AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Pseudomembranous colitis is an inflammatory disease of the colon that has changed in the last 100 years from a fatal disease caused by a postoperative event. In the era of antibiotics, it is a commonly occurring complication of antibiotic use that may lead to serious morbidity but usually is treated easily.

• In the late 1800s, prior to the availability of antibiotics, Finney reported the first case of pseudomembranous colitis, calling it "diphtheritic colitis."¹
• Hall and O'Toole first described Clostridium difficile in 1935.²
• C difficile was first implicated as a causative factor in pseudomembranous colitis in the 1970s.

Problem

Pseudomembranous colitis is an acute inflammatory disease of the colon that in mild cases may appear as minimal inflammation or edema of the colonic mucosa. In more severe cases, the mucosa often is covered with loosely adherent nodular or diffuse exudates. These raised exudative plaques are 2-5 mm in size. Coalescence of these plaques generates an endoscopic appearance of yellowish pseudomembranes lining the colonic mucosa.

Frequency

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. Similar numbers were found in debilitated patients and in patients who received 1 dose of prophylactic antibiotics before surgical procedure.

C difficile is an unusual component of healthy bowel flora. It is found in 3-5% of healthy adults; however, as many as 50% of infants and young adults harbor both the bacteria and its toxins. Pseudomembranous colitis is a surprisingly rare disease in infants and young children—a population recognized as frequent asymptomatic colonizers. The low incidence of colitis in the pediatric population is attributed to the strength of the immune system. Antibodies to C difficile frequently are detected in infected young patients.

Twenty-five percent of human C difficile isolates are nontoxigenic. C difficile colitis is the fourth most common nosocomial disease reported to the Centers for Disease Control and Prevention. C difficile is one of the most frequently isolated enteric pathogens, second only to Campylobacter jejuni.

High-risk populations include elderly people, patients in the intensive care unit (ICU), people with uremia, people with burns, people undergoing abdominal surgery, people undergoing cesarean delivery, and cancer patients. One suggestion is that these patients do not have greater susceptibility to the disease but are at heightened risk of nosocomial infection. C difficile can be transmitted nosocomially, via the hands of personnel or by contaminated objects. It can survive in spore form for as long as 5 months on hospital floors.

For prevention, use antibiotics prudently. Wash hands and use examination gloves routinely. Clean potentially contaminated surfaces. Use glutaraldehyde disinfection of instruments that come into contact with gastrointestinal secretions. Enteric isolation of patients at risk is recommended. Treatment of asymptomatic carriers is not recommended because treatment may prolong carriage, which usually resolves spontaneously.

Etiology

• Pseudomembranous colitis usually is associated with antibiotic use, which may alter the balance of normal gut flora and allow overgrowth of certain organisms.
• C difficile, a gram-positive, spore-forming, anaerobic bacillus, is isolated in almost all of these cases.
• Clindamycin, lincomycin, ampicillin, or cephalosporin has been implicated in most of the reported cases, but any antimicrobial agent (including antifungal, antiviral, and metronidazole) could incite the disease, regardless of the amount administered or the route of administration.
• Rare cases have been related to Staphylococcus aureus, Salmonella species, Clostridium perfringens, Yersinia species, Shigella species, Campylobacter species, cytomegalovirus, Entamoeba histolytica, and Listeria species.
• Conditions other than antimicrobial administration could predispose to C difficile pseudomembranous colitis. Such conditions include bowel ischemia, recent bowel surgery, uremia, dietary change, change in bowel motility, malnutrition, chemotherapy, shock, and Hirschsprung disease.

Pathophysiology

The antibiotic-induced change in the balance of normal gut flora allows overgrowth of C difficile. Colitis results from the bacterial production of large amount of toxins. The most important toxins are toxin A (enterotoxin) and toxin B (cytotoxin). One theory explains the variable severity of clinical disease through differential production rates of one or the other toxin by selected bacterial isolates. Most experts, however, believe that these variations are due to host factors.

The toxins bind to the mucosa, attack the membranes and the microfilaments of the mucosal cells, and subsequently result in cytoplasmic contraction, hemorrhage, inflammation, cellular necrosis, and protein loss. They also interfere with mucosal protein synthesis, stimulate granulocyte chemotaxis, and increase both capillary permeability and intestinal myoelectric responses and peristalsis. Intestinal tissue invasion by C difficile has been reported in fatal cases of pseudomembranous colitis in pediatrics patients with hematologic malignancy.

