and Treatment of Opportunistic Infections in IBD

Prevention and Treatment of Opportunistic Infections in IBD. Mark T. Osterman, MD MSCE Assistant Professor of Medicine University of Pennsylvania. Case #1. 64 year-old man UC pancolon Dx’d age 50 Started Pred / Pentasa without benefit Tried IFX x5 doses without benefit

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Prevention and Treatment of Opportunistic Infections in IBD

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  1. Prevention and Treatment of Opportunistic Infections in IBD Mark T. Osterman, MD MSCE Assistant Professor of Medicine University of Pennsylvania

  2. Case #1 • 64 year-old man • UC pancolon Dx’d age 50 • Started Pred / Pentasa without benefit • Tried IFX x5 doses without benefit • Finally tried IV CsA with much benefit • Transitioned to AZA • Stopped AZA on own after 2y during which he took Colazal 6.75 g/d • Remained on this for 5y

  3. History • Then had flare so started Pred 40 mg/d without benefit • Referred to me and I admitted him • Looked and felt poorly • 15 loose BM/d • Moderate L mid abd pain

  4. Subsequent Course • Treated with PO Vanc 125 mg QID • Tapered Pred • Improved quickly and went home after 5d • Completed 14d of Vanc • Admitted 2mo later with same symptoms as initially • C. diff negative • Stool Cx negative

  5. Colonoscopy

  6. Subsequent Course • Started IV steroids without benefit x 3d • Started IV CsA with much benefit after 2d • Went home after 7d of IV CsA on PO CsA and AZA • Admitted 2mo later with same symptoms and T102 • C. diff positive

  7. Subsequent Course • Held CsA / AZA • Started PO Vanc 500 mg QID + IV MTZ 500 mg Q8h with benefit • Restarted CsA / AZA after 1wk • Started Vanc pulse after 2wk: 500 mg Q3d x 10 doses • Doing well since

  8. Clostridium Difficile Infection (CDI)

  9. Burden of CDI in IBD 1Rodemann JF et al, Clin Gastroenterol Hepatol 2007 2Issa M et al, Clin Gastroenterol Hepatol 2007 3Anathakrishnan AN et al, Gut 2008 4Nguyen GC et al, Am J Gastroenterol 2008 5Ricciardi R et al, Dis Colon Rectum 2009 6Anathakrishnan AN et al, Inflamm Bowel Dis 2011

  10. Clinical Outcome in IBD 1Issa M et al, Clin Gastroenterol Hepatol 2007 2Anathakrishnan AN et al, Gut 2008 3Nguyen GC et al, Am J Gastroenterol 2008 4Ricciardi R et al, Dis Colon Rectum 2009 5Anathakrishnan AN et al, Inflamm Bowel Dis 2011 6Jodorkovsky D et al, Dig Dis Sci 2010 7Jen M-H et al, Aliment Pharmacol Ther 2011

  11. Risk Factors: Gen Population • Exposure (hospital, retirement home) • Duration of hospitalization • Increasing age (especially >65) • Comorbidities (number, severity) • GI surgery • NG feeding • Immune suppression • Ig deficiency McFarland LV et al, N Engl J Med 1989 McFarland LV et al, J Infect Dis 1990 Pepin J et al, CMAJ 2004 Vesteinsdottir I et al, Eur J Clin Microbiol Infect Dis 2012 Surawicz CM et al, Am J Gastroenterol 2013

  12. Risk Factors: Gen Population • Abx • Broad-spectrum, but every abx a/w CDI1 • Short / long exposure, single / multiple1 • Quinolones: up to 1/3 of cases today2 • PPIs 3Janarthanan S et al, Am J Gastroenterol 2012 4Kwok CS et al, Am J Gastroenterol 2012 5Deshpande A et al, Clin Gastroenterol Hepatol 2012 1Cohen SH et al, Infect Control Hosp Epidemiol 2010 2Pepin J et al, Clin Infect Dis 2005

  13. Risk Factors: IBD • UC (vs. CD) • Colonic disease1,2 • Extent of colonic disease (left-sided / extensive vs. distal)3 • Active disease (vs. remission)4 • Comorbidities2 • Hospitalization5,6 and abx use5,7 may be less of a factor than in gen population 1Issa M et al, Clin Gastroenterol Hepatol 2007 2Nguyen GC et al, Am J Gastroenterol 2008 3Powell N et al, Gut 2008 4Pascarella F et al, J Pediatr 2009 5Bossuyt P et al, J Crohns Coliits 2009 6Clayton EM et al, Am J Gastroenterol 2009 7Goodhand JR et al, Aliment Pharmacol Ther 2011

