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									  Clostridium difficile
Associated Disease: The
    New Epidemic
Walter J. Coyle, MD, FACP, FACG
           Lecture Outline
   History and background
       Emerging epidemic
   Pathophysiology
   Risk factors and Clinical Presentation
   Diagnosis
   Treatment
   New horizons
C. diff on microvilli
   Entity described in 1935 by Hall and O’Toole
   C. diff associated with disease in 1978 with clindamycin-
    associated diarrhea
      Larson et al described toxin in stool of affected
   Difficult to define disease because of problems with
    culture techniques and description as a commensal
    organism (found in healthy neonates)
   Discovery of stool toxins defined pathophysiology

                    NEJM 1978;298     Ann Intern Med 2006;145
   Well known entity for years
   Easily diagnosed
   Responsive to treatment
       Known relapse rate
   Essentially a “nuisance” infection with known
    risk factors
   Epidemiology has now changed…
           The New Epidemic
   First reported increased frequency and severity
    in Quebec, Canada
   From 1991-2003, 4 fold rise in incidence (10
    fold for > 65 yo)
     Increased hospitalizations (from 3-43 per 1000)
     More complications: megacolon, need for
      colectomy, shock and death
     Increased mortality (16%)

                    NEJM 2005;353    CMAJ 2004;171
           The New Epidemic

   Similar increases noted in US
   From 1996-2003, >2 fold rise in reports (82,000
    cases to 178,000 cases; by ICD codes )
      Most reports from 6 Northeast states

      Increase severity also noted: including
       megacolon, need for surgery, shock and death

              NEJM 2005;353    Ann Intern Med 2006;145
           The New Epidemic

   Most severe disease associated with a new
    strain of C. difficile
   Issues of resistance and recurrence noted.
   Risk factors expanding from “classic”

             NEJM 2005;353    Ann Intern Med 2006;145
 Colonization, alteration of flora, organism
  growth and toxin elaboration
 Toxin A –
     enterotoxin-causes tissue damage and fluid
      secretion, inflammation
     Not necessary for virulence
     Less potent than B

   Cytotoxin B 1000X more potent than A
       Activate release of cytotoxins from monocytes
   Type I-patchy epithelial
    necrosis with fibrin/polys
   Type II-prominent
    exudate as “summit
    lesion” from ulcer
   Type III-diffuse
    necrosis/ulceration with
    composed of neutrophils,
    fibrin, mucin, cellular
                  Risk Factors
   Classic factors were exposure to antibiotics,
    advanced age, hospitalization, and GI surgery or
     Initially, clindamycin, ampicillin or amoxacillin
     Then cephalosporins, Augmentin, quinolones

     20 fold rise in risk with aging

     20-40% colonization in inpatients (vs 2-3%)

                   Clin Infec Dis 1998;26 NEJM 1989;320
               New Risk Factors
   Inflammatory bowel disease (3.6 X, ARR)
   Acid suppressive agents
     H2-blockers (2.0 X, ARR)
     PPIs (2.9 X, ARR)

   Exposure to antibiotics not seen as frequently
       3.1 X , ARR
   Immunosuppression/chemotherapy
   Age >65, ARR 16.3 ; CRF: 3.7X, ARR

                       JAMA 2005; 294:2989-2995
Clinical presentation: Traditional
   Almost always diarrhea
       Rarely hematochezia
   Cramps, fever, malaise, anorexia
   Ileus
   Advanced disease has pseudomembranes
       Nearly pathonogmonic of CDAD
    Clinical presentation: Epidemic

   Similar to old cases but more severe
     More toxic megacolon (less diarrhea)
     Profound leukemoid reactions

     Severe hypoalbuminemia (PLE)

     Septic shock

     Need for colectomy

     Increased mortality

                         Ann Intern Med 2006;245
        The New Strain: Epidemic
   New strain identified from Quebec and
    Northeast US outbreaks
   BI / NAP1 : 5 unique features
     High levels of both A and B toxin
     A is Toxinotype III (most strains are 0)

     Deletion of gene tcdA

     Binary toxin produced (seen in C perfringens)

     Resistance to quinolones

            Lancet 2005;366 Ann Intern Med 2006;245
                      Diagnosis: Lab
   Elevated serum WBC and usually fecal WBC
   Culture (with strain identification)
       Difficult, not routine for most labs
   Detection of toxin remains the mainstay of dx
       Tissue culture assay (only B toxin)
            Spec 99-100% Sens 80-90%
       Enzyme immunoassay (can detect A and B)
            Spec 95-100% Sens 65-85%
            Most widely available test
       PCR detection of toxin (not well standardized)
            Spec 100% Sens 92-97%
   Need multiple samples to adjust for instability/poor samples

                             J Clin Micro 2005;43 J Clin Micro 2006;44
Diagnostic tests

     J Clin Micro 2005;43 J Clin Micro 2006;44
         Diagnostic Tests: Rads
   Do not forget the KUB
   Not everyone who has belly pain needs a CT of
   KUB
     ileus vs toxic megacolon
     Perforation, thumbprinting
       Radiologic Findings: CT
   CT-nonspecific ”thumbprinting” of mucosa
    suggesting edema
   Wall thickening
   Fat stranding
   Severe cases: ascites
   Perforation
CT Appearance
         Diagnosis: Endoscopic

