1. 
   

   Which factors are associated with an increased risk of primary or recurrent Clostridium difficile–associated disease (CDAD)?

   
   
2. 
   

   What factors affect the accuracy of diagnostic testing of CDAD?

   
   
3. 
   

   What are the most common complications of CDAD?

   
   
4. 
   

   What therapies are most efficacious for primary, recurrent, or refractory CDAD?

   
   
5. 
   

   What system improvements can reduce the incidence of CDAD?

Clostridium difficile was first described in 1935 by pediatricians studying the acquisition of bowel flora in newborns and was termed “difficult” because of its resistance to growth on conventional media. It was not until 1978 that it was found to be associated with toxins in the stools of patients with colitis. Clostridium difficile–associated disease (CDAD) has now become a major nosocomial problem, affecting 3 million inpatients yearly in the United States. Acquisition of C difficile occurs in up to 30% of hospitalized patients, although only 30–60% have symptoms. Patients with symptomatic disease stay an average of 3.6 days longer in hospital than expected, at a cost of over $1 billion annually in the United States.

Normal gut flora confers resistance to C difficile colonization; only 1–4% of healthy adults carry C difficile in their bowel flora. Loss of normal colonic flora, usually from antibiotics, allows C difficile proliferation (clindamycin, cephalosporins, and fluoroquinolones are common offenders). C difficile colitis is also associated with other events that disturb gut flora or host immunity, such as bowel preparations, cytotoxic agents, and colonic inflammation due to inflammatory bowel disease.

CDAD was first described in frail or elderly hospitalized patients after antibiotic exposure, but it is now occurring in younger, healthy individuals with no apparent exposure to health care environments or antibiotics. Up to 20% of CDAD cases are now community acquired. C difficile and its spore form are easily transmitted from person-to-person or by contact with objects in the hospital environment, such as stethoscopes, clothing, and toilets. The spore form is ubiquitous in the hospital environment, resistant to alcohol-based treatment and other disinfectants, and can survive for months. Even after routine cleaning, 10–50% of room surfaces still contain spores.

C difficile is an anaerobic spore-forming bacterium that produces two exotoxins (A and B) that adhere to intestinal epithelial cells, causing cell death. These toxins are transcribed from a locus composed of five genes (two toxin genes and three regulatory genes). The current epidemic strain of C difficile (BI/NAP1/027) has several factors that increase its virulence. A mutation in one of the regulatory genes results in a massive increase in amount of toxin production. This strain also shows high-level fluoroquinolone resistance, giving it a competitive advantage in environments where fluoroquinolone use is widespread. This strain also produces an additional toxin (binary toxin), the clinical significance of which is not clear.

Patient risk of acquiring CDAD and severity of clinical illness are variable (Table 188-1). The clinical spectrum of CDAD ranges from minor diarrhea to fulminant colitis with toxic megacolon. Most patients present with some combination of acute, nonbloody, watery diarrhea (although some present with obstipation), lower abdominal pain, and leukocytosis. Fever is relatively uncommon (present in less than one-third of patients). Mimickers of CDAD include bowel obstruction, fecal impaction, or toxic megacolon.

The differential diagnosis of acute diarrhea in hospitalized patients is extensive, and less than a third of cases of nosocomial diarrhea are due to CDAD. Non-CDAD causes of diarrhea should be considered in all patients, especially those for whom C difficile testing is negative, or those who do not respond to appropriate treatment. Common benign conditions causing nosocomial diarrhea include medications (stool softeners or laxatives as part of standardized order sets), foods (including tube feedings), oral contrast (from computed tomographic scans), and antibiotic-induced alterations of bowel flora. Less common microbial causes of diarrhea include Klebsiella oxytoca, Klebsiella pneumoniae, and Staphylococcus aureus. For a full discussion of the approach to nosocomial diarrhea, see Chapter 80.

The diagnosis should be made on the combination of symptoms and microbiologic data. Testing for C difficile is imperfect (Table 188-2). The cytotoxic assay is the gold standard, with excellent sensitivity (94–100%) and specificity (99%), but it is expensive and time consuming, hence most medical centers no longer routinely perform it. More commonly used are enzyme-linked immunosorbent assay (ELISA) tests for toxins. Most detect both toxin A and B, but some only detect toxin A. ELISA tests have the advantage of being quicker and cheaper but have a sensitivity of only 70–90%. Sensitivity is reduced in some strains that do not produce toxin A (or have mutant toxin A), as well as in patients that have already received antibiotic treatment for CDAD. False-positive tests are rare, and any symptomatic patient with a positive test should be treated. Culture of the organism is not routinely available, and is best reserved for outbreak investigations.

Severe colitis with pseudomembranes is virtually pathognomonic for C difficile (Figure 188-1). It is diagnosed endoscopically by the appearance of raised yellow or white plaques scattered over the colonic mucosa.