Pseudomembranous colitis Pathophysiology Jien Ni Cheng
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
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.
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.
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:
Other risk factors
inflammatory bowel disease,
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)
peripheral leukocyte count (10,000 to 20,000/mm3, but it may be much higher.)
hypoalbuminemia – due to loss of protein in the stool
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
disruption of the normal bacterial flora of the colon
colonization with C. difficile
release of toxins
mucosal damage and inflammation.
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
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
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
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
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.
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
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.
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.
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.
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.
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.
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
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.
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%.
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.
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.