DEFINITION

The first report of antibiotic-associated diarrhea (AAD) was found in the Bulletin of the Johns Hopkins Hospital of 1893, where John Finney and Sir William Osler described the case of a young woman who died of a severe case of “diphtheric colitis” shortly after gastric surgery.¹ It was not until the mid-1900s, with the use of preoperative antibiotics, that AAD became a common medical problem.

For years, the cause of the pseudomembranous colitis remained elusive; indeed, the term staphylococcal enterocolitis was used, reflecting the belief that the disease was commonly caused by staphylococci. In the 1970s, important clinical observations of clindamycin-associated pseudomembranous colitis and the demonstration of the potent cytopathic effects of Clostridium difficile–derived toxin in animal models established the cause and pathogenesis of this condition.²

Today, the term antibiotic-associated diarrhea refers to a benign, self-limited diarrhea following the use of antimicrobials. Typically, no pathogens are identified and the diarrhea is caused by changes in the composition and function of the intestinal flora. Most patients respond to supportive measures and discontinuation of antibiotics. On the other hand, C. difficile diarrhea refers to a wide spectrum of diarrheal illnesses caused by the potent toxins produced by this organism, including cases of severe colitis with or without the presence of pseudomembranes.

PREVALENCE

The occurrence of AAD varies greatly and is influenced by a number of factors, including nosocomial outbreaks, patterns of antimicrobial use, and individual susceptibility. It is estimated that 10% to 15% of all hospitalized patients treated with antibiotics will develop AAD. Most important, twice as many will become asymptomatic carriers. Risk factors include compromised immune status, advanced age, abdominal surgery, comorbidity, types and prolonged use of antibiotics, and the length of hospitalization. For example, infection rates for C. difficile are reported to be around 10% after 2 weeks of hospitalization but may reach 50% after 4 or more weeks.²

All groups of antibiotics may cause AAD, but those with broad-spectrum coverage-in particular cephalosporins, extended-coverage penicillins, and clindamycin-are the most common culprits.³ C. difficile diarrhea is largely a nosocomial disease and is the most frequent cause of diarrhea in hospitalized patients. Its occurrence in the outpatient setting other than in patients confined to nursing homes is much less common.²

Epidemiologic studies have shown that C. difficile is often isolated in hospital wards, including the floors, door handles, and furniture, even weeks after patients with AAD have been removed from the area. Less frequently, similar observations have been made among asymptomatic medical personnel and in hospital wards occupied by unaffected patients. Patients readmitted after recent hospitalizations are found to have a high prevalence of C. difficile colonization, representing an important source of infection. Because of the sporulating properties of this organism, all these observations have suggested an important role for cross-contamination between patients, contact with environmental surfaces, and transmission via hands of medical personnel.⁴ During the past few years, there has been renewed interest in C. difficile diarrhea reflecting a form of disease that is more frequent, more severe, and more refractory to standard treatment. These observations are explained by the presence of a new strain of C. difficile, designated NAP-1, that produces more toxins A and B in vitro, produces binary toxin that is of uncertain significance, and is resistant to fluoroquinolones.¹⁶

PATHOGENESIS

The prolonged use of multiple antibiotics, especially broad-spectrum agents with poor intestinal absorption or high biliary excretion, induces a change in the composition and function of the intestinal flora and therefore results in a higher incidence of AAD.^2,5 The degree of alteration will be influenced by the ability of the normal flora to resist colonization and the type of antibiotic used. A decrease in the colonic anaerobic flora interferes with carbohydrate and bile acid metabolism. Osmotic or secretory diarrhea may occur. Overgrowth of opportunistic pathogens takes place as a result of microbiologic and metabolic alterations.

C. difficile, an anaerobic gram-positive rod, accounts for 15% to 20% of all AAD cases. In particular, this organism can be isolated in a great number of AAD cases with evidence of colitis and in all those with pseudomembranes. It is widely present in the environment, may survive for a considerable time, and is transmitted by the fecal-oral route to susceptible individuals. It is considered part of the normal flora of infants and can be isolated in about 5% of healthy adults and in up to one third of asymptomatic or colonized hospitalized patients.

