11. Pseudomembranous Colitis Images

1. Pseudomembranous Pseudomembranous
colitiscolitis
PathophysiologyPathophysiology
Jien Ni ChengJien Ni Cheng

2. •Pseudomembranous colitis (PMC) is a
toxin-mediated enteric disease caused
by Clostridium difficile.
•first described in 1893 when a patient
with severe diarrhea was found to have
"diphtheritic colitis" at autopsy
•Only in 1977 was C. difficile identified
as the causal organism for the cytotoxin
responsible for PMC

3. Clostridium difficile
•survives well in nature and is widely
distributed in the environment
• can be cultured from stool in 5% of
healthy adults
• 10- 30% of symptomatic hospital
and nursing home patients
• 30- 50% of healthy infants.
•Therefore, the mere presence of C.
difficile does not necessarily
indicate disease.

4. Incidence
•Incidence of antibiotic-associated
diarrhea varies from 5-39%
depending on the antibiotic type.
•Pseudomembranous colitis
complicates 10% of the cases of
antibiotic-associated diarrhea.
•C difficile is found in the stool of
15-25% of asymptomatic, antibiotic-
treated, hospitalized adults.

5. •Most cases of PMC over the last three
decades have occurred in association
with antimicrobial therapy. Nearly all
antimicrobial agents have been
implicated in causing PMC
•Most frequently associated
antimicrobials are:
–Clindamycin,
–cephalosporins, and
–penicillins

6. Other risk factors
•advanced age,
• hospitalization,
• inflammatory bowel disease,
•chemotherapy, and
•immunosuppression.

7. Clinical presentation
•watery diarrhea, with as many as 15
to 30 stools per day.
•abdominal pain or cramps (often have
lower quadrant tenderness in
association with fever and
leukocytosis.)
• Fever - absent, low-grade, or quite
high.
•oligoarticular, asymmetric, large joint
arthropathy.(most common
gastrointestinal symptom)

8. •peripheral leukocyte count (10,000 to
20,000/mm3, but it may be much
higher.)
•hypoalbuminemia – due to loss of protein
in the stool

9. •The mucosal surface of the colon seen here is
hyperemic and is partially covered by a yellow-green
exudate. The mucosa itself is not eroded. Broad
spectrum antibiotic usage (such as clindamycin)
and/or immunosuppression allows overgrowth of
bacteria such as Clostridium dificile

12. Pathophysiology
•disruption of the normal bacterial
flora of the colon
• colonization with C. difficile
• release of toxins
• mucosal damage and inflammation.

13. Colonization resistance
•Definition - ability of the normal intestinal
microflora to resist overgrowth by pathogenic
organisms
•Mechanisms- competition for nutrients,
production of bacteriocins and receptor site
competition
•disruption of this barrier effect by
antibiotics or medical procedures decreases
the normal colonization resistance and allows
pathogens to overgrow in the colon
•Broad-spectrum antibiotics that have a grater
impact on normal flora populations are
associated with higher rates of intestinal
disease

14. toxin production by
pathogens
•toxin A (or enterotoxin)
•toxin B (or cytotoxin).
•Both are heat-labile proteins that
activate the release of cytokines
from human monocytes.
•Work in tandem - one disrupting the
cell cytoskeleton and the other
involving the activation of the signal
transduction pathways of the
immune system

15. •Toxins are released by C.difficile and
internalised by endocystosis
•Inactivate rhoA, a protein responsible
for the maintenance of cytoskeleton of
cells
•Widening of junctions of enteroctyes
leading to fluid loss and diarrhea
•Toxin A will cause release of viscous
hemorrhagic fluid like diarrhea

16. attraction of cytokines
•Caused by activation of components of
immune system
•toxins A and B cause mast cell
degranulation, upregulation of leukocyte
adhesion and release of cytokines from
granulocytes
•Toxin A attracts neutrophils and both
toxins stimulate the release of cytokines,
such as interleukin (IL) 1, IL-6, IL-8 and
tumor necrosis factor from human
monocytes
•Both toxins A and B act on mast cells to
release histamine

17. •Both toxins activate phospholipase A2 leading
to calcium influx and the production of
arachidonic acid metabolites. The arachidonic
acid cascade leads to the production of
prostaglandins and leukotrienes
•Prostaglandins and leukotrienes produce
increased blood flow in local capillary beds
and an increase in capillary permeability.
Prostaglandins can also induce chemokinesis
and cellular infiltration by phagocytes
•release of leukocytes, mucin, fibrin and
cellular debris results in the formation of a
pseudomembrane.

