Clostridium difficile-associated Diarrhea

					 Case Presentation

Thamer Abdullah Bin Traiki
             Case Presentation

• A 44-year-old woman with a history of
  multiple complicated urinary tract infections
  requiring intermittent hospitalization over the
  previous year was referred with anasarca and
  bloody diarrhea.
• Type 2 diabetes mellitus, morbid obesity,
  congestive heart failure, and severe
  pulmonary hypertension.
                   Cont…
• Two months earlier, the patient had been
  treated sequentially with levofloxacin,
  ceftriaxone, and augmentin for an Escherichia
  coli urinary tract infection.
• Eight weeks after this antibiotic treatment,
  while at a rehabilitation center, frequent
  watery diarrhea developed, with
  approximately 15 watery bowel movements
  per day mixed with blood.
                   Cont…
• There was NO fever .
• But there was cramping lower abdominal
  pain.
• Stool culture results and microscopy for ova
  and parasites were negative.
• Stool enzyme immunoassay (EIA) for C difficile
  was positive.
                   Cont…
• Treatment with oral metronidazole was
  initiated .

• However, her diarrhea persisted after 6 days
  of treatment.
• The pt then readmitted.
                 Cont…
Investigation upon admission :
• WBCs 16
• Hb 10
• MCV 83
• Nucleated RBCs 83%
• Plat 361
• Bands 7%
• U&E were N except urea & creat
                   Cont…
• Treatment with oral vancomycin was initiated
  and oral metronidazole was continued.
• The patient's diarrhea persisted, now 3 weeks
  after initiation of treatment.
• She began to develop worsening pulmonary
  edema and anasarca.
• Oral vancomycin was continued and
  treatment with intravenous metronidazole
  was initiated.
                   Cont…

• WBCs repeated 23

• CT showed thickening of the wall of the colon
  but NO megacolon or abscess .

• The pt underwent Flex Sig .
                           Flex Sig
Nodular-appearing mucosa with diffuse erythema and marked edema.
        The colonic mucosa was friable and bled with biopsy
                      Flex Sig
Large pseudomembranes suggestive of C difficile colitis
                Cont…Pathology

• Biopsies of the descending colon showed microulcerations in
  the epithelium with overlying pseudomembrane (Figure 3).
  There was no evidence of cytomegalovirus infection on biopsy
  or by viral cultures.
                          Cont…
• Vancomycin enemas were started and treatment with oral
  vancomycin and intravenous metronidazole were continued
  without improvement.
• The patient continued to have abdominal pain and now also
  had intermittent low-grade fevers.
• One dose of intravenous immune globulin (IVIG) was
  administered, with an improvement in diarrhea symptoms
  within 36 hours of administration.
• Six weeks after the onset of symptoms, the patient's diarrhea
  has resolved, with normalization of her white blood cell count
  and renal function.
• She has been discharged on a prolonged taper of oral
  vancomycin and a 1-month course of oral metronidazole.
Clostridium difficile-associated
           Diarrhea
            )CDAD(
               Clostridium Difficile
• motile Gram positive rod.
• quite commonly in the faeces of neonates.
• Considered to be normal till the age of 2 years
   because the cells of a newborn's colon are too
  immature to bind the toxins produced by the
  bacteria.     Gastroenterol Clin North Am, 2001 30(3), 753.


• not generally regarded as a normal
  commensal in adults .
                     Cont…
• produces an enterotoxin (toxin A) and a
  cytotoxin (toxin B)

• Clostridium difficile is the leading infectious
  cause of nosocomial diarrhea.
                                  Arch Intern Med. 1996;156:1449-1454.



• can cause life-threatening diarrhea and colitis
                            Cont…
• occurs in about 20% of hospitalized patients
  taking antibiotics .
                                              Arch Intern Med 1986;146(1):95-100

• Most patients treated for this infection
  improve, but about 20% relapse.                  Clin Infect Dis 1997;24(3):324-33


 Relapse is defined as recurrence of symptoms and
  documentation of infection within 2 months of successful
  standard therapy.
 Patients with relapsing C difficile colitis are prone to further
  relapses, each one making eradication more difficult.
       Risk factors for CDAD

C. difficile-associated disease occurs when
the normal intestinal flora is altered,
allowing C. difficile to flourish in the
intestinal tract and produce a toxin that
causes a watery diarrhea .
                     Cont…risk factor
Antimicrobial use,
• C difficile infection has been reported with use of virtually all
  antibiotics and some antiviral and antifungal agents. It most
  commonly occurs with use of the penicillins , ampicillin and
  amoxicillin, the cephalosporins, and clindamycin.

