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Clostridium difficile Infection and Fecal Microbiota Transplantation

Clostridium difficile Infection and Fecal Microbiota Transplantation. SGNA Meeting, Bend OR October 2013 Harald Schoeppner MD PhD Legacy Health Gastroenterology. Disclosures!. Am J Gastroenterol 2013; 108:478–498; doi:10.1038/ajg.2013.4; published online 26 February 2013

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Clostridium difficile Infection and Fecal Microbiota Transplantation

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  1. Clostridium difficile Infectionand Fecal Microbiota Transplantation SGNA Meeting, Bend OR October 2013 Harald Schoeppner MD PhD Legacy Health Gastroenterology

  2. Disclosures!

  3. Am J Gastroenterol 2013; 108:478–498; doi:10.1038/ajg.2013.4; published online 26 February 2013 Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections Christina M Surawicz MD1, Lawrence J Brandt MD2, David G Binion MD3, Ashwin N Ananthakrishnan MD, MPH4, Scott R Curry MD5, Peter H Gilligan PhD6, Lynne V McFarland PhD7,8, Mark Mellow MD9 and Brian S Zuckerbraun MD10

  4. C. Diff colitis and FMTObjectives • Discuss epidemiology of C. diff infections • Discuss detection, treatment options • Discuss Fecal Microbiota Transplantation • Technique • Results • Legal Elements

  5. Case study • TW: 55 y o male, ETOH, smoker, COPD • Tongue cancer (HPV+) T2N3 2010 • Neoadjuvant tx • Neck dissection, tracheostomy • Non ST MI, PVOD • PEG tube • 8/12 Tracheobronchitis (MRSA/pseudomonas) • Linezolid • Augmentin • Bactrim Admitted 9/22 with 4 days of diarrhea from Rehab facility!

  6. CT images

  7. Costs ($), LOS 32 d • ICU 114.346 • Enterostomal Rx 2.140 • Med Specialties 28.631 • Resp Rx 40.764 • Endoscopy 982 • ED 5.116 • Lab 23.489 • Blood bank 1.030 • Radiology Diagnostic 1.875 • CT scan 6.432 • Rehab 4.017 • Pharmacy 48.858 • IV therapy 3.211 • Food 1.144 • TOTAL 282.159

  8. CDI (C. difficile Infection) Gram positive anaerobe Produces spores Toxins cause disease (A,B) Nosocomial diarrhea

  9. First Case of PMC 22 Y. O. Woman w/ 3 Months N/V Malnourished (Osler) Dilated stomach, with palpable mass Surgery – Pyloric ulcer Rx Post-Op enemas of saline and whiskey Johns Hopkins Hosp. Bull. 1893

  10. Post-Op Course At 10 days , Diarrhea - Tenesmus + blood Died 15 days post-op Autopsy (Councilman) “diphtheritic” colitis, cecitis

  11. Pre-antibiotic Era – Risk Factors Altered gut flora GI tract disease GI surgery Alcohol enemas

  12. Current Risk Factors Age over 65 Abx – 2 months Hospitalization Comorbid – multiple illnesses Immunosuppression Inflammatory bowel disease

  13. C. Diff statistics • Discharge dx 110.553 (2009) • Ca. 500.000/y • 237% Δ (2009)

  14. C diff deaths 2009: I 7251 II 11,319

  15. Since 2000, A New Epidemic of CDI • US, Canada, Quebec, Europe, Japan • Hypervirulent strain • Gene deletion –  toxin production • Quinolone and Clindamycin resistance

  16. Fulminant C. difficile-Associated Disease (CDI) in Pittsburgh 37 severe cases: 28 colectomies; 18 deaths

  17. Risk of CDI According to Antibiotic Class 3.9 4 3.8 3.5 3 2.5 2 Odds Ratio 1.6 1.5 1.3 1 0.5 0 Cephalosporins Fluoroquinolones Clindamycin Macrolides Loo VG, et al. N Engl J Med. 2005;353:2442-2449.

  18. Aggressive Strains in Quebec Onset 2002 3262 cases in 2000 12% mortality 7004 cases in 2003 18% mortality Pepin, Clin Infect Dis 2005

  19. New Epidemic Strain BI Nap 1/027 • More fluoroquinolone resistance Moxi + Gati • Binary toxin Unknown significance • Produces more toxins A + B in vitro tcdC gene deletion

  20. States with the Epidemic Strain of C. difficileConfirmed by CDC(N=38) Updated October, 2008 DC 38 States confirmed by CDC HI PR AK

  21. What About PPI’s? Acid suppression –  CD colonization? Multiple studies - some with association and some with no association Recent systematic review: Acid suppression does  risk of enteric infections and may increase CDI Leonard et al, Am J Gastro 2007

  22. PPIs are associated with C difficile

  23. New Risk Factors Community acquired Pregnant women IBD patients

  24. Community Acquired CDI Is increasing Usually antibotic related, especially multiple Abx Recent Hospitalization 1/2 - no antibiotics 1/3 – no hospitalization or antibiotics Wilcox et al, J Antimicro & Chemo 2005

  25. Severe CDI in Pregnant Women 10 cases - 2005 – 2006 During pregnancy or 1 month peripartum Severe – hospitalized, ICU, colectomy or death Rouphael et al, Antibiotics and ObGyn 2008

  26. Severe CDI in Pregnant Women 10 cases, mean age 28 Prior antibiotics in 9 Outcome • ICU or colectomy 3 Women died 3 Still births • Had epidemic strain Rouphael et al, 2008

