Thamer Abdullah Bin Traiki
• 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
• Type 2 diabetes mellitus, morbid obesity,
congestive heart failure, and severe
• 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.
• There was NO fever .
• But there was cramping lower abdominal
• Stool culture results and microscopy for ova
and parasites were negative.
• Stool enzyme immunoassay (EIA) for C difficile
• Treatment with oral metronidazole was
• However, her diarrhea persisted after 6 days
• The pt then readmitted.
Investigation upon admission :
• WBCs 16
• Hb 10
• MCV 83
• Nucleated RBCs 83%
• Plat 361
• Bands 7%
• U&E were N except urea & creat
• 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
• WBCs repeated 23
• CT showed thickening of the wall of the colon
but NO megacolon or abscess .
• The pt underwent Flex Sig .
Nodular-appearing mucosa with diffuse erythema and marked edema.
The colonic mucosa was friable and bled with biopsy
Large pseudomembranes suggestive of C difficile colitis
• 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.
• Vancomycin enemas were started and treatment with oral
vancomycin and intravenous metronidazole were continued
• 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.
• 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 .
• 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
• 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
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 .
• 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
• 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
• 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
• Systemic manifestations may include dehydration,
prerenal azotemia, sepsis syndrome, toxic colitis, and
even death in seriously ill patients.
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.
• Laboratory tests may demonstrate a marked
elevation in the white blood cell count with a
left shift to immature forms.
C difficile produces 2 protein exotoxins,
toxin A and toxin B, that induce fluid secretion,
inflammation, and apoptosis of intestinal epithelial
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.
• 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.
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
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 .
• 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.
Standard therapy for Clostridium difficile
• 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
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
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
• Not related to bacterial resistance to standard
antimicrobial therapies but “Hypothesis”
• breakdown of the normal flora barrier of the colon after antibiotic
• 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
• previous C difficile diarrhea,
• onset of disease in spring,
• exposure to additional antibiotics for treatment of
• 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
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 .
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.
• 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 .
• In a recent meta analysis, only the probiotic
Saccharomyces boluardi was effective for C
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.
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.
• 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.
• 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