• The prevalence of complicating pseudomembranous colitis
  is variable but can be as great as 10% in patients taking
  clindamycin or lincomycin .
                                               Mayo Clin Proc 2001;76(7):725-30
              Cont…risk factor
• gastrointestinal surgery or manipulation,
• severe underlying disease increases the risk
  of nonoscomial CDAD in hospitalized patients
                         Infect Control Hosp Epidemiol. 2002;23:653-659

• elderly and patients with colonic disease are
  predisposed for the c. diff
• Repeated enemas, prolonged nasogastric tube
  insertion .
                        CDAD
• Symptoms typically occur 7-10 days following
  antibiotic therapy, but have been reported to occur
  as early as on the first day of therapy or as long as 10
  weeks after the completion of therapy.
                                      Med Clin North Am. 1982;66:655-664.

• Frequent bowel movements, abdominal pain, and
  fever.
• Systemic manifestations may include dehydration,
  prerenal azotemia, sepsis syndrome, toxic colitis, and
  even death in seriously ill patients.
                           Cont…
The clinical presentation

• range from an asymptomatic carrier state, to unexplained
  leukocytosis in the absence of diarrhea or to fulminant colitis.
• In subacute cases of infection, hypoalbuminemia results from
  pancolitis, leading to the loss of albumin, which is only
  partially compensated for by hepatic synthesis.
• Host immune factors and the virulence of the C difficile strain
  account for differences in clinical presentation.
                                              Infect Immun. 1991;59:2456-462.
                    Cont…
• Laboratory tests may demonstrate a marked
  elevation in the white blood cell count with a
  left shift to immature forms.
                       Cont…
• Diagnosis
 C difficile produces 2 protein exotoxins,
  toxin A and toxin B, that induce fluid secretion,
  inflammation, and apoptosis of intestinal epithelial
  cells.
 Most C difficile strains that cause disease produce
  both toxin A and toxin B. However, 2% of the isolates
  of C difficile associated with outbreaks are A-B+ (ie,
  toxin A negative, toxin B positive).
                               J Clin Micribiol. 2004;42:1035-1041.
                       Cont…
• Enzyme immunoassay (EIA) for C difficile toxins has a
  sensitivity that ranges from 88%-93%.
                                  Eur J Clin Microbiol Infect Dis. 2007;26:115-11

              ELISA usually detect toxin A

• Stool cytotoxic assay has a significantly higher
  sensitivity for the detection of both toxins, but
  requires 48 hours to perform.
                Cont…
  If the clinical suspicion for C difficile
infection is high and stool EIA is negative,
     initiation of treatment should be
 considered while awaiting the results of
          the stool cytotoxic assay.
    You have to keep in your mind
• Osmotic diarrhea frequently occurs with the use of
  antibiotics.
  This is secondary to the inhibition of colonic microflora that normally
  ferment unabsorbed carbohydrate to short-chain fatty acids that are
  subsequently absorbed by colonic mucosa.
• antibiotic-associated diarrhea not caused by C.Diff.
  e.g.Klebsiella oxytoca infection
  In contrast to CDAD, characterized by 3 or 4 loose bowel movements a day,
  usually without any other systemic complaints. It can be treated
  conservatively by stopping the inciting antibiotic .
                        Treatment
•   Discontinuation of the offending antibiotic .
•   Avoidance of antimotility agents
•   Start oral metronidazole or vancomycin 10-14 days.
•   Earlier studies which demonstrated a 96%
    response rate to metronidzole therapy,
                                        Gastroenterol Clin North Am, 2001 30(3), 753.

• BUT prospective observational study performed in 2005
    by Musher et al involving 207 patients with C difficile
    diarrhea found that 22% continued to have symptoms
    after 10 days of treatment.
                   Cont…
Standard therapy for Clostridium difficile
  infection
• Metronidazole (Flagyl) 250-500 mg PO tid or
  qid X 10-14 days

• Vancomycin HCl (Vancocin, Vancoled) 125 mg
  PO qid X 10-14 days
                       Cont…
Metronidazole is first-line therapy. WHY ?