  27. CDI Increasing as a Risk Factor in IBD2 Retrospective Studies St. Louis – 3397 IBD pts 1998-2004 CD - doubled -9.522.3 / 1000 admissions UC tripled -18.4 57.6 / 1000 admissions Rodemann et al. Clin Gastro Hep 2005 CDAD rates rose 1.8% (2004) to 4.6% (2006) Issa et al. Clin Gastro Hep 2007

  28. Other Results • Acquired CDAD at home 2/3 St. Louis 3/4 Milwaukee • Associated with quinolone use • *39% - no abx in 2 months • Milwaukee : risks • Immunomodulators • Colon disease

  29. Other Results - IBD Caused more severe disease Colectomy 20% (Milwaukee) More switched to vancomycin No pseudomembranes seen Multiple stool specimens needed

  30. CDI and IBD Patients hospitalized for CDI and IBD compared to only CDI or only IBD Younger (average age 42) More likely to die (4x) In hospital longer (3d) Ananthakrishnan et al, Gut 2007

  31. Severe CDI / PMC

  32. CDI severity scoring SEVERITY CRITERIA Diarrhea + additional signs, not severe or complicated Albumin <3g/dl + WBC > 15.000 Abdominal tenderness Admit to ICU Hypotension + Vasopressors Fever (>38.5C) Ileus MS changes WBC > 35.000 or <2.000 Lactate > 2.2mmol/l End organ failure (RF, resp.) • Mild to moderate • Severe disease • Severe + complicated • Any of listed

  33. PMC Clinical Features High fever !! Abdominal tenderness * High white blood count !! * Low albumin May not have diarrhea with toxic colon

  34. If a patient has strong pre-test suspicion for CDI, empiric Therapy for CDI should be considered, regardless of test results!

  35. Recommendations about Stool Testing Do not test solid stools No need for repeat testing Do not test asymptomatic carriers! Do not test patients after successful treatment

  36. Effective Antibiotics for C. difficile Oral Metronidazole $22 500 mg tid x 14 d Oral Vancomycin $680 125 – 250 mg qid x 14 d FDA approved ($400) Oral Fidaxomicin $2.800 200mg bid FDA approved

  37. Metronidazole Response Rates Fernandez JCG 2004 61/99 62% Musher 161/207 78% CID 2005 Pepin 323/435 74% CID 2005

  38. Why Doesn’t Metronidazole Always Work - Severity of disease Predictors: ↓ albumin, ICU, (Fernandez, JCG 2004) - Continued antibiotics Prospective 27 patients Antibiotics discontinued - 10/10 better Antibiotics continued - 10/17 better (51%) • Probably not resistance to metronidazole Modena, J Clin Gastro 2006

  39. Risk Factors for Fulminant CDI Retrospective – Mt. Sinai, NYC 35 patients / 70 controls Risk for progression: Leukocytosis Surgery w/in 30 d Hx IBD IVIG Rx Greenstein et al, Surgery 2008

  40. Oral VancomycinvsMetronidazolein Mild and Severe Disease Clinical Cure in Severe Disease (n=69) 98 100 100 97 90 90 90 76 80 80 70 70 60 60 50 50 Percent of Patients Percent of Patients 40 40 30 30 20 20 10 10 0 0 P = NS Metronidazole Vancomycin Metronidazole Vancomycin P = 0.02 172 patients enrolled and 150 completed the trial Zar FA, et al. Clin Infect Dis. 2007;45:302-307.

  41. Adjunct Therapy – Small Series IV Metronidazole monotherapy Vancomycin Enemas 500 mg IV vancomycin in 100 ml NS via Foley, clamp 60 min. Repeat q. 6 hrs. Friedenberg, et al, 2001; Apisarnthanarak – Clin Inf Dis 2002 Friedenberg – Dis Col Rect 2001

  42. New Guidelines - Rx of CDI Mild – Moderate Metronidazole PO 500 mg t id or if unable Vanco 125mg Severe Vancomycin PO WBC > 15,000 125 mg q i d Albumin <3g/dl stop other antibiotics, avoid antiperistaltic meds

  43. New Guidelines - Rx of CDI(Cont’d) Complicated + Severe • Ileus • WBC >35k, <2k • Fever >38.5 • MS Δ • Lactate >2.2mmol/l • ICU care • Hypotension/pressors • Vanco 500mg Q 6h • IV Flagyl 500mg Q8h • Rectal Vanco • Surgical consultation • ICU care • DVT prophylaxis !

  44. Indications for Surgery Severe PMC • Increased pain • Septic appearance • Subserosal air • Rising WBC

  45. CT imaging for C. diff • Colon wall thickening • Ascites • “megacolon” • Ileus • Perforation

  46. Colectomy Better than Left Hemicolectomy Retrospective study – 14 cases Indications 10 – systemic toxicity + peritonitis 3 – progressive toxic colon 1 – progressive toxic colon with perforation Mortality 36% - Colectomy 11% - L Hemicolectomy 100% Koss 2006

  47. 161 Patients – Colectomy in 38 Persistent shock 15 NR to med Rx 10 Megacolon 11 Perforation 2 Medical Rx 58% Surgical 34%

  48. Recurrent CDI Recurrent C. difficile disease difficult to treat months  years One recurrence (20%)  more very likely (45 - 65%) Repeat abx are necessary No single effective treatment

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