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Recurrent Clostridium Difficile Associated Diarrhea

Patient Case: Mr. M. 62 yo M with HTN, gout presents with 2-3 weeks of watery diarrhea, 1-2 times dailyT 36.4 HR 75 BP 128/50RR 16General: awake and alert, very pale appearing HEENT: PERRLA, EOMI, dry mm Neck: supple, no JVD, no LAD CV: RRR s1, s2, no murmurs Pulm: CTA-B Abd: bs, soft, mildly distended, suprapubic ttp, no guarding or rebound Ext: trace BLE non-pitting edema Neuro: unable to cooperate with exam 2/2 severe pain.

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Recurrent Clostridium Difficile Associated Diarrhea

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    1. Recurrent Clostridium Difficile Associated Diarrhea Daniel Soberon CQC: December 16, 2008

    2. Patient Case: Mr. M 62 yo M with HTN, gout presents with 2-3 weeks of watery diarrhea, 1-2 times daily T 36.4 HR 75 BP 128/50 RR 16 General: awake and alert, very pale appearing HEENT: PERRLA, EOMI, dry mm Neck: supple, no JVD, no LAD CV: RRR s1, s2, no murmurs Pulm: CTA-B Abd: +bs, soft, mildly distended, +suprapubic ttp, no guarding or rebound Ext: trace BLE non-pitting edema Neuro: unable to cooperate with exam 2/2 severe pain

    3. Mr. M WBC 36.1, Hgb 13.1, Plt 375, 91% segs Na 147, K 4.2, Cl 98, CO2 21, BUN 36, Cr 2.24, Gluc 148, nl AST, nl ALT 2 Bld cx (-), Urine Cx (-), Normal fecal flora, no Ova or parasites, no cryptosporidia, no giardia, normal fecal fats C. Diff toxin A or B (+)

    4. Epidemiology Incidence of CDAD has more than doubled when comparing 1996 to 2005 31/100,000 in 1996 to 84/100,000 in 2005 Epidemics Quebec, 2003: Incidence = 92/100,000 Single strain isolated in IL, GA, ME, NJ, PA, OR Rates of non-response to Metronidazole increased from 2.5% in 2000 to 18.2% in 2005 Recurrence rate of CDAD is 20% after first episode 40% recurrence after second episode > 60% recurrence after third episode NAP-1/027 Strain Increased toxin A + B, fluoroquinolone resistance, binary toxin production

    5. Pathophysiology Obligate anaerobe Gram positive rod, spore forming, Exotoxin producing Toxin A = enterotoxin Toxin B = cytotoxin A + B inactivate cytoskeleton regulatory pathways, GTP signal transduction Increased secretion of electrolytes, mucosal damage

    6. Pathophysiology Normal flora of the gut is polymicrobial Bacteroides , Bacillus, Enterococcus, Clostridia, Mollicutes, including some never isolated Antibiotics alter the gut flora, selecting for C. Difficile. Toxin production causes diarrhea C. Diff causes 15-25% of antibiotic associated diarrhea Notorious antibiotics : Clindamycin, Cephalosporins, Fluoroquinolones, amoxicillin/ampicillin

    7. Toxic Megacolon

    8. Toxic Megacolon

    9. Why do patients get Recurrent CDAD? Resistance to Metronidazole is rare. Resistance to Vancomycin in patients with C. Difficile infection has NOT been reported Recurrent CDAD may be caused by a selection of patients with less protective immunity Patients with non-recurrent CDAD had higher serum levels of anti-toxin A IgM on day #3 and anti-toxin A IgG on day #12 than patients in whom CDAD recurred There exist symptomless carriers of toxigenic C. Diff Data supporting IVIG and toxoid vaccination

    10. Why do patients get Recurrent CDAD? Other possibilities: Relapse, residual spores Re-infection New hyper-virulent strain Other forms of colitis, IBD, IBS, malabsorption Repeating Toxin Assay is NOT test of cure Symptomless carriers Non-toxigenic C. Diff

    11. Solutions

    12. What is Severe CDAD? When should you start off treatment with Vanc? Must have 2 or more of the following: Age > 60 Temp > 38.3o C Albumin < 2.5 mg/dL WBC > 15k Of the “severe” cases, Metronidazole resolved diarrhea in 76%, where Vancomycin resolved 97%

