GI Consult: Pseudomembranous Colitis

Who is vulnerable to pseudomembranous colitis and what complications might they develop? How does the clinician determine which diagnostic stool test to order? What are the considerations in choosing between metronidazole and vancomycin? These and other issues are discussed.

By Marc S. Itskowitz, MD, and Paul J. Lebovitz, MD

 
What is pseudomembranous colitis?

Pseudomembranous colitis (PMC) is a toxin-mediated enteric disease caused by Clostridium difficile. It has been increasingly recognized as a serious and sometimes lethal gastrointestinal disease. During the past decade, considerable advances have been made in our understanding of the pathophysiology of diarrhea and colitis caused by C. difficile infection. Nonetheless, this tenacious organism continues to infect millions of patients each year and poses a diagnostic and therapeutic challenge.

Pseudomembranous colitis was first described in 1893 when a patient with severe diarrhea was found to have "diphtheritic colitis" at autopsy. The condition was attributed to mucosal ischemia or viral infection until 1977, when it was reported that stool specimens from affected patients contained a toxin that produced cytopathic changes in tissue-culture cells. Within a year of that report, C. difficile, a spore-forming, gram-positive, anaerobic bacillus, was identified as the source of the cytotoxin.

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. Clindamycin, cephalosporins, and penicillins are the antibiotics most frequently associated with C. difficile diarrhea. Other risk factors for PMC include advanced age, hospitalization, inflammatory bowel disease, chemotherapy, and immunosuppression.
 

What is the clinical presentation of PMC?

Typical features of PMC include watery diarrhea, with as many as 15 to 30 stools per day. Most patients complain of abdominal pain or cramps, and they often have lower quadrant tenderness in association with fever and leukocytosis. Fever may be absent, low-grade, or quite high. The most common extraintestinal manifestation is an oligoarticular, asymmetric, large joint arthropathy. The peripheral leukocyte count is usually in the range of 10,000 to 20,000/mm³, but it may be much higher.

Pseudomembranous colitis causes an enteropathy that results in protein loss in the stool, leading to hypoalbuminemia. Stool examination may show occult blood, but grossly bloody stools are unusual. Microscopic examination for white blood cells is often positive.

Fulminant colitis develops in approximately 1% to 3% of patients. Serious complications include dehydration, electrolyte imbalance, hypotension, hypoalbuminemia with anasarca, and toxic megacolon. Colonic perforation is a rare but devastating complication.
 

What is the pathophysiology of PMC?

The following chain of events results in PMC: a disruption of the normal bacterial flora of the colon, colonization with C. difficile, and release of toxins that cause mucosal damage and inflammation. Antibiotic therapy is the key factor that alters the colonic flora and allows C. difficile to flourish. Antibiotic exposure may be as brief as a preoperative prophylactic dose. Chemotherapy agents that possess antibacterial properties may also result in sufficient disturbance of the intestinal microflora to allow colonization with C. difficile.

First described in 1935, C. difficile survives well in nature and is widely distributed in the environment. It can be cultured from stool in 5% of healthy adults, in 10% to 30% of symptomatic hospital and nursing home patients, and in 30% to 50% of healthy infants. Therefore, the mere presence of C. difficile does not necessarily indicate disease.

At least two toxins are involved in the disease process: toxin A (or enterotoxin) and toxin B (or cytotoxin). Both are heat-labile proteins that activate the release of cytokines from human monocytes. These proinflammatory effects on leukocytes are instrumental in inducing the marked colonic inflammation seen in PMC.
 

What are the pathologic findings in PMC?

Pseudomembranes are present in the intestinal mucosa. On gross inspection, there are multiple elevated yellow-white plaques (see image, below) in PMC, which vary in size from 2 to 20 millimeters. The intervening mucosa appears normal or shows hyperemia and edema. With advanced disease, the pseudomembranes may coalesce and eventually slough, leaving large denuded areas.

Endoscopic evidence. Characteristic raised, adherent, yellow-white plaques are visible on the colonic mucosa in PMC. The intervening mucosa is hyperemic but not ulcerated.

Histologic studies show that the pseudomembrane typically arises from a point of superficial ulceration and is accompanied by an acute or chronic inflammatory infiltrate in the lamina propria. Bacterial invasion of the bowel mucosa by C. difficile does not occur; PMC is a toxin-mediated disease.
 

How does one evaluate a patient with suspected PMC?

Pseudomembranous colitis should be considered in any patient with diarrhea and recent exposure to antimicrobials. The suspicion should be increased if the patient has severe, prolonged diarrhea and leukocytosis.

Stool findings are nonspecific, although patients with pancolitis usually have fecal leukocytes. Radiologic findings are also nonspecific but may be helpful in patients with advanced disease. Plain films of the abdomen may show a markedly edematous and distended colon and distorted haustral markings. Diagnostic accuracy is improved with air-contrast studies, which must be performed with caution because of the potential complication of colonic perforation. Computed tomography (CT) often shows a thickened colon, with evidence of ascites. However, nearly half of patients with PMC have normal CT findings.

