Disease
C. difficile causes antibiotic-associated pseudomembranous colitis (Figure 1). C. difficile is the most common nosocomial (hospital-acquired) cause of diarrhea. It is the leading infectious cause of gastrointestinal-associated deaths in the United States. The name C. difficile has recently been changed to Clostridioides difficile but for this edition, the previous name will be used.
Fig1. Pseudomembranous colitis. Note yellowish plaque-like lesions in colon. Caused by an exotoxin produced by Clostridium difficile that inhibits a signal transduction protein, leading to death of enterocytes. (Reproduced with permission from Usatine RP, Smith MA, Mayeaux EJ Jr, et al: The Color Atlas of Family Medicine, New York, NY: McGraw Hill; 2009. Photo contributor: E.J. Mayeaux, Jr., MD.)
Transmission
The organism colonizes the large intestine of approximately 3% of the general population and up to 30% of hospitalized patients. Note that most people are not colonized, which explains why most people who take antibiotics do not get pseudomembranous colitis. C. difficile is transmitted by the fecal–oral route. Either the spores or the bacterial organism itself can be transmitted.
The majority of cases occur in hospitalized patients, but about one-third of cases are community acquired. The hands of hospital personnel are important intermediaries.
Pathogenesis
Antibiotics suppress drug-sensitive members of the normal flora of the colon, allowing C. difficile to multiply and produce large amounts of exotoxins A and B. Both exotoxin A and exotoxin B are glucosyltransferases (i.e., enzymes that glucosylate [add glucose to] a G protein called Rho GTPase). The main effect of these exotoxins is to cause depolymerization of actin, resulting in a loss of cytoskeletal integrity, apoptosis, and death of the enterocytes. Exotoxin B is thought to play the leading role in producing the signs and symptoms of human disease.
Clindamycin was the first antibiotic to be shown to pre dispose to pseudomembranous colitis, but many antibiotics are known to predispose to this disease. At present, third generation cephalosporins are the most common because they are so frequently used. Ampicillin and fluoroquinolones are also commonly implicated. In addition to antibiotics, cancer chemotherapy and proton pump inhibitors predispose to pseudomembranous colitis. C. difficile rarely invades the intestinal mucosa.
Clinical Findings
C. difficile causes diarrhea associated with pseudomembranes (yellow-white plaques) on the colonic mucosa (see Figure 1). The diarrhea is usually not bloody, and neutrophils are found in the stool in about half of the cases. Fever and abdominal pain often occur. The organism rarely enters the bloodstream and rarely causes metastatic infection.
The pseudomembranes are visualized by sigmoidoscopy. Toxic megacolon can occur, and surgical resection of the colon may be necessary. Pseudomembranous colitis can be distinguished from the transient diarrhea that occurs as a side effect of many oral antibiotics by testing for the presence of the toxin in the stool. Even with adequate treatment, the organism may not be eradicated from the colon, and recurrences occur at a rate of approximately 15% to 20%.
Laboratory Diagnosis
The presence of exotoxins in the filtrate of a patient’s stool specimen is the basis of the laboratory diagnosis. It is insufficient to culture the stool for the presence of C. difficile because people can be colonized by the organism and not have disease.
A useful screening test is the enzyme immunoassay for the glutamine dehydrogenase (GDH) of C. difficile. GDH is produced by all isolates of C. difficile so detection of GDH as an antigen supports the diagnosis. Testing for the presence of the toxin or its genes is then warranted.
There are two types of tests used to make the laboratory diagnosis. One detects the exotoxin itself, and the other detects the genes that encode the exotoxin. To detect the exotoxin itself, an ELISA test employing antibody to the exotoxin is used. To detect the genes that encode the exotoxin, a PCR assay to determine the presence of the toxin gene DNA is used. The DNA-based test has greater sensitivity and specificity than the ELISA test. However, these nucleic acid amplification tests (NAATs) should be interpreted with caution because a person may only be colonized by C. difficile and be recorded as positive when, in fact, C. difficile is not the cause of the patient’s disease.
Treatment
The causative antibiotic should be withdrawn whenever possible. Either fidaxomicin or vancomycin, administered orally, is the drug of choice for the initial episode and for recurrences. In the past metronidazole has been a commonly used treatment but has shown to be less effective than vancomycin or fidaxomicin.
Prevention
There are no preventive vaccines or drugs. Because antibiotics are an important predisposing factor for pseudomembranous colitis, they should be prescribed only when necessary. In patients with, recurrent episodes of C. difficile infection or at high-risk for recurrent C. difficile infections, Bezlotoxumab, a monoclonal antibody against exotoxin B of C. difficile and fecal transplantation, administering bowel flora from a normal individual either by enema or by nasoduodenal tube, can both help reduce risk of recurrence.
