Clostridium difficile can cause a wide spectrum of conditions, from an asymptomatic carrier state to diarrhea without colitis to C. difficile-associated colitis (CDC).

What are the risk factors for CDC?

Although antibiotic-associated colitis can result from pathogens such as Salmonella, Clostridium perfringens type A, and Staphylococcus aureus, C. difficile has been implicated in 50% to 75% of antibiotic-associated colitis, with 90% of those cases being of the more serious pseudomembranous type. Clostridium difficile colitis is one of the most common nosocomial infections, resulting in much morbidity and mortality. The patients most susceptible to CDC are those who are elderly or debilitated (especially hospitalized patients), have been exposed to multiple antibiotics, have had gastrointestinal surgery, or are severely ill on hospital admission.

In addition, proton pump inhibitors appear to increase the risk of acquiring CDC by reducing the acid concentration in the stomach and allowing the organism to pass unharmed into the intestine. Patient-to-patient transmission increases the risk of acquiring CDC. Patients with an infected roommate are more likely to get CDC than patients without an infected roommate. Transmission of infection by hospital personnel contaminated with C. difficile is possible but preventable by using disposable gloves and washing hands thoroughly after examining patients.

The initial event leading to CDC is the disturbance of the normal colonic microflora by antibiotic therapy. The antibiotics that predispose to CDC are listed in the table below. With the alteration of colonic microflora, there is subsequent exposure to and colonization of C. difficile, a gram-positive anaerobic organism. Once colonized, pathogenic strains of C. difficile release toxins that cause mucosal inflammation and damage. The two distinct toxins are toxin A, which is an enterotoxin, and toxin B, which is a cytotoxin. Both these toxins are high-molecular-weight proteins that bind to specific receptors on the intestinal mucosa. Once bound to these receptors, the toxins inactivate Rho proteins intracellularly, which leads to actin filament disintegration.

When the actin filaments disintegrate, the cells round off and are sloughed from the basement membrane, leading to a shallow ulcer on the mucosal surface of the bowel lumen. These ulcers may be scattered or diffuse and may or may not develop a pseudomembrane. Pseudomembranes develop when serum proteins, mucus, and inflammatory cells flow from the ulcer and form a membranous layer covering it. They may be confined only to the epithelium and adjacent lamina propria, in mild cases; in severe cases, they involve the full thickness of the mucosa, with necrosis and confluent pseudomembrane formation. The pseudomembrane appears as a yellow or off-white raised plaque. In addition to these ulcers and pseudomembranes, the entire bowel wall may become edematous and hyperemic from inflammation.


What are the clinical manifestations of CDC?

Clostridium difficile diarrhea without colitis is the most common manifestation of C. difficile infection. The more serious Clostridium difficile colitis accounts for much of the morbidity and mortality associated with C. difficile. The CDC spectrum includes colitis without pseudomembrane formation, pseudomembranous colitis, and fulminant colitis. The basis for this varied response is related to host factors such as the immune response, the presence of colonic receptors for the toxins, and the concentration of antitoxin antibodies in the sera and intestinal secretions.

Patients with CDC almost always require therapeutic intervention. The illness seldom resolves spontaneously, unlike most cases of C. difficile diarrhea without colitis, which do resolve when the offending antibiotic is withdrawn. While CDC occurs mainly during or shortly after antibiotic usage, infections can occur up to six months after antibiotic exposure.

Following are key presenting characteristics of the CDC variants.

C. difficile colitis without pseudomembrane formation. These patients have 10 or more loose bowel movements per day, with only occasional occult bleeding per rectum. The diarrhea is more profuse compared to patients without colitis, and it is associated with cramping abdominal pain in the lower quadrant that is temporarily relieved with passage of loose bowel movements. Patients may have accompanying symptoms of nausea, anorexia, fever, and malaise. On physical exam, they may have signs of dehydration with abdominal distension and tenderness.

