Narrative Review: The New Epidemic of Clostridium difficileAssociated Enteric Disease

Key Summary Points Clostridium difficile is the most common identifiable bacterial cause of diarrhea in the United States. Tissue culture assay is the best diagnostic test to detect the cytotoxin; enzyme immunoassay is the test used in most hospitals, but it has a sensitivity of only about 75%. A new epidemic strain of C. difficile has emerged that causes more frequent and more serious disease. Features of severe disease include ileus, toxic megacolon, pseudomembrane formation, leukemoid reactions, hyperalbuminemia, requirement for colectomy, sepsis, and death. Risk factors are use of antibiotics (especially broad-spectrum cephalosporins and fluoroquinolones), advanced age, hospitalization, and gastrointestinal surgery or gastrointestinal procedures. Oral vancomycin is the preferred treatment for seriously ill patients. Infection control and antibiotic control are important preventive measures. Diarrhea and colitis due to Clostridium difficile are well-recognized and extensively studied iatrogenic complications of antibiotic use and have been for nearly 30 years. Important risks for infection include hospitalization, advanced age, gastrointestinal surgery or gastrointestinal procedures, and antibiotic exposure. The most common inducing agents have been clindamycin or broad-spectrum cephalosporins, but nearly all agents with an antibacterial spectrum may be responsible. The cytotoxin assay that originally led to the detection of C. difficile in 1978 remains the most sensitive diagnostic test, but the enzyme immunoassay is now used by most laboratories because of ease of processing, cost, and speed of results. Standard treatment of C. difficile infection includes withdrawal of the inducing agent and use of oral metronidazole or oral vancomycin; metronidazole is preferred in guidelines, but vancomycin is probably more effective, especially in seriously ill patients. The major complications of treatment are failure to respond, primarily because of advanced disease with ileus, and relapse or reinfection after treatment is discontinued. Prevention principles include hospital infection control and antibiotic restraint. Against this background, there is a new epidemic of C. difficile infection that is occurring more frequently and is more serious and more refractory to therapy. Evidence of the severity of the infection includes high rates of toxic megacolon, leukemoid reactions, severe hypoalbuminemia, requirement for colectomy, shock, and death. These complications are most common in elderly patients, and the inducing agents are often fluoroquinolones and cephalosporins. Analysis of outbreaks in North America implicates a unique strain of C. difficile that produces large amounts of toxin in vitro, produces a binary toxin of uncertain clinical significance, and is resistant to fluoroquinolones in vitro. Successful management of patients with this strain requires early detection of infection, rapid treatment, and implementation of infection control, sometimes including antibiotic control. Clostridium difficile was identified as the major cause of antibiotic-associated diarrhea and the nearly exclusive cause of pseudomembranous colitis in 1978. Subsequent work in the following 2 years defined the clinical features, methods of laboratory diagnosis, epidemiology, principles of infection control, and treatment of C. difficileassociated disease. Clostridium difficile infection is an important and frequent iatrogenic complication, but it has been relatively easy to manage, with the exception of occasional institutional outbreaks and a nagging problem of relapsing disease following treatment. However, during the past 5 years, an unanticipated increase in infection has been recognized, particularly in some locations where C. difficileassociated disease has become more frequent, more serious, and more refractory to standard therapy. It now seems that this change is explained by a unique strain of C. difficile that has unusual virulence factors, which may account for increased severity, and fluoroquinolone resistance, which may account for increased frequency. These recent observations have resulted in renewed interest in an old pathogen. This review updates the status of C. difficileassociated enteric disease and its management in light of these new observations. Initial Studies (1974 to 2003) Antibiotic-associated enterocolitis was generally attributed to Staphylococcus aureus in the first 25 years of the antibiotic era (1, 2). In 1974, Tedesco and colleagues (3) reported results of a prospective study of 200 patients given clindamycin who underwent endoscopy after reporting diarrhea. In this study, 41 (20.5%) patients had diarrhea and 20 (10%) had pseudomembranous colitis (3). Despite the ease of recovering S. aureus in stool, tests to detect the organism yielded negative results. This led our group and others to pursue an alternative putative agent by using the hamster model (4) for correlations with observations in patients. Clostridium difficile was reported as the agent of antibiotic-associated pseudomembranous colitis in 1978 (5). During the ensuing 25 years, researchers established essential data documenting associated risks, clinical features, diagnosis, and management of C. difficileassociated diarrhea that became widely accepted. Risk Factors Almost all studies include the 3 major risks for infection with C. difficile: antibiotic exposure, advanced age, and hospitalization (68). With regard to antibiotic exposure, any antimicrobial agent with an antibacterial spectrum can be the cause, but there is a hierarchical list of agents that has been subject to change. Clindamycin followed by ampicillin or amoxicillin played prominent roles in the 1970s, but these were largely supplanted by cephalosporins in the 1980s (9, 10). Researchers from Sweden showed that advanced age was a risk in population-based analyses indicating that the rate per 100000 persons older than 65 years of age was 20 times higher than that in persons younger than 20 years of age (11). The risk associated with hospitalization and chronic care facilities is attributed to high rates of C. difficile colonization. Studies have shown a 20% to 40% rate of colonization in hospitalized adults compared with 2% to 3% in healthy adults (12, 13), reflecting widespread contamination of hospital environments, especially in areas associated with infection (6, 7, 14, 15). Gastrointestinal surgery and gastrointestinal procedures are also risks. Clinical Expression Clinical disease and C. difficile toxin are present almost exclusively in patients with recent antibiotic exposure (6, 7, 12, 16), with rare exceptions (17, 18). A recent report implicates gastric acidsuppressive agents as a risk for disease (19), but this has not been consistently observed (20). Clinical expression of infection almost always includes diarrhea, but severity of this and constitutional symptoms (68, 16, 17) varies widely. Common findings in patients with infection include colitis with cramps, fever, fecal leukocytes, and inflammation on colonic biopsy. Pseudomembranous colitis represents an advanced stage of disease, and although considered nonspecific, it is nearly diagnostic of C. difficile infection (17). The disease is almost always restricted to the colon (21). Clostridium difficile infection is a protein-losing enteropathy that is often associated with hypoalbuminemia and sometimes with anasarca (3). Most patients have leukocytosis, and this infection is now recognized as a prominent cause of leukemoid reactions (22). Diagnosis The standard test for infection is detection of C. difficile toxin in stool. The initial report in 1978 (5) used the tissue culture assay, and no subsequent test has proven superior in terms of sensitivity or specificity (2325). The main limitations of the test are the 24 to 48 hours required for results, work intensity, and cost (25). Most laboratories now use enzyme immunoassay to detect toxin A or toxins A and B, but several studies show that these are only about 75% sensitive compared with tissue culture assays (2325) so that repeated tests or empirical treatment may be required (26). Alternative methods of detection include detection of C. difficile by culture, by polymerase chain reaction testing, or by analysis for the common antigen of C. difficile (25, 27, 28). An inherent problem with detection of the organism rather than the toxin is that 10% to 30% of hospitalized patients are colonized without disease (13). Some laboratories use 1 of these last methods to screen stool samples, with subsequent testing for the cytotoxin in samples with positive results (25, 28). Infection Control Standard recommendations of the Society for Healthcare Epidemiology of America for infection control include the following: patient isolation in a single room, preferably with a bathroom; contact precautions; room cleansing with a 1:10 dilution of bleach; avoidance of rectal thermometers; and soap and water for handwashing rather than alcohol-based hand hygiene (14). Alcohol-based hand cleaning is considered inferior because clostridia spores survive alcohol. This is important because health care workers can transmit C. difficile via their hands. Antibiotic control of clindamycin or cephalosporins has sometimes been necessary during epidemics (29, 30). Attempts to prevent infection with prophylactic metronidazole or oral vancomycin may actually increase the rate of C. difficile carriage (31). Treatment Recommendations for treatment are supportive care, withdrawal of the implicated antibiotic, and avoidance of unnecessary use of drugs with antiperistaltic activity (Table). When continued antibiotic treatment is necessary, it is best to use agents with a low probability of causing C. difficileassociated disease, such as urinary antiseptics, tetracyclines, narrow-spectrum betalactams, macrolides, sulfonamides, aminoglycosides, vancomycin, metronidazole, and trimethoprimsulfamethoxa