18. neurologic interactions
•toxin A has been found to increase
myoelectric activity before causing
mucosal damage in rabbit colonic loop
models
•The interaction between and the
intestinal disease is still not
understood fully

19. Medical Treatment
•In mild or moderate cases, supportive
therapy alone is sufficient. This includes
discontinuing or changing the offending
antibiotics, avoiding narcotics and
antidiarrheal agents, maintaining fluid and
electrolyte intake, and enteric isolation.
• Most patients, 75% of symptomatic
patients and 25% of patients with colitis,
will experience complete recovery within
10 days. In fulminant or intractable cases,
hospitalization for IV hydration will be
necessary.

20. •Oral treatment with antimicrobial agents
effective against C difficile is the preferred
treatment. No reliable parenteral treatment
for pseudomembranous colitis exists.
•In elderly patients and in severely ill patients,
empirical antibiotic treatment should be
started when the diagnosis is suspected.
•In severe cases, in cases where supportive
therapy fails, and in cases where the
offending antibiotic cannot be discontinued, a
short course (7-10 d) of specific antibiotic
therapy should be administered along with the
supportive therapy, and the offending
antibiotic should be changed to another
appropriate agent when possible.
•Recurrent diseases respond well to re-
treatment with vancomycin.

21. •In cases with multiple recurrences, a few
suggested therapeutic regimens exist. A long
course of oral antibiotic (4-6 wk) may be
administered, followed by gradual tapering, or
pulsing, of vancomycin (125 mg qid for 1 wk,
125 mg bid for 1 wk, 125 mg qd for 1 wk, or
125 mg qod for 1 wk; followed by 125 mg q72h
for 2 wk).
• Another suggested regimen is administering
5-7 days of intermittent antibiotic treatment
periods alternating with periods off
antibiotics. Treatment with a combination of
vancomycin and rifampin was reported to be
successful in some cases.

22. •Antidiarrheal agents - Antiperistaltic drugs
should be avoided. They may provide temporary
symptomatic relief, but they may protract the
disease by prolonging the mucosal exposure to
the bacterial toxins, resulting in more severe
colonic damage. Postoperative narcotics may play
a similar role.
•Restoration of normal flora - In patients with
multiple relapses, attempts have been made to
recolonize the colon by introducing organisms to
suppress C difficile. Oral Lactobacillus GG has
been used. Enema with feces from healthy
person, though it carries the risk of disease
transmission, also has been used. Oral
nonpathogenic yeast, such as Saccharomyces
boulardii, also has been used effectively in
treatment of multiple relapses.

23. Surgical Therapy
•Two thirds of patients with toxic megacolon require surgical
intervention.
•Diverting ileostomy or resection of diseased bowel (subtotal
colectomy)
–This was necessary treatment before antibiotic therapy was
available.
–This treatment currently is used only as a life-saving measure,
such as in cases of perforated cecum or toxic megacolon.
•Colostomy or ileostomy
–This approach is used rarely for direct instillation of antibiotic
into the colon lumen in patients with paralytic ileus.
–Pseudomembranous colitis could be the cause of early
dysfunction of the colostomy.
–Ileal involvement in the disease has been reported as a
complication of ileostomy.
•Early subtotal colectomy: It is advocated by some surgeons in
fulminant toxic cases that do not respond after a week of
intensive medical therapy because the risk of perforation
increases after 7 days of ineffective medical therapy.

24. Follow up care
•Many patients remain asymptomatic
carriers for C difficile, and most of them
never relapse.
•Ten percent to 20% of all treated patients
will have a relapse regardless of the
therapeutic agent used. This could be due
either to germination of spores or
reinfection. Response to re-treatment
with vancomycin usually is favorable.
•In patients with multiple symptomatic
relapses, vancomycin pulsing is
recommended

25. Complications
•Hypovolemic shock, dehydration, and
electrolytes depletion may occur.
•Hypoproteinemia as a result of
protein-losing enteropathy may occur
in patients with prolonged diarrhea.
•Cecal perforation, toxic megacolon,
hemorrhage, and sepsis also can
occur.

26. Outcome and Prognosis
•The overall mortality rate is 2%.
•The mortality rate in untreated
elderly or debilitated patients is
10-20%.
•Even with surgical intervention, the
mortality rate in patients with toxic
megacolon is 35%.

27. •Prevention
•Passive immunization, which has been effective in
animals, may be potentially useful in protecting those
with high risk of acquiring the disease. Immunologic
studies of toxin A, toxin B, and other virulence
factors have led to toxoids that have been used for
the production of antibodies that might be used to
generate a vaccine in this group of patients.
•Treatment
•Therapeutic strategies to inhibit toxin A-induced
colitis are being tested. APAZA, a new compound
consisting of a molecule of 5-aminosalicylic acid linked
to one molecule of 4-aminophenylacetic acid by an azo
bond, has been found to significantly inhibit toxin A-
induced myeloperoxidase activity, luminal fluid
accumulation, and structural damage to the colon
when administered chronically for 5 days in drinking
water.
–Sulfasalazine has been reported to have similar effects.