Pseudomembranous colitis: Not always Clostridium difficile

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ABSTRACTAlthough Clostridium difficile infection is the cause of most cases of pseudomembranous colitis, clinicians should consider less common causes, especially if pseudomembranes are seen on endoscopy but testing remains negative for C difficile or if presumed C difficile infection does not respond to treatment. Histologic review of colonic mucosal biopsy specimens can provide clues to the underlying cause.


  • Pseudomembranous colitis is a nonspecific pattern of injury resulting from decreased oxygenation, endothelial damage, and impaired blood flow to the mucosa that can be triggered by a number of disease states.
  • Chemicals, medications, ischemia, microscopic colitis, other infectious organisms, and inflammatory conditions can all predispose to pseudomembrane formation and should be included in the differential diagnosis.
  • As most patients with pseudomembranous colitis have C difficile infection, it should be excluded first. Empiric treatment for C difficile should be started if the patient is seriously ill.
  • Testing for C difficile is with polymerase chain reaction, enzyme immunoassay for toxins A and B, and glutamate dehydrogenase measurement.



Pseudomembranous colitis is most often due to Clostridium difficile infection, but it has a variety of other causes, including other infections, ischemia, medications, and inflammatory mucosal diseases (Table 1). When pseudomembranes are found, one should consider these other causes if tests for C difficile are negative or if anti-C difficile therapy does not produce a response.

These less common causes are important to consider to avoid needlessly escalating anti-C difficile antibiotic therapy and to provide appropriate treatment. Pseudomembranous colitis is a nonspecific finding that suggests a larger disease process. Associated signs and symptoms, including fever, abdominal pain, leukocytosis, diarrhea, toxic megacolon, and electrolyte imbalances, may portend a life-threatening condition.1 Awareness of causes of pseudomembranous colitis other than C difficile infection, the focus of this review, is key to prompt diagnosis and potentially life-saving patient care.


A pseudomembrane is a layer of fibropurulent exudate composed of acute inflammatory cells and mucus originating from inflamed and erupting crypts.2 Although most often seen in C difficile infection, pseudomembranous colitis is a nonspecific pattern of injury resulting from decreased oxygenation, endothelial damage, and impaired blood flow to the mucosa that can be triggered by a number of disease states.2

Figure 1. Pseudomembranes (arrow) seen on flexible signoidoscopy in a patient with Clostridium difficile infection.

On endoscopy, pseudomembranes appear as raised whitish or yellowish plaques that may be scattered or confluent in distribution (Figure 1).2 They are usually found in the recto­sigmoid colon but may be isolated to more proximal segments.3 Lower endoscopy is often performed in the diagnostic evaluation of patients with unexplained diarrhea, hematochezia, and abnormal abdominal computed tomographic findings (eg, colonic thickening).


When pseudomembranous colitis is confirmed endoscopically, C difficile infection naturally comes to mind, but the two terms are not interchangeable. A wide differential diagnosis should be maintained, especially when there are clues that C difficile infection may not be the correct diagnosis.

Chemicals and medications

Several chemicals and medications can injure the bowel and predispose to pseudomembrane formation.

Glutaraldehyde has long been used to sanitize endoscopes because of its broad antimicrobial activity. Nevertheless, if the disinfecting solution is not adequately rinsed off the endoscope, direct contact with colonic mucosa can produce an allergic and a chemical reaction, resulting in an acute self-limited colitis with pseudomembrane formation.4

Chemotherapeutic and antiproliferative agents can be toxic to the bowel, generally through production of free radicals and up-regulation of inflammatory cytokines. The colonic epithelium is then more susceptible to ulceration and mucosal necrosis with pseudomembrane development. Cisplatin, cyclosporine A, docetaxel, and 5-fluorouracil are prominent examples.5–8

Nonsteroidal anti-inflammatory drugs can damage the mucosa at all levels of the gastrointestinal tract. Although gastric ulcerations are more typical (from nonselective cyclooxygenase inhibition), colonic ulcerations and colitis can occur.9 These drugs, particularly diclofenac and indomethacin, have been associated with non-C difficile pseudomembranous colitis when used by themselves or in conjunction with other agents such as cyclosporine A.8,10,11


C difficile is the organism most commonly linked to pseudomembranous colitis, but other bacterial, viral, and parasitic pathogens have also been implicated.

Staphylococcus aureus was believed to be responsible for enterocolitis in a series of 155 surgical patients between 1958 and 1962 receiving antibiotic therapy. All had a positive stool culture for S aureus, and nine were found to have pseudomembranes at autopsy.12

Although this finding has been disputed as a misdiagnosis, since C difficile infection was not widely recognized until the 1970s, there is evidence that S aureus may indeed be a cause of non-C difficile pseudomembranous colitis. In a review of 36 cases of methicillin-resistant S aureus bacteremia in Japan, four patients were documented to have intestinal pseudomembranes either by endoscopy or autopsy. In two of these patients, biopsies of the pseudomembranes were positive for methicillin-resistant S aureus.13

Escherichia coli O157:H7. Pseudomembranes have been seen endoscopically in several adults and children with enterohemorrhagic E coli O157:H7 infection.14,15 This invasive gram-negative rod normally resides in the gastrointestinal tract of cattle, sheep, and other animals and can be pathogenic to people who eat undercooked beef. The organism attaches to and effaces intestinal epithelial cells, and bacterial proteins and the Shiga toxin then damage the vasculature, precipitating bloody diarrhea. Colonic damage can range from mild hemorrhagic colitis to severe colitis with ischemic changes. In patients with enterohemorrhagic E coli O157:H7 infection, pseudomembrane formation results from colon ischemia due to microvascular thrombosis or from destructive effects of bacterial enterotoxin.1,15

Cytomegalovirus is a ubiquitous human herpes virus that can affect nearly all organ systems. Infection is often reported in immunocompromised patients, eg, those with acquired immunodeficiency syndrome, chronic corticosteroid use, inflammatory bowel disease, malignancy, or solid-organ transplants. Gastrointestinal manifestations can be nonspecific and range from abdominal discomfort to diarrhea to tenesmus. Pseudomembranous colitis can be a presenting feature of cytomegalovirus involvement.16,17 Ulcerative lesions in the colonic mucosa are a frequent accompanying finding on endoscopy.18,19

Other rarer infectious causes of pseudomembranous colitis identified in case reports include Clostridium ramosum, Entamoeba histolytica, Klebsiella oxytoca, Plesiomonas shigelloides, Schistosomiasis mansoni, and Salmonella and Shigella species.20–26 Additionally, there have been two reports of Strongyloides stercoralis hyperinfection manifesting as pseudomembranous colitis.27,28

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