Pseudomembranous colitis. These patients have more profuse diarrhea than patients without pseudomembranes, and their systemic symptoms of nausea, anorexia, fever, and malaise are more intense. On clinical exam, they may be more dehydrated and have marked abdominal tenderness and distension.

Fulminant colitis. These patients have severe diarrhea but may also have decreased bowel movements if paralytic ileus intervenes. They are lethargic with high fever, chills, tachycardia, and profound systemic manifestations of the disease such as severe dehydration. They may present with an acute abdomen and have peritoneal signs if there is perforation. This fulminant process can lead to megacolon, ileus, perforation, and death. Patients with toxic megacolon have a dilated colon, with a diameter greater than 7 cm, accompanied by severe systemic toxicity such as marked leukocytosis, dehydration, and metabolic acidosis. Patients with bowel perforation often have abdominal rigidity, reduced bowel sounds, and in some cases, symptoms of shock.

C. difficile colitis with protein-losing enteropathy. This is an additional variant that occurs in a small number of patients, who usually have subacute CDC with low-grade, intermittent diarrhea, abdominal pain, and fever. Such patients have hypoalbuminemia secondary to the pancolitis, which causes leaking of serum albumin through the inflamed mucosa. The serum albumin may be as low as 2 g/dl or less, with accompanying ascites and peripheral edema.

Most of the manifestations of CDC are related to the colon, but infection of the small bowel and extraintestinal manifestations such as reactive arthritis can occasionally occur.


How is CDC recognizable in patients with inflammatory bowel disease?

Clostridium difficile colitis in a patient with inflammatory bowel disease may be missed because the symptoms of diarrhea, abdominal pain, and low-grade fever are attributed to a flare-up of the underlying disease process. The diagnosis, however, can be established by identifying the cytotoxin in the stool sample.

Patients with inflammatory bowel disease are at risk of acquiring CDC because they have impaired immune systems, are exposed to antibiotics, including sulfasalazine, and are frequently hospitalized due to the underlying disease process.


What is the differential diagnosis for CDC?

In addition to CDC, diagnostic considerations for patients presenting with fever, diarrhea, and abdominal pain include diverticulitis, inflammatory bowel disease (ulcerative colitis or Crohn's disease), and bacterial colitis.

While patients with diverticulitis have fever and abdominal pain, they usually will not have profuse diarrhea. On exam, there is usually left lower quadrant tenderness with a palpable mass.

Patients with ulcerative colitis usually have bloody diarrhea with fecal urgency. In severe disease, there is associated hypoalbuminemia and severe anemia. Stool cultures are negative. Patients may also have extraintestinal manifestations such as erythema nodosum, episcleritis, and oligoarthritis. In Crohn's, patients may present with intermittent diarrhea with cramping or steady right lower quadrant pain. On exam, a right lower quadrant mass may be palpable. Patients may have evidence of fistulas and abscesses in the perineum or intra-abdominally.

Besides C. difficile, bacterial colitis can be caused by Salmonella, Shigella, Campylobacter, Yersinia, and Escherichia coli. Patients with Salmonella, Shigella, or Campylobacter usually have a self-limiting diarrhea that can be differentiated from CDC by stool culture. Patients with E. coli colitis have diarrhea that may be bloody when provoked by enteroinvasive or enterohemorrhagic E. coli strains. Outbreaks of enterohemorrhagic E. coli O157:H7 that occur from consumption of undercooked hamburgers and unpasteurized apple juice can result in complications such as hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura. Isolation of E. coli O157:H7 requires identifying this strain on sorbitol-MacConkey agar and confirming it with serologic typing.

Other processes that should be considered in the differential diagnosis are viral gastroenteritis, malabsorption, and irritable bowel syndrome.


What diagnostic tests are useful in identifying CDC? Does endoscopy have a role?

