Final Diagnosis -- Necrotizing Pseudomembranous Colitis Secondary to Clostridium Difficile Infection



Contributor's Note:

Clostridium difficile is a Gram positive, obligate anaerobic, spore-forming, bacillus. Found in marine sediment, soil, the hospital environment, and feces, it produces two protein toxins (A and B) and a motility altering factor. Toxin A, a 308 kDa protein consisting of 2710 amino acids, is a potent enterotoxin and a weak cytotoxin which causes a proteinaceous fluid response and affects cell viability by disrupting the cytoskeleton. Toxin A also has a chemotactic effect on neutrophils and causes the release of prostaglandins and leukotrienes which contribute to the inflammatory process. Toxin B, a 279 kDa, 2366 amino acid protein, is a cytotoxin.

Up to 50% of neonates have colonizing C. difficile in their intestines but an inherent protection against toxin A. Once the normal intestinal flora is established, C. difficile is not as prevalent. Found in the feces of only 3% of normal adults, it is a very important nosocomial pathogen. Infection by C. difficile may result in an asymptomatic carrier state, mild diarrhea, or at the extreme end of the spectrum, pseudomembranous colitis, a severe colitis which can lead to megacolon, sepsis, and death.

If normal intestinal flora is altered, colonization by toxigenic C. difficile can occur. Most responsible for the alteration of the normal intestinal flora and decreased resistance to C. difficile is the use of antibiotics, especially clindamycin. Other antibiotics associated with C. difficile infection include the amino penicillins, second and third generation cephalosporins, clarithromycin, pristinamycin, and antineoplastic chemotherapeutics with antibiotic activity. Besides antibiotic therapy, other risk factors include prolonged hospitalization or nursing home care (several weeks), old age, and debilitating disease or immunosuppression.

The clinical diagnosis of C. difficile infection is based upon the observation of inflammatory, sometimes bloody, diarrhea, and endoscopic evidence of colitis or pseudomembranous colitis. Endoscopy is useful but detects only 50-55% of pseudomembranous colitis. Histologically, the acute inflammation results in epithelial necrosis overlain by a fibrinous, neutrophilic exudate which forms a mushroom-like lesion. As the necrosis and ulceration spread, larger areas of fibrin, neutrophils, and cellular debris develop forming "pseudomembranes".

Once a clinical diagnosis is suspected, laboratory confirmation is required. The first step in this process involves the collection of an appropriate specimen, specifically a watery, or loose, stool. The ideal laboratory test has not been developed and false negative results do occur. Toxin A and/or Toxin B cytotoxic are the most specific tests, but are time-consuming with a less than optimal sensitivity. Direct detection methods include immunoassays, PCR assays, and methods utilizing molecular probes for the presence of Toxin A. Another method which tests for the clostridial enzyme, glutamate dehydrogenase, is neither sensitive nor specific.

The recommended treatment for Clostridium difficile infection includes: in mild infections, the discontinuance of antibiotics and avoidance of antiodiarrheals; oral metronidazole 250 mg four times a day or oral vancomycin 125 mg four times a day for 7-10 days in moderate infections; and intravenous metronidazole plus oral vancomycin in severe infections. Narcotics and antidiarrheals must be avoided in moderate and severe infections. Relapse after antibiotic treatment does occur, but resistance to metronidazole and vancomycin has not been reported. Novel treatment methods include: the administration of immunoglobulins; the establishment of a microbiological environment less friendly to toxigenic C. difficile with "probiotics" such as nontoxigenic C. difficile or Lactobacillus GG; "bacteriotherapy" with enemas using normal stool flora or other bacteria; and Saccharomyces boulardii, a nonpathogenic yeast. Surgical intervention consisting of colonic diversion or partial to total colectomy is used for patients with sepsis and toxic megacolon or ileus; treatment failure after 48 to 72 hours; or suspected bowel perforation.

The prevention of C. difficile requires the reduction of antibiotic-associated disease by minimizing high dosage, long-term, or combination antibiotic therapy. Reducing disease transmission depends upon isolation of carriers and symptomatic infected patients and minimization of patient-to-patient transmission. Disinfection of all colonoscopy equipment in 2% alkaline glutaraldehyde for 20 minutes destroys clostridial spores.

In this case, the patient was treated with metronidazole after a clinical diagnosis of pseudomembranous colitis was made. His numerous medical problems increased his risk of C. difficile infection and sepsis.


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