  14. Risk Factors: IBD • IBD meds • Maintenance IM + anti-TNF: OR 2.6 (1.3-5.1)1 • IFX: no increased risk vs. IM2 • Corticosteroids vs. IM2 • Any: RR 3.4 (1.9-6.1) • Monotherapy: RR 2.7 (1.5-4.6) 1Issa M et al, Clin Gastroenterol Hepatol 2007 2Schneeweiss S et al, Aliment Pharmacol Ther 2009

  15. NAP1/BI/027 • Likely in N. America/Europe since 1980s1 • Epidemic outbreaks: US/Quebec 2000s1-3 • High quinolone resistance • ↑ use of quinolones • Severe, recurrent • 16 and 23X more toxin A/B, binary toxin4 • Conflicting data on true severity5 • Severe disease seen with other strains5 • Multiple techniques to type C. diff6 1McDonald LC et al, N Engl J Med 2005 2Loo VG et al, N Engl J Med 2005 3Muto CA et al, Infect Control Hosp Epidemiol 2005 4Warny M et al, Lancet 2005 5Surawicz CM et al, Am J Gastroenterol 2013 6Cohen SH et al, Infect Control Hosp Epidemiol 2010

  16. Diagnosis • Test liquid stool • Do not retest for negative result • Retest positive in <5% • Chance for false positive • Do not retest for cure • EIA and TC often positive 30d after symtoms resolve • Symptoms often identical to IBD • Pseudomembranes often not present Cohen SH et al, Infect Control Hosp Epidemiol 2010 Surawicz CM et al, Am J Gastroenterol 2013

  17. Diagnosis Planche T et al, Lancet Infect Dis 2008 Cohen SH et al, Infect Control Hosp Epidemiol 2010 Shetty N et al, J Hosp Infect 2011 Deshpande A et al, Clin Infect Dis 2011 Peterson LR et al, Am J Clin Pathol 2011 Surawicz CM et al, Am J Gastroenterol 2013

  18. Treatment of Initial Episode Cohen SH et al, Infect Control Hosp Epidemiol 2010 Surawicz CM et al, Am J Gastroenterol 2013

  19. Severe CDI 98 97* 90 *p = 0.02 76 Response (%) 37/41 39/40 29/38 30/31 Mild Severe Zar FA et al, Clin Infect Dis 2007

  20. Severe CDI • Nonstandard dose of MTZ (250 mg QID) • Nonvalidated definition of cure (negative follow-up toxin assay) • MTZ known to be inferior to Vanc for microbiological endpoints • Best outcomes: symptom resolution, recurrence, complications • Definition of mild included many who would be considered severe today Cohen SH et al, Infect Control Hosp Epidemiol 2010 Surawicz CM et al, Am J Gastroenterol 2013

  21. Fidaxomicin 88 86 88 87 *p = 0.005 *p = 0.0002 Patients (%) 27* 25* 15 13 Clinical Cure Recurrence Clinical Cure Recurrence n = 596 n = 509 Louie TJ et al, N Engl J Med 2011 Cornely OA et al, Lancet Infect Dis 2012

  22. Fidaxomicin • Recurrence measured only up to d40 • Need 90d to document strain recurrence • Strain-specific effect implausible • No difference in MIC between NAP1 and non-NAP1 strains • Vanc and Fidax have similar spectra of activity against Gram-positive stool bacteria • 1 Fidax patient with in vitro ↑ MIC • No in vitro resistance to Vanc in Vanc trials Surawicz CM et al, Am J Gastroenterol 2013

  23. Antibiotic Comparison Cohen SH et al, Infect Control Hosp Epidemiol 2010 Surawicz CM et al, Am J Gastroenterol 2013 Louie TJ et al, N Engl J Med 2011

  24. IBD Meds and Clinical Outcome Das R et al, Am J Gastroenterol 2010

  25. IBD Meds and Clinical Outcome • IS + abx vs. abx alone • IS not randomly assigned • 67% required treatment with IS + abx • Death / colectomy / megacolon / perf / shock / resp failure: 12% vs. 0% (p=0.01) • 2-3 IS: OR 17 (3.2-91) but small n • No difference in CDI relapse, hospital stay, death/colecomy within 1 year Ben-Horin S et al, Clin Gastroenterol Hepatol 2009