Depending on the severity of the illness, patients with CDC may have leukocytosis with a left shift, electrolyte abnormalities, and even hypoalbuminemia in severe cases. Stool examination will reveal leukocytes in half the cases and may even be hemoccult positive. The diagnosis of CDC is established most often by stool bioassay, but in certain patient populations, endoscopy and abdominal CT scans are done to obtain additional information.

Stool bioassay. The stool cytotoxicity assay is the test of choice for diagnosing CDC. Diarrheal stool is diluted with buffer, then filtered and added to fibroblasts. The toxins exert a cytopathic effect on the cells that causes rounding. The test is usually reported as positive or negative and titers, if reported, are of little importance. Sensitivity is 94% to 100%, and specificity is up to 99%. Cytotoxicity assays are expensive and take two to three days to complete, so they have been largely replaced by rapid and easier-to-perform immunoassays such as ELISA, which detect toxin A. Although cytotoxicity assays and immunoassays are comparable in specificity, the sensitivity of cytotoxicity assays is greater, resulting in detection of 5% to 10% more cases. This is mainly due to negative ELISA assay results seen in patients with stool containing toxin B and mutant toxin A.

Endoscopy. Though sigmoidoscopy and colonoscopy are seldom performed in patients with classic clinical findings, they are helpful when the diagnosis is in doubt or rapid diagnostic information is required. If a patient is ill with symptoms suggestive of CDC but has a negative ELISA assay, then colonoscopy can be invaluable in providing an expeditious diagnosis. The presence of pseudomembranes is virtually diagnostic of CDC. In general, colonoscopy is superior to sigmoidoscopy because in 10% of patients, CDC is rectosigmoid-sparing. The findings with colonoscopy vary from diffuse, patchy colitis in mild cases to the characteristic raised, adherent, yellow plaques seen in pseudomembranous colitis. Other endoscopic findings include erythema, edema, friability, and erosions.

Computed tomography (CT) scan. The CT scan of the abdomen is used to evaluate for other intra-abdominal pathology. The findings of mild CDC include diffuse or patchy colitis. In pseudomembranous colitis, they include mucosal edema, thickened colon, thumbprinting, pancolitis, and even pericolonic inflammation, depending on the severity of the disease. These findings are not specific for CDC, as they may be seen in colitis from other causes. A CT scan may be helpful, however, in revealing complications of CDC such as ileus and megacolon and identifying any other intra-abdominal pathology.


What therapies are effective in resolving CDC?

The initial step in management of CDC is to discontinue the offending antibiotics. Supportive measures, such as intravenous (IV) fluids and correcting electrolyte imbalances, should be instituted.

Antiperistaltic agents such as diphenoxylate plus atropine, opiates, or loperamide should be avoided because they can delay the clearance of the toxin and exacerbate toxin-mediated colonic injury. Such agents may also precipitate ileus and cause toxic dilation of the colon.

Since the diarrhea in CDC is usually profuse, specific therapy with oral metronidazole or vancomycin is usually warranted. Metronidazole has been found to be effective in 98% of patients treated. It is as effective as vancomycin both in initial treatment of CDC and in patients who relapse. If IV antibiotic therapy is required, only metronidazole should be used. It achieves bactericidal levels in the bowel lumen whether given orally or intravenously, in contrast to vancomycin, which does so only when given orally.

The systemic side effects of metronidazole are uncommon and include nausea, vomiting, and a disulfiram-like reaction with alcohol. It should be given with caution to pregnant and nursing women due to the unknown effects on fetal organogenesis. Resistant C. difficile isolates have occasionally been reported, as have cases of metronidazole-induced C. difficile diarrhea and colitis.

Vancomycin is effective in more than 96% of patients treated. Since it is neither absorbed nor metabolized when given orally, it reaches high intraluminal concentrations, making it very effective in treating both mild and severe CDC. Doses of 125 mg four times daily suffice for treating milder forms of the disease; higher doses such as 500 mg may be needed in patients who have severe or fulminant colitis. Vancomycin can be administered orally, by nasogastric tube, or by enema. Again, it should not be given intravenously because effective intraluminal concentrations cannot be achieved by that route.