Clinical

• Symptoms may not begin until a few weeks after discontinuation of the antibiotic.
• Symptoms range from loose stool in the mildest cases to toxic megacolon (fever, nausea, vomiting, and ileus) and colonic perforation (rigid abdomen and rebound tenderness) in the most severe cases.
• Symptoms include the following:
  • Profuse, watery or mucoid, green, foul-smelling, liquid stool may contain small amounts of blood.
  • Cramping abdominal pain may occur.
  • Temperature may reach 103-105°F.
  • Extraintestinal manifestations of oligoarthritis and iridocyclitis are extremely rare.
• One day to 6 weeks may elapse between starting the antibiotic and the beginning of the clinical symptoms. In most cases, however, symptoms begin 3-9 days after starting the antibiotics.
• In some cases (5-19%), the disease is localized to the cecum and the proximal colon. These patients may present with acute abdomen and localized rebound tenderness in the right lower quadrant but no diarrhea. When facing such a clinical presentation, considering this diagnosis and confirming it with stool studies (stool cytology results might be negative for C difficile toxins) and CT scan may help avoid unnecessary surgery.
• C difficile colitis should be suspected in infants and children with Hirschsprung disease when it is complicated by enterocolitis. These cases require special attention because they often are associated with high risk.

Differential diagnosis

• Staphylococcal enterocolitis and typhlitis: These are diseases that were more prevalent before the advent of new antibiotics that caused an etiologic shift favoring the emergence of C difficile. Currently, these entities are observed in patients receiving chemotherapy who may present with clinical symptoms similar to those of C difficile colitis. These diagnoses should be suspected when gram-positive cocci are identified on Gram stain of stool smear with negative results for C difficile tests and when the terminal ileum is involved in the disease.
• Human immunodeficiency virus: HIV can cause similar inflammatory process.
• Acute exacerbation of Crohn disease and ulcerative colitis: Pseudomembranous colitis could be superimposed infection in these chronic patients. In cases of acute symptoms that do not respond to standard therapy, investigation and therapy for C difficile should be considered, especially when a history of antibiotics exposure is present.
• Chemical colitis: This can occur after chemotherapy and gold exposure.
• Ischemic colitis
• Other bacterial colitis: Colitis may be caused by Campylobacter species, C perfringens, Salmonella species, Shigella species, Escherichia coli, and Yersinia species.

INDICATIONS

Section 3 of 10  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Pseudomembranous colitis usually is associated with antibiotic use. 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. In fulminant or intractable cases, hospitalization for IV hydration will be necessary. Two thirds of patients with toxic megacolon require surgical intervention.

RELEVANT ANATOMY

Section 4 of 10  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Pseudomembranous colitis is an inflammatory disease of the colon. In some cases (5-19%), the disease will be localized to the cecum and the proximal colon.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Lab Studies

• CBC: CBC will reveal leukocytosis with WBC varying from 10,000-50,000/mL.
• Blood chemistry: Hypoalbuminemia is common.
• Fecal leukocytes: Positive tests for fecal leukocytes (3-5 leukocytes per high-power field [HPF]) excludes benign diarrhea; however, a negative result does not exclude colitis.
• Stool culture: Culture of C difficile is relatively demanding, with low predictive value due to the large number of asymptomatic carriers. Many laboratories do not perform this test.
• Stool assay for C difficile toxins (mostly toxin B)
• • This test requires 2 days. It is considered positive when cultured cells undergo cytopathic changes when exposed to stool, and the result then is confirmed by neutralizing these toxins with specific antitoxins.
  • This is the criterion standard test (sensitivity is 95% in patients with antibiotic-induced diarrhea, and sensitivity increases with the severity of the colitis); however, results are negative in 5-10% of patients with endoscopic evidence of pseudomembranous colitis.
• Enzyme-linked immunoabsorbent assay (ELISA) for toxin A: It is less expensive than stool assay for C difficile toxins and is completed in 2.5 hours; however, sensitivity is lower, 75-85%.
• Latex agglutination test: This test has poor sensitivity and specificity.
• Polymerase chain reaction (PCR) is an expensive, highly sensitive test that is currently used only as a research tool in laboratories for detecting C difficile toxin genes in fecal specimens.³
• The enzyme glutamate dehydrogenase is expressed at high levels by all strains of C difficile and is referred to as the common antigen.³ ELISA screening tests that detect this enzyme have been shown to be highly sensitive, simple, and cost-effective. Although none of these screening tests specifically identify toxigenic strains, since the enzyme is produced by toxigenic and nontoxigenic strains, they have negative predictive values of roughly 99%, which support their value for ruling specimens negative for C difficile.³