Although not usually required for diagnosis, endoscopy may reveal the typical mucosal plaque-like lesions. Since the distal colon is involved in most patients, sigmoidoscopy is usually performed. However, in as many as one third of patients, the lesions are restricted to the right colon, which would require colonoscopy for detection. In general, sigmoidoscopy or colonoscopy should be avoided in fulminant colitis because of the risk of perforation.

The most accurate diagnostic test for C. difficile detection is the cytotoxin assay using tissue-cultured cells (see table, below). Multiple alternative tests are available and are readily used because they can be performed easily, provide quick results, and are cost-effective. The preferred method for most laboratories is enzyme immunoassays (EIA) that can detect toxins A and B. The sensitivity of these tests ranges from 70% to 90%; the specificity, 95% to 100%.

It is useful to test more than one stool specimen for C. difficile toxin. Performing EIA on two or three specimens increases the diagnostic yield by 5% to 10%. Assays for C. difficile toxin are unnecessary immediately after the completion of treatment; the results may be misleading, since about one-third of patients for whom therapy is successful have positive assays.

Polymerase chain reaction (PCR), with the use of specific primers based on the genes for toxins A and B, has been used to detect toxigenic C. difficile. Although this is a highly sensitive and specific test, PCR is laborious and requires an initial culture of C. difficile.
 

What is the treatment for PMC?

Therapy for PMC includes discontinuation of implicated antimicrobial agents, administration of antimicrobial agents directed against C. difficile, and supportive measures. Diarrhea will resolve without specific antimicrobial therapy in 15% to 25% of patients. Supportive measures include intravenous (IV) fluids to correct dehydration and electrolyte imbalance. Nutritional support may be required to correct hypoalbuminemia. Antiperistaltic agents should be avoided because they may delay clearance of toxins from the colon, leading to increased colonic injury, ileus, and toxic dilation.

Antimicrobial options include oral metronidazole or vancomycin for 10 days. Antibiotic treatment should be oral, since C. difficile is restricted to the lumen of the colon. If IV treatment is necessary because the patient cannot tolerate oral medication or a feeding tube, only metronidazole is effective. Vancomycin should not be given intravenously because effective colonic luminal concentrations cannot be attained by this route.

Comparative clinical trials indicate that metronidazole and vancomycin are therapeutically equivalent. Disadvantages of vancomycin are cost and a possible role in promoting growth of vancomycin-resistant Enterococcus faecium. Metronidazole is often favored as first-line therapy because it is less expensive than vancomycin. Indications for oral vancomycin are pregnancy, lactation, intolerance of metronidazole, or failure to respond to metronidazole after three to five days of treatment. Symptomatic improvement can be expected within 72 hours, and diarrhea and colitis resolve completely in more than 95% of patients after 10 days of treatment.

Seriously ill patients who have fulminant or intractable symptoms may require intestinal surgery. The major indications for surgery are failure to respond to medical management, with progressive organ failure, toxic megacolon, or signs of peritonitis. The preferred procedure is a colectomy with a temporary diverting ileostomy.
 

What is the relapse rate in patients treated for PMC?

Clostridium difficile diarrhea recurs in up to 20% of cases. Subsequent relapses may occur in approximately 8% of cases after treatment of the initial relapse. Studies have found variable relapse rates, but comparative trials have shown no difference in incidence based on treatment with metronidazole or vancomycin. The typical clinical pattern is recurrence of diarrhea 3 to 10 days after treatment is discontinued.

Treatment of a relapse is a second course of antimicrobial therapy. There is no clear rationale for using vancomycin as a treatment for a relapse after metronidazole therapy, since the development of antibiotic resistance is not usually the cause of a relapse. Treatment of patients with multiple relapses is controversial; it may include prolonged antibiotic therapy and the administration of other agents, including cholestyramine, lactobacilli, Saccharomyces boulardii, or IV immune globulin. Enemas with human stool have been suggested as a means of reconstituting normal flora, but this approach lacks aesthetic appeal and carries the risk of transmitting infection. (There have also been anecdotal reports of success with yogurt enemas.)
 

What infection control measures are necessary for patients with PMC?

Clostridium difficile is a major nosocomial pathogen. Some hospitals and long-term facilities have reported epidemics of diarrhea caused by this agent. The organism can be cultured from hospital floors, toilets, bedpans, bedding, mops, scales, and furniture, especially in hospital rooms where patients with diarrhea from C. difficile infection have recently been treated. Patients in hospitals or nursing homes who have C. difficile-associated diarrhea should be cared for with enteric precautions, with assiduous attention to prevention of fecal-oral contamination. Extensive handwashing and use of vinyl gloves are important to prevent transmission. It is also desirable to assign patients with early-stage disease to private rooms.
 

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