    13. Other Solutions Vanc +Saccharomyces boulardii resulted in less recurrence than vanc + placebo. Lactobacillus was not different from placebo Other abx: Nitazoxanide, Rifaximin chaser, Ramoplanin, Difimicin IVIG Toxoid vaccination resulted in no recurrence, and measureable toxin Ab Tolevamer: high MW polymer that binds toxins A+B in Phase II clinical trial Fecal transplant had 90% success rate

    14. Mr. M 14 days later: C. Diff toxin (-) 16 days later: C. Diff toxin (-) 18 days later: C. Diff toxin (-) Diarrhea persisted despite 21 days of Metronidazole. Vanc started ENDOSCOPIC IMPRESSION on Day #26: Nonspecific colitis, likely from C.diff, may be resolving Small ulcers and raised areas covered with exudate from the cecum to the descending colon Edematous sigmoid colon Normal appearing terminal s/p biopsies Biopsies of right and left colon and rectum for viral and C.diff culture

    15. SMALL BOWEL, TERMINAL ILEUM;BIOPSY: (SPECIMEN A) FRAGMENTS OF SMALL BOWEL WITHOUT SIGNIFICANT PATHOLOGY APPENDIX, APPENDICEAL ORIFICE; BIOPSY: (SPECIMEN B) APPENDIX, APPENDICEAL ORIFICE; BIOPSY: (SPECIMEN B) FRAGMENTS OF COLONIC MUCOSA WITH PATCHY SEVERE ACUTE COLITIS WITH EROSION FRAGMENTS OF ACUTE INFLAMMATORY DEBRIS SUGGESTIVE OF INFLAMMATORY PSEUDOMEMBRANES IMMUNOHISTOCHEMICAL STAIN FOR CMV IS NEGATIVE ILEOCECAL VALVE; BIOPSY: (SPECIMEN C) FRAGMENTS OF COLONIC MUCOSA FOCAL ACUTE COLITIS, EROSION AND INFLAMMATORY DEBRIS IMMUNOHISTOCHEMICAL STAIN FOR CMV IS NEGATIVE COLON, RIGHT; BIOPSY: (SPECIMEN D) FRAGMENTS OF COLONIC MUCOSA WITH FOCAL SEVERE ACUTE COLITIS WITH EROSION HEMATOPATHOLOGY NEGATIVE FOR LYMPHOMA COLON, LEFT; BIOPSY: (SPECIMEN E) FRAGMENTS OF COLONIC MUCOSA WITHOUT SIGNIFICANT PATHOLOGY RECTUM; BIOPSY: (SPECIMEN F) FRAGMENTS OF COLONIC MUCOSA WITHOUT SIGNIFICANT PATHOLOGY Comment: The areas of acute colitis associated with erosions and acute inflammatory debris suggestive an infectious etiology, however the possibility of early ischemic changes can not be entirely ruled out. Pathology Report

    16. Mr. M Switched to PO vanc on hospital day #21 Diarrhea resolved on hospital day #27 = Day 6 of vanc Off to Subacute Rehab!

    17. Works Cited Kelly, C. “Clostridium Difficile – More Difficult Than Ever.” New England Journal of Medicine. Oct 2008; 359: 1932-1940 Johnson, S. “Recurrent Clostridium Difficile Infection: Causality and Therapeutic Approaches.” [Pre-published Manuscript] McDonald et al. “Clostridium Difficile Infection in patients discharged from US short stay hospitals.” Emerg Infect Dis. 2006; 12: 409-415 Pepin et al. “Clostridium Difficile – Associated diarrhea in a region of Quebec from 1991-2003.” CMAJ. 2004; 171: 466-472 Pepin et al. “Increasing risk of relapse after treatment of Clostridium Difficile Colitis in Quebec.” Clin Infect Dis. 2005; 40: 1591-1597 Kyne et al. “Association between antibody response to toxin A and protection against recurrent Clostridium Difficile Diarrhea.” Lancet. 2001; 357: 1189-193 Borody, TJ. “Flora Power– fecal bacteria cure chronic C. difficile diarrhea.” Amer J Gastroenterology. 2000; 95: 3028-3029 Zar et al. “A comparison of vancomycin and metronidazolefor the treatment of Clostridium Difficile Associated Diarrhea, stratified by disease severity. Clin Inf Dis. 2007; 45:302-307 Special thanks to Dr. Stuart Johnson

    18. Questions?

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