Imaging Studies

• Plain abdominal x-ray
• • This may show mucosal edema and abnormal haustral pattern.
  • Ileus pattern was described in 28% of the patients.
  • It is useful to rule out toxic megacolon or perforation.
• Air contrast barium enema study
• • It can outline the mucosal abnormalities further; however, these are late and nonspecific findings.
  • This procedure is not recommended because it carries the risk of perforation and may precipitate toxic megacolon.
• CT scan: It may show distension and diffuse and focal thickening of the wall of the colon, along with pericolonic inflammation.
• Nuclear study: Indium-labeled leukocyte scan will show nonspecific inflammation of the colonic mucosa.

Other Tests

• Therapeutic trial
• • The disease is uncommon in infants and young children. They commonly harbor C difficile and its toxins in their stool, which makes it difficult to diagnose the disease in this age group.
  • A therapeutic trial with vancomycin may be the only way to confirm the clinical significance of the positive toxins in the stool.
• Rigid proctosigmoidoscopy
• • This test is diagnostic in 77% of patients.
  • Endoscopic visualization of the pseudomembranes characteristic of the disease is the most rapid and definitive diagnostic method.
  • When the pseudomembranes are manipulated, ulcerated mucosa is uncovered.
  • In early stages of the disease, lesions may be confused with Crohn disease, Behçet disease, and viral colitis.
• Flexible sigmoidoscopy: This procedure is diagnostic in 91% of the patients.
• Colonoscopy
• • This procedure may be required in 10% of the cases where the disease is localized to the cecum or transverse colon with rectal sparing.
  • It is a hazardous procedure in patients with toxic megacolon.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Medical therapy

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.

Vancomycin

It is the most reliable treatment of the disease (response rate in adult men is 90-100%). The risk of developing resistant bacterial strains should be considered. Because oral vancomycin is absorbed poorly, the high stool concentration that is required for the treatment of C difficile can be achieved without systemic side effects. The recommended dose is 125 mg every 6 hours for 7-14 days for adults and 500 mg/1.73 m² every 6 hours for infants. It can be used as therapeutic trial in infants to establish the diagnosis.

Vancomycin 500 mg qid is the treatment of choice for staphylococcal enterocolitis, typhlitis, and severely ill patients with C difficile colitis. In patients who do not improve promptly, reassessment is warranted to make sure that no other diagnosis has been missed. If the diagnosis remains the same, vancomycin should be switched to metronidazole. When parenteral therapy is the only possible treatment due to paralytic ileus, using both vancomycin and metronidazole intravenously, supplemented by vancomycin 500 mg qid via nasogastric tube or by enema, is recommended.

Metronidazole

It is inexpensive, effective treatment for pseudomembranous colitis. It is the preferred first line of treatment, with a response rate of 86-92% when used orally in adult men. It is equal to vancomycin in relapse rate with higher side effect profile. An oral dose of 250 mg qid for 7-10 days is recommended. It is not recommended for children or for women during pregnancy.

Bacitracin

Recommended oral dose is 500-1000 mg qid for 7-19 days. As alternative therapy for symptomatic relief, it is less effective than vancomycin in clearing C difficile from stool.

Teicoplanin

It is a new antibiotic with a recommended oral dose of 100 mg bid. It compares favorably with vancomycin, with a longer half-life that allows less frequent dosage.

Cholestyramine

It contains anion exchange binding resins, which exert their beneficial effect in pseudomembranous colitis by binding C difficile toxins and eliminating these toxins from the colonic lumen. It is used in patients with mild disease and in relapses. The response rate is variable and low in general. The recommended oral dose is 4 g qid. Obstipation is the most common adverse effect. It should not be used simultaneously with vancomycin.

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. Lomotil is especially dangerous in infants.

Restoration of normal flora

In patients with multiple relapses, attempts have been made to recolonize the colon by introducing organisms to suppress C difficile. Some of the results were encouraging. 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.

Steroids

Corticosteroid therapy was reported to be safe and effective in the treatment of severe cases but is not widely recommended.

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.

Follow-up

• 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 (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).

COMPLICATIONS

Section 7 of 10  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

• 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

Section 8 of 10  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

• 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%.

FUTURE AND CONTROVERSIES

Section 9 of 10  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Diagnosis

Polymerase chain reaction has been used to detect the gene sequences for toxins A and B in the stool. It is a fast, sensitive, and specific diagnostic method that still is not available commercially.

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.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

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Article Last Updated: Nov 21, 2007