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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

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
CDI: Objectives
  • Changing epidemiology of CDI
  • Diagnosis
  • Risk factors
  • Treatment
cdi epidemiology
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
cdi epidemiology1
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
cdi epidemiology2
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
cdi epidemiology3
CDI: Epidemiology
  • Community acquired
  • No exposure to antibiotics
  • Severe course
      • Pregnant women
      • IBD
      • cirrhosis
cdi ibd
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
cdi risk factors
CDI: Risk Factors
  • Age > 65
  • Antibiotics – 2 months
  • Hospitalization
  • Comorbid/Multiple illness
  • Immunosuppression
cdi diagnosis
CDI: Diagnosis
  • Clinical Dx:
    • Diarrhea +/- abdominal pain, n/v
    • Current or recent antibiotics
    • Fever
    • Leukocytosis
    • Febrile/Septic picture in a post-op patient
cdi diagnosis1
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
cdi diagnosis2
CDI: Diagnosis
  • Colonoscopy/Sigmoidoscopy:
    • Rarely required
    • To be done cautiously
    • Non-specific colitis to pseudomembranous colitis
    • Rectum and Sigmoid usually but not always involved
cdi treatment
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
cdi severe disease
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
cdi severe disease1
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
cdi severe disease outcome
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

cdi severe disease outcome1
CDI: Severe disease. Outcome
  • 14 cases managed surgically
    • Overall mortality 36%
      • Subtotal colectomy: 11%
      • L. Hemicolectomy: 100%
                  • Koss, CRD, 2006
recurrent cdi rcdi
Recurrent CDI (RCDI)
  • First episode: 10-20%
  • Second episode: 40-60%, yrs
  • Vicious cycle of abnormal flora
  • Complex Rx options
  • No single effective Rx
rcdi mechanisms
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
rcdi risk factors
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………
rcdi and the appendyx
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
rcdi rx options
RCDI: Rx options
  • Repeat antibiotics: vanco>metro
  • Pulse/taper vanco
  • “Rifaximin chaser”
  • Immune approaches
  • Probiotics
  • Fidaxomicin
  • Restoring normal flora: Fecal Microbiota Transplantation
rcdi evolving rx options
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
rcdi vancomycin pulse
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
rcdi rifaximin chaser
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
rcdi immune approaches
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
rcdi probiotics
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
rcdi fidaxomicin
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
rcdi fidaxomicin1
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
rcdi restoring normal flora
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
rcdi fmt
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
rcdi fmt1
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
cdi fmt
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