   Normal to patchy, nonspecific colitis to
    inflamed mucosa studded with adherent raised
    white and yellow plaques 2-10mm
   May be confined to proximal colon
   Caution: Avoid endoscopy in patients with
    fulminant colitis due to risk of megacolon and
Endoscopic Appearance
More endoscopic images
   DC offending antibiotic (s) if possible
   Avoid antiperistaltic agents (incl narcs)
   Supportive care (hydrate, electrolytes)
   Antimicrobial therapy:
     Oral metronidazole: 250 mg qid or 500 mg TID for
      10 days; low cost, effective
     Oral Vancomycin: 125-250 mg QID for 10 days
           High cost

                           Ann Intern Med 2006;145
   Oral metronidazole vs Vancomycin:
     Vanc is the only FDA approved Rx
     Metro preferred by IDSA, CDC, SHEA

     Metro cheaper than Vanco

     Vanc more effective in some studies

     Vanc active against all strain; some metro resistance
      seen in vitro now
   Sicker patients should get vancomycin
                               Ann Intern Med 2006;145
        The New Strain: Treatment
   Cannot identify new strain at this time
     Only research labs
     Suspect if epidemic or severe case

   Usual Rx as outlined above except:
     Early diagnosis more critical
     Vancomycin may have an advantage
           Preferred drug in any patient with severe C diff or slow
            response to therapy

                       Lancet 2005;366 Ann Intern Med 2006;245
             Treatment: Surgery
   Indications:
     medical non-responders (decreased motility impairs
      delivery of medication) with severe disease
     colonic perforation
     toxic megacolon
     refractory shock due to abdominal source (surgical
   Subtotal or total colectomy with temporary
    diverting ileostomy: procedure of choice
       Mortality in one study: 45%

            Int Care Med. 2003;29 Ann Intern Med 2006;145
C diff megacolon
   If not tolerating PO
     IV metronidazole (500 mg q6)
     Vancomycin by NG or retention enema (500 mg q6)

     NO IV VANC-not excreted into the colon

     Consider IVIG:
         Retrospective review of 10 (of 228) pts tx with IVIG since
          Nov 2003; 8 were severe, 2 recurrent (4 with megacolon)
         8 responded to IVIG with normal BM in median 8 days

                Dis Colon Rectum 2006;49   Ann Intern Med 2006;145
         Infection Control

 Single room with bathroom
 Barrier precautions

 Hand hygiene with soap and water

 No rectal temps

 Room cleaning with 1:10 bleach
   Hand wash with soap (resist ETOH/antiseptics)
   Contact/enteric precautions
   Probiotics given with abx tx
   Vaccines?
   Tx of asx carriers with vanc or flagyl does NOT
    reduce rate of carriage
   15-30% of patients (20% average)
     Usu by 1 wk (1-8 wks)
     Same symptoms recur

   50% due to re-infection (new strain)
   50% due to relapse
     Abx resistance is rare
     Residual spores

               Gastro 2006;130 Ann Intern Med 2006; 145

   Risk factors: age>65, comorbidities, extra abx
    after tx, poor immune response to toxin A
     Low serum IgG to toxin A may be most important
      risk factor
     May be related to lack of exposure to C diff in

                Gastro 2006;130 Ann Intern Med 2006; 145
C diff spores
          Recurrence: Treatment
   Repeat same dose of same antibiotic: Can use
    same agent; not resistance
       Rare reported cases of added rifampin
 Taper and pulse metronidazole or vancomycin
 Add Anion-binding resins:
     Cholestyramine 4g tid
     Colestipol 5g q 12 hours

     Best evidence for use with pulse therapy.
                 Gastro 2006;130 Ann Intern Med 2006; 145
         Recurrence: Treatment
   Probiotics
      Saccharomyces boulardii: 500 mg bid for 4-6 weeks

         Best evidence of all probiotics

         Several DB / PC trials show good efficacy

      Lactobacilli: 1 g qid for 4-6 weeks

         Evidence not as convincing

      PO nontoxicogenic C Diff: experimental

         Effective but only case reports to date

                 Gastro 2006;130 Ann Intern Med 2006; 145
        Recurrence: Treatment
   Stool transplants: “prepared” feces by NGT or
      Usually family member; 30-50 g fresh stool

      Case series of 18 refractory C diff patients
        Stool via NG from healthy family member
        15 of 18 became recurrence-free

                 Gastro 2006;130 Clin Infect Dis 2003;36
 Coyle’s Corollary

It is better to be
  a stool donor
than a recipient.
Stool donor cards will be
made available after this
               New Horizons
   Tolevamer: Toxin receptor decoy, mimics
    a part of the toxin receptor
     Binds both A and B toxins
     Large human trial underway

   Vaccination: toxoid vaccine
     Good serum response in normal subjects
     Few open label studies; large trial pending

                   Gastro 2004;126 Gastro 2005;128 Gastro
                       New Horizons

   Rifaximin-In vitro; ideal in theory
       Not absorbed by GI tract or inactivated by gastric
       Active entirely in intestinal lumen; broad-spectrum,
        GPR/GNR, anaerobes and aerobes
       MIC superior to metronidazole and vancomycin
       Low incidence of resistant strains
            Actively being studied in severe C diff and recurrent C diff

                        Chemotherapy 2000;46 Ann Intern Med 2006; 145
   CDAD is increasing; mostly due to a new strain
   The disease is more severe and mortality is
       Surgery more often required.
   Prevention and suspicion are the keys to
    controlling the disease
   Vancomycin most effective for severe diseases
    but early detection and treatment are key.
   Recurrence of CDAD can be treated with
    pulsed therapy, toxin binders, and probiotics.
       Role of stool transplants being “explored”.
   IVIG may a role in the critically ill patients.
   Rifaxamin will be used more frequently now
   Tolevamer and vaccination are promising new
    therapies on the horizon.

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