Clostridium Difficile Infection

Clostridium difficile, or C. difficile (a gram-positive anaerobic bacterium), is now recognized as the major causative agent of colitis (inflammation of the colon) and diarrhea that may occur following antibiotic intake. C. difficile infection represents one of the most common hospital (nosocomial) infections around the world. In the United States alone, it causes approximately three million cases of diarrhea and colitis per year. This bacterium is primarily acquired in hospitals and chronic care facilities following antibiotic therapy covering a wide variety of bacteria (broad-spectrum) and is the most frequent cause of outbreaks of diarrhea in hospitalized patients. One of the main characteristics of C. difficile-associated colitis is severe inflammation in the colonic tissue (mucosa) associated with destruction of cells of the colon (colonocytes).

The disease involves, initially, alterations of the beneficial bacteria, which are normally found in the colon, by antibiotic therapy. The alterations lead to colonization by C. difficile when this bacterium or its spores are present in the environment. In hospitals or nursing home facilities where C. difficile is prevalent and patients frequently receive antibiotics, C. difficile infection is very common. In contrast, individuals treated with antibiotics as outpatients have a much smaller risk of developing C. difficile infection. Laboratory studies show that when C. difficile colonize the gut, they release two potent toxins, toxin A and toxin B, which bind to certain receptors in the lining of the colon and ultimately cause diarrhea and inflammation of the large intestine, or colon (colitis). Thus, the toxins are involved in the pathogenesis, or development of the disease.

Transmission Factors - An important characteristic of C. difficile-associated diarrhea and colitis is its high prevalence among hospitalized patients. Thus, C. difficile contributes significantly to hospital length of stay, and may be associated in some elderly adults with chronic diarrhea, and occasionally other serious or potentially life-threatening consequences. One study demonstrated that 20% of patients admitted to a hospital for various reasons were either positive for C. difficile on admission or acquired the microorganism during hospitalization. Interestingly, only one-third of these patients developed diarrhea while the remainder were asymptomatic carriers serving as a reservoir of C. difficile infection. The organism and its spores were also demonstrated in the hospital environment, including toilets, telephones, stethoscopes, and hands of healthcare personnel.

While patient-to-patient spread and environmental contamination can be some of the reasons of cross-infection in C. difficile-associated diarrhea and colitis, antibiotic therapy is the major risk factor for this disease. Thus, antibiotic use only when necessary is the most effective measure of preventing C. difficile infection.

Clinical Features - A wide range of conditions is associated with C. difficile infection. Most cases develop 4 to 9 days after the beginning of antibiotic intake. It should be noted, however, that some patients develop diarrhea after antibiotics are discontinued and this may lead to diagnostic confusion. Although nearly all antibiotics have been implicated with the disease, the commonest antibiotics associated with C. difficile infection are ampicillin, amoxicillin, cephalosporins, and clindamycin.

The most common presentation is either mild colitis, or simple diarrhea that is watery and contains mucus but not blood. Examination by sigmoidoscopy usually reveals normal colonic tissue. General symptoms are commonly absent and diarrhea usually stops when antibiotics are discontinued. C. difficile can also cause non-specific colitis quite reminiscent of other intestinal bacterial infections such as Shigella or Campylobacter. This is a more serious illness than simple antibiotic-associated diarrhea; patients experience watery diarrhea 10 to 20 times a day and lower, crampy abdominal pain. Low-grade fever, dehydration, and non-specific colitis are common manifestations.

Pseudomembranous colitis represents the characteristic manifestation of full-blown C. difficile-associated colitis. Sigmoidoscopic examination reveals the presence of characteristic plaque-like pseudomembranes, scattered over the colonic tissue. The presence of these plaques is a distinctive indicator of C. difficile infection in patients with diarrhea following antibiotic treatment.

The most serious manifestation of C. difficile infection, fulminant colitis (severe sudden inflammation of the colon), is frequently associated with very serious complications. This can be a life-threatening form of C. difficile infection and occurs in 3% of patients; most are elderly and debilitated from other diseases. Patients with this form of the disease experience severe lower abdominal pain, diarrhea, high fever with chills, and rapid heart beat. Timely treatment of fulminant colitis is essential; this condition can be life threatening.

C. difficile infection in patients with other intestinal diseases - It is well documented that C. difficile may complicate the course of ulcerative colitis or Crohn's disease and it is responsible for 4 to 12% of diarrhea in AIDS patients. In this case, patients develop the typical symptoms of C. difficile colitis, including diarrhea, abdominal pain, and fever reminiscent of exacerbation of inflammatory bowel disease. The reason for this complication is not entirely clear. It may be that the frequent hospitalizations and exposure to antibiotics of patients with inflammatory bowel disease or AIDS places them at increased risk for the infection. So far there is no evidence to indicate that C. difficile can complicate the symptoms associated with irritable bowel syndrome (IBS).

Laboratory Diagnosis - The laboratory diagnosis of C. difficile infection is primarily related to the demonstration of C. difficile toxins in the stool of suspected patients. The detection of C. difficile toxins in the stool can be made by a laboratory test (cytotoxicity assay) where the toxins can be easily observed in the microscope. This tissue culture assay is considered the gold standard because of its high sensitivity and specificity. Since there is no correlation between levels of C. difficile toxins in the stool and severity of the disease, the results are reported simply as "positive" or "negative." However, time is a drawback of this assay since it requires 24 to 48 hours to read the results.

Over the past few years several rapid tests that take just a few hours, and which do not require specialized personnel to run, have been developed (immuno-enzymatic assays) for the detection of C. difficile toxins in the stool. These tests are commercially available in the form of diagnostic kits. Although they are relatively less sensitive and demonstrate lower specificity compared to the laboratory tests, they are very useful not only in the every day practice when specialized personnel is not available, but also in emergency situations and in rapid screening of patients during spreading of the disease in hospitals.

Therapy - Therapy of C. difficile is directed against eradication of the microorganism from the colonic microflora. No therapy is required for asymptomatic carriers. In noncomplicated patients with mild diarrhea, no fever, and modest lower abdominal pain, discontinuation of antibiotics (if possible) is often enough to alleviate symptoms and stop diarrhea. When severe diarrhea is present and in cases of established colitis, the patients should receive the antibiotics, metronidazole or vancomycin, for 10 to 14 days. Several clinical trials have shown that these antibiotics are equally effective in cases of mild to moderate C. difficile infection and more than 95% of patients respond very well to this treatment. Diarrhea following treatment with either vancomycin or metronidazole is expected to improve after 1 to 4 days with complete resolution within 2 weeks. However, some patients do not respond despite aggressive medical therapy and require surgical intervention.

Therapy for relapsing C. difficile infection - Although C. difficile infection usually responds well to treatment with metronidazole or vancomycin, approximately 15 to 20% of patients will experience re-appearance of diarrhea and other symptoms weeks or even months after initial therapy has been discontinued. The usual therapy for relapse is to repeat the 10 to 14 day course of either metronidazole or vancomycin and this is successful in most patients. However, a subset of patients continues to relapse whenever antibiotics are discontinued and this represents a therapeutic challenge. Some authorities recommend switching to the alternative antibiotic from the one used initially. A variety of other therapies have also been described for relapsing disease. It is hoped that development of vaccines against C. difficile toxins may someday control the problem of C. difficile infection in hospitals.

Article by: Charalabos Pothoulakis, M.D., Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.