  26. Recurrent CDI • <8 weeks after completion of treatment1 • 10-20%, but 40-65% after 1 recurrence1 • Same strain or different strain • Risk factors • Continued non-CDI abx: OR 4.2 (2.1 – 8.6)2 • Older age: OR 1.6 (1.1 – 2.4)2 • Antacids: OR 2.2 (1.1 – 4.1)2 • Low level of anti-toxin IgG3 • Altered colon microbiota 1Surawicz CM et al, Am J Gastroenterol 2013 2Garey KW et al, J Hosp Infect 2008 3Kyle L et at, Lancet 2001

  27. Recurrent CDI: Treatment Cohen SH et al, Infect Control Hosp Epidemiol 2010 Surawicz CM et al, Am J Gastroenterol 2013

  28. FMT • Indication • >3 recurrences • Consider for initial episode • Moderate: no response to Vanc after 1wk • Severe: no response after 2d • Donor exclusion • ID: HIV, hepatitis, infx, high-risk behaviors • GI: IBD, IBS, chronic constipation / diarrhea, CA / polyposis • Meds: immunosuppressants, recent abx Bakken JS et al, Clin Gastroenterol Hepatol 2011

  29. FMT • Donor testing • FDA guidelines for cells / tissue / products • Stool: CDI, Crypto/Giardia, Iso/Cyclospora, O&P, Hp (if using UGI route) • Blood: HIV, hepatitis, syphilis • Stool preparation / administration • Use within 6h but up to 24h • Dilute w/ NS / H2O / 4% milk, then blend / filter • Route: N-GDJ-T, EGD, colonoscope (ileum and/or R colon or throughout), enema, pill • Volume: UGI 25-50 mL, colon 250-500 mL Bakken JS et al, Clin Gastroenterol Hepatol 2011

  30. FMT • Nonrandomized outcomes • Short-term • Cure rate: 1° 89-94%, 2° 94-100%1-3 • Time to Sx resolution (mean): diarrhea 5d, pain 10d2 • Effective for NAP13 • Long-term (up to 68 mo)2 • 2/77 had improvement in pre-existing disease: arthritis and allergic sinusitis • 4/77 developed new disease: RA, Sjogren’s, ITP, peripheral neuropathy • No death thought related to FMT 1Gough E et al, Clin Infect Dis 2011 2Brandt LJ et al, Am J Gastroenterol 2012 3Mattila E et al, Gastroenterology 2012

  31. FMT 81* *p <0.001 Patients (%) 31 23 3/13 13/16 4/13 Cure Rate van Nood E et al, N Engl J Med 2013

  32. FMT • Other findings1 • 3 non-responders to FMT had rpt FMT from different donor: 2 were cured • 18 initial non-responders in other groups had off-protocol FMT: 11 cured after 1st FMT, 4 more after 2nd FMT • NIH-funded blinded FMT RCT underway: donor vs. recipient stool via colonoscopy 1van Nood E et al, N Engl J Med 2013

  33. FMT for CDI in IBD 100 94 88 80 Patients (%) 8/10 29/33 10/10 31/33 1° Success 2° Success Hamilton MJ et al, Am J Gastroenterol 2012

  34. Probiotics • Prevention of abx-associated diarrhea1 • Meta-analysis: 25 studies, RR 0.43 (0.31-0.58) • CDI recurrence prevention (with abx)2 1McFarland LV, Am J Gastroenterol 2006 2McFarland LV, Anaerobe 2009

  35. Other Treatments for CDI • IV Tigecycline as rescue for severe • Immunotherapy • IVIG for severe or recurrent • mAb to toxin A/B for recurrent: in phase III trials • Vaccines (containing toxin A/B) for recurrent: in trials • No convincing evidence for Rifaximin or Rifampin for recurrent CDI

  36. Prevention • Infection control • Abx stewardship: can ↓ rate by 60% • Contact precautions: gloves, gown • Gloves (vinyl): can ↓ rate by >80% • Isolation rooms • Disinfection of surfaces: EPA-approved agent • Hand hygiene (soap): ?chlorhexidine needed • Single-use disposable equipment • Hospital-based infection control program: can ↓ rates by 33% during epidemic Cohen SH et al, Infect Control Hosp Epidemiol 2010 Surawicz CM et al, Am J Gastroenterol 2013

  37. Prevention Johnson S et al, Int J Infect Dis 2012

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