• Cost as well as concern about antibiotic resistance.
• Can be given orally & parenterally while Vanco can’t
  reach high concentration if given IV
• Development of vancomycin-resistant Enterococcus
  faecium infection .
                                  Am J Infect Control 1995;23(2):87-94
                    Cont…
The indications for oral vancomycin :
• WBCs of (> 20,000 cells/mm3),
• new elevation in serum creatinine,
• toxic megacolon,
• septic shock, or
• if there is failure to respond to metronidazole
  within 48-72 hours.
                                Curr Opin Gastroenterol. 2007; 23:4-9.
          Cont…indication of Vanco

• Patients who are documented to be allergic to
  or intolerant of metronidazole
• Patients receiving warfarin
• Woman who are pregnant or lactating
• Patient with at least 2 recurrent episodes &
  treated with oral metronidazole .
              Causes for Recurrence
• The exact mechanism of recurrent C difficile colitis is
  unclear.
• Not related to bacterial resistance to standard
  antimicrobial therapies but “Hypothesis”
• breakdown of the normal flora barrier of the colon after antibiotic
  treatment.
• Vancomycin and metronidazole kill the vegetative form of C difficile but do
  not kill the spores, which can germinate and eventually produce toxins
• repeated use of antibiotics
      Who Will Have Recurrence?
Fekety and colleagues 1997 studied the
  characteristics of patients with recurrent C
  difficile infection.
• previous C difficile diarrhea,
• onset of disease in spring,
• exposure to additional antibiotics for treatment of
  other infections,
• infection with immunoblot type 1 or type 2 strains of
  C difficile, and
• female sex.
Patients who have one recurrence are
    65% more likely to have further
             recurrences.
      Treatment of Recurrences
Tapering oral antibiotic dose
• The goal of initial treatment is to eliminate the
  bacteria and vegetative spores.
• Tapering the dose of vancomycin or
  metronidazole over 4 to 6 weeks has been
  shown to be effective.
• Tapering the dose works to kill viable C
  difficile bacteria while allowing restoration of
  normal colonic flora .
                   Cont…
What about vanco enemas ?
• A small retrospective case series suggested
  that intracolonic vancomycin (ICV) may be
  effective as adjuvant treatment in patients
  with severe disease.
                                  Clin Infect Dis. 2002;35:690-696.
          PROBIOTIC THERAPY
• to repopulate or restore colonic bacteria as an
  adjunct to antibiotic therapy
                             Am J Gastroenterol 2000;95(1 Suppl):S11-13

• Saccharomyces boulardii is a nonpathogenic
  yeast that releases a protein that interferes
  with the binding of toxin A to its receptor .
                                    Gastroenterology 1993;104:1108-15
                      Cont…
• In a recent meta analysis, only the probiotic
  Saccharomyces boluardi was effective for C
  difficile disease.
                                   Am J Gastroenterol. 2006;101:812-822.




• The administration of S boulardii has been shown to
  be effective both on its own and in combination with
  metronidazole or vancomycin in patients with
  recurrent C difficile infection.
In a randomized placebo-controlled trial ,
S boulardii in combination with vancomycin or
metronidazole reduced the relapse rate by
50% and was well tolerated.
                        Cont…
Is there any role for IV immunoglobulin ?
• Because C difficile colitis is a toxin-mediated disease,
  it has been assumed that immune globulin acts by
  binding and neutralizing toxin but the exact
  mechanism by which IVIG antitoxin binds to toxins A
  and B in the colonic lamina propria or intestinal
  lumen is unclear.
                       Cont…
• In a retrospective review of 14 patients with severe,
  refractory or recurrent C difficile diarrhea who
  received adjunctive treatment with IVIG, 9 (64%)
  responded to treatment .
                                        Dis Colon Rectum. 2006;49:1-6.
Surgery

• Subtotal colectomy
• patients with severe CDAD who fail to respond to
  medical therapy or have signs of systemic toxicity,
  organ failure, or peritonitis.


                                            J Surg. 1998;85:229-231
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