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Clostridium difficile infection (CDI)

Clostridium difficile infection (CDI). Jorge A. Gilbert, MD, FACG,AGAF Sanford GI Clinic Associate Clinical Professor of Medicine Sanford School of Medicine University of South Dakota. CDI: Objectives. Changing epidemiology of CDI Diagnosis Risk factors Treatment. CDI: Epidemiology.

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Clostridium difficile infection (CDI)

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  1. Clostridium difficile infection(CDI) Jorge A. Gilbert, MD, FACG,AGAF Sanford GI Clinic Associate Clinical Professor of Medicine Sanford School of Medicine University of South Dakota

  2. CDI: Objectives • Changing epidemiology of CDI • Diagnosis • Risk factors • Treatment

  3. CDI: Epidemiology • 1935: G+, spore-forming anaerobic bacillus • 1978: Pseudomembranous colitis • Leading cuase of diarrhea in healthcare setting, common now in community • Greater incidence, morbidity, mortality • Hypervirulent strains • Use and misuse of antibiotics • Increase of susceptible at-risk populations

  4. CDI: Epidemiology • USA National Hospital Discharge Survey: • 31/100.000 in 1996 • 61/100.000 in 2003 • 2010: • Yearly incidence of 500.000 • Mortality: 15000 – 20.000 • 1 Billion/yr • Ghantoji. J Hosp Infect 2010

  5. CDI: Epidemiology • North American pulse-field-gel electrophoresis, Type1, restriction endonuclease analysis group BI, PCR ribotype 027, (NAP1/BI/027) • Highly resistant to fluoroquinolones • Binary toxin genes • tcd C gene deletion • Large quantities of toxin A &B • >80% of cases in Quebec outbreak (2003) • Confirmed in 40 states in US by 2008

  6. CDI: Epidemiology • Community acquired • No exposure to antibiotics • Severe course • Pregnant women • IBD • cirrhosis

  7. CDI: IBD • Increase in rate: x2 in CD, x3 in CUC • More severe disease • No exposure to antibiotics • Colonic disease • Immunomodulators • No pseudomembranes • Rx: Vanco. Reassesment of immunosupression

  8. CDI: Risk Factors • Age > 65 • Antibiotics – 2 months • Hospitalization • Comorbid/Multiple illness • Immunosuppression

  9. CDI: Diagnosis • Clinical Dx: • Diarrhea +/- abdominal pain, n/v • Current or recent antibiotics • Fever • Leukocytosis • Febrile/Septic picture in a post-op patient

  10. CDI: Diagnosis • Stool tests • EIA for toxins A/B • Rapid • 75% sensitive • Tissue Cxcitotoxicity • >90% sensitive • Takes 24hrs, more expensive • PCR • Rapid, >95% sensitive • Dx test at Sanford Health

  11. CDI: Diagnosis • Colonoscopy/Sigmoidoscopy: • Rarely required • To be done cautiously • Non-specific colitis to pseudomembranous colitis • Rectum and Sigmoid usually but not always involved

  12. CDI: Diagnosis

  13. CDI: Treatment • Mild to moderate disease • Metronidazole: 500mg potidx 10-14 days • Severe disease • Vancomycin: 125mg poqidx 10-14 days • No antiperistaltics • Avoid/Minimize systemic abx • Consider Rx before documentation of Dx if clinical suspicion high

  14. CDI: Severe disease • Fever, chills • Severe abdominal pain, rebound • Severe diarrhea. None if toxic megacolon • Ileus • Shock • Wbc >15k, creatinine >50%, low albumin, high lactate • pseudomembranes

  15. CDI: Severe disease • Treatment • Vancomycin: 250mg or 500mg po QID • Vancomycin enemas: 500mg iv vanco in 100 cc of NS via Foley. Clamp. Q 6hrs • IV Metronidazole, 500mg q 8hrs • Early surgical consultation

  16. CDI: Severe disease. Outcome 161 ICU pts with severe C.diff; 30d mortality 38/161 colectomy: NR to med.Rx, shock, megacolon, perforation Mortality: 58% with medical Rx, 34% surg. Rx Predictors of 30d mortality: -Lactate >5 -wbc >20k -shock/pressors -age > 75 Lamontagne, Ann Surg, 2007

  17. CDI: Severe disease. Outcome • 14 cases managed surgically • Overall mortality 36% • Subtotal colectomy: 11% • L. Hemicolectomy: 100% • Koss, CRD, 2006

  18. Recurrent CDI (RCDI) • First episode: 10-20% • Second episode: 40-60%, yrs • Vicious cycle of abnormal flora • Complex Rx options • No single effective Rx