There are only rare cases of systemic adverse effects from oral vancomycin because it is not absorbed from the lumen when given orally. Despite these advantages of vancomycin, it is used as second-line therapy because it is costly and because its use may encourage the growth of deadly vancomycin-resistant nosocomial bacteria. Vancomycin is usually given to patients who cannot tolerate metronidazole, pregnant women, children less than 10 years of age, and in cases of severe pseudomembranous colitis.

Less frequently employed therapies include bacitracin, teicoplanin, colestipol, and fusidic acid. Bacitracin has been used to treat CDC but has proven to be less effective. The response rate is about 80% and the relapse rate is more than 30%, which is higher than conventional therapy.

Teicoplanin is a glycopeptide similar to vancomycin, but more potent than vancomycin. It is as effective as vancomycin and is associated with a lower relapse rate, but is seldom used in the United States because it is not readily available and is costly.

Ion exchange resins such as colestipol have a response rate of only 36% and as a result are not recommended for treatment of CDC. Similarly, fusidic acid is seldom used because it is not as effective as conventional therapy and is associated with a higher relapse rate.


How is severe pseudomembranous colitis managed?

Severe pseudomembranous colitis, which occurs in 3% to 5% of patients with CDC, is associated with a mortality of about 65% and must be aggressively treated. In critically ill patients, vancomycin is recommended as first-line therapy, mainly due to a quicker clinical response in comparison with metronidazole. Patients with severe disease and ileus may even be given a combination of antibiotics such as vancomycin via nasogastric tube, IV metronidazole, and vancomycin-retention enemas. The enemas are given through a number 18 Foley catheter, with 500 mg vancomycin in 100 ml saline administered every six hours.

Other modalities include giving pooled human immunoglobulin intravenously to increase serum IgG antitoxin levels, which are depressed in patients with severe disease. Patients who have not responded to conventional therapy have been successfully treated in this manner.

Occasionally, emergency surgery with colectomy is required to prevent death in patients with severe CDC who have failed antibiotic therapy and have established or impending bowel perforation. The surgery of choice, subtotal colectomy with ileostomy, has a failure rate of 24%.


What factors contribute to relapse of CDC and how is the recurrence managed?

In as many as one in five cases, CDC may relapse on discontinuation of therapy. When it occurs, the symptoms usually reappear between 3 and 21 days after conventional therapy is completed. The cause of relapse is not known, but it may be related to an impaired host immune system, low levels of immunoglobulins against C. difficile toxins, and persistent germination of C. difficile spores in the colon that remain despite treatment. To date, there is little evidence that relapses are caused by resistant organisms.

The management of recurrent CDC involves retreatment with the same antibiotic that was used to treat the initial episode. According to one study, the response was 92% after a single repeat course of antibiotics. If there is a second relapse, a taper-and-pulse course of vancomycin 125 mg is given over five weeks as follows: four times daily for one week, twice daily for one week, daily for one week, every other day for one week, and every three days for one week.

Other therapies that have been tried include combining the vancomycin taper-and-pulse therapy with cholestyramine, rifampicin, or biotherapy. Cholestyramine should be given two to three hours apart from vancomycin to prevent it from binding with vancomycin. Biotherapy, which is therapy with microorganisms such as Saccharomyces boulardii to restore normal colonic flora, has been successfully tried in combination with metronidazole or vancomycin in patients with recurrent CDC, but it has not been as effective in initial episodes. These combination therapies have been tried in small studies and should be utilized when other options have been exhausted.


How can CDC be prevented?

Prevention of CDC can largely be achieved by limiting antibiotic use, proper hand washing between contacts with all patients, using disposable gloves and gowns when dealing with patients and objects infected with C. difficile, enteric isolation of infected patients, and disinfecting contaminated objects with sodium hypochlorite or ethylene oxide. Educating hospital personnel about the disease and its epidemiology is also important.

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