  19. RCDI: Mechanisms • Impaired immune response • Lower IgG to Toxin A • Vaccinated pts: lower levels of anti-toxin B abs associated with recurrence • Altered fecal flora • Marked change in fecal microbiota in RCDI • Bacteroidetes, Firmicutes • Leav, Vaccine, 2009 • Chang, JID, 2008

  20. RCDI: Risk Factors • Age >65 • Severe /Comorbid underlying illness • Continued use of non-C diff antibiotics • Acid-antisecretory agents (controversial) • Prior appendectomy • A curious connection………

  21. RCDI and the appendyx • Appendyx may protect against C.diff recurrence • Retrospective study, 396 pts, 2005-2007 • Presence or absence of appendyx by Hx or CT • Multivariate analysis of variables associated with recurrence • Age >60 ARR of 2.44 • Appendyx present ARR of 0.398 • Im et al. ClinGastHep. Dec 2011

  22. RCDI: Rx options • Repeat antibiotics: vanco>metro • Pulse/taper vanco • “Rifaximin chaser” • Immune approaches • Probiotics • Fidaxomicin • Restoring normal flora: Fecal Microbiota Transplantation

  23. RCDI:Evolving Rx options • First relapse: Second 14d course of vanco or metro • Second relapse: Prolonged tapering & pulse dose of vanco +/- probiotic • Third relapse: follow vanco Rx with 2wk of rifaximin • INFECTION CONTROL • Kyne. Gut 2001

  24. RCDI: Vancomycin Pulse • Wk1: 125mg qid • Wk2: 125mg bid • Wk3: 125mg daily • Wk4: 125mg qod • Wk5-6: 125mg q3d • Kyne. Gut 2001 • Tedesco. AJG 1985

  25. RCDI: Rifaximin chaser • 7 pts with severe RCDI • 5-7 episodes • Vanco, then 2 wks of rifaximin • 6/7 no further relapses • Later series: 4/6 responded • Not FDA approved for CDI • Johnson. ClinInfDis 2007 • Johnson. Anaerobe 2009

  26. RCDI: Immune approaches • Scattered reports of response to IgG • Limittedeuropean data in vaccines • Research on monoclonal antibodies to Toxin A and B • VonDissel. J Med Micro. 2006 • McPherson. Dis Col Rect. 2006 • Lowy. NEJM. 2010

  27. RCDI: Probiotics • Benefit of S. boulardii • Metaanalyses. Pillai. Cochrane Lib 2008 • With antibiotics • Increasing dose of vanco • L. plantarum • Small trial, benefit (Wullt, SJID, 2003) • L. GG • No benefit in 2 small trials

  28. RCDI: Fidaxomicin • Dificid • Approved by FDA in May 2011 • Macrocyclic, macrolide antibiotic • Inhibits bacterial RNA polymerase • Narrow spectrum, C. diff specific • Minimal absorption, high fecal concentration

  29. RCDI: Fidaxomicin • 2 phase III randomized studies against vanco • >1000 patients • First bout of C.Diff, some with 1 prior bout • Similar rates of cure • Lower rates of recurrence with fidaxomicin • No difference in recurrence in NAP1/BI/027 • In SD area, 2 wk course of Rx • Metro: $40 • Vanco capsules: $1500 • Vanco liquid: $51 • Fidaxomicin (200mg bid): $4700

  30. RCDI: Restoring Normal Flora • Fecal Microbiota transplantation (FMT) • Old practice in veterinary world • Trasfaunation • Equine diarrhea • 1958: First human report of 4 pts with severe pseudomembranous colitis • 1983: First documented case of succesful Rx of RCDI with FMT • Scattered reports, different routes, controversies and health concerns

  31. RCDI: FMT • Increasing clinical evidence of success • Greater acceptance by GI/ID communities • 16S rRNA-encoding gene clone libraries of pts with CDI, RCDI, controls • Bacteroidetes and Firmicutes dominant bacterial phyla in the colon of controls and pts with first CDI • RCDI pts: marked decrease in normal phyla and rich in others such as Vellonella, Clostridium, Lactobacillus, Streptococcus, Erysipelothrix-like bacteria • Restoration of normal phyla after FMT • Chang.JInf Ds. 2008. Khorus. J ClinGast 2010

  32. RCDI: FMT • 77 elderly pts, colonoscopic FMT • RCDI for 11 months • >90% success, f/up 17 months • >53% “would do it again” as first Rx option • Response in 6 days • 8/30pts(27%) who needed an antibiotic had recurrence • Mellow. ACG Meeting, Washington DC, Oct 2011

  33. CDI: FMT • Sanford Clinic protocol • Approved by Clinical Practice Committee • Open-label • Colonoscopic delivery • Patients with at least 3 bouts of C. diff. or 2 bouts with significant morbidity • May consider in acutely ill patients (fulminantC.diff) deemed not surgical candidates

  34. Clinical Presentation and Diagnosis of Clostridium difficile Infection (CDI)a

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