Both C. difficile toxins A and B exhibit potent enterotoxic and cytotoxic effects that are responsible for the clinical manifestations. The mechanism of action is by toxin binding on intestinal receptors, leading to disruption of the cellular skeleton and intracellular junctions. Protein synthesis and cell division are inhibited. Important inflammatory mediators attract neutrophils and monocytes, increasing capillary permeability, tissue necrosis, hemorrhage, and edema.

Serum and fecal antibodies to C. difficile infection are detected in many infected patients. The host’s immune response appears to be critical in the clinical outcome. Elevated levels of serum immunoglobulin G and A (IgG and IgA) and fecal IgA against toxin A have been demonstrated in asymptomatic patients and in those with mild forms of C. difficile colitis, in contrast to those with severe illness, showing that antibodies provide a protective function.⁶

Histologically, three different stages in C. difficile colitis can be identified. Initially, focal epithelial necrosis, along with fibrin-rich exudates and neutrophils, is present. In the second phase, a marked exudate protruding through an area of mucosal ulceration represents the classic volcano lesion (Fig. 1). The third stage is characterized by diffuse and more severe mucosal ulceration and necrosis, often associated with a pseudomembrane composed of fibrin, leukocytes, and cellular debris.⁷

Figure 1 Typical volcano lesion.

A marked exudate can be seen protruding through an area of mucosal ulceration (arrows).

(Hematoxylin and eosin stain ×105.5) (From Feldman M, Friedman LS, Brandt LJ [eds]: Sleisenger and Fordtran’s Gastrointestinal and Liver Diseases, 8th ed. Philadelphia, WB Saunders, 2006.)

SIGNS AND SYMPTOMS

The clinical manifestations of AAD may vary from mild diarrhea to fulminant colitis.⁸ The severity of C. difficile colitis appears to be influenced by a myriad of factors, including age, comorbidity, host’s immune response, and the use of antiperistaltic agents. Interestingly, bacterial genotype and toxin production appear to play minimal roles.⁹ The cardinal symptom of the disease is diarrhea, which commonly develops during treatment but may appear as late as 8 weeks after discontinuation of antibiotics. In most cases of AAD, patients present with loose stools, minimal signs of colitis, and no constitutional symptoms. The diarrhea promptly responds to supportive measures and withdrawal of the antimicrobial agent.⁸

In contrast, typical cases of C. difficile infection manifest with a profuse, mucous, foul-smelling diarrhea associated with cramps and tenesmus. Frank bleeding is rare, although fecal occult blood and leukocytes are frequently detected. The abdomen is generally soft, with increased bowel sounds and mild tenderness over the left lower quadrant. Constitutional symptoms are common, and include nausea, vomiting, dehydration, and low-grade fever. Mild leukocytosis is frequently present and may occur even in the absence of diarrhea. An occasional leukemoid reaction has been reported. For colitis limited to the right colon, prominent findings of localized abdominal pain, leukocytosis, and fever can be found in the presence of minimal diarrhea.

In severe cases, toxic megacolon may occur along with the deceiving findings of “improved diarrhea.” A dramatic clinical picture of marked colonic distention, peritoneal irritation, fever, and elevated white blood count is commonly found. Hypoalbuminemia, hypovolemia, and ascites are common. A plain abdominal x-ray may show marked colonic distention or thumbprinting, with or without pneumatosis intestinalis. Computed tomography often reveals colonic wall thickening, lumen obliteration, pericolonic fat stranding, and ascites. Surgical intervention is often required, and carries significant morbidity and mortality.¹⁰

The diagnosis of AAD should be considered in any patient recently treated with antibiotics and presenting with new-onset diarrhea. Exposure up to 8 weeks before onset to any antimicrobial, including antifungal agents, should be considered. Clinical presentation, laboratory data, imaging studies, and endoscopic examinations are all useful. Atypical subtle presentations, especially in ambulatory patients with a remote and brief antibiotic exposure, require high suspicion. Leukocytosis, fecal leukocytes, and fecal occult blood are supportive of the diagnosis but not always present. Imaging studies, including plain radiographic films and computed tomography, are of marginal benefit as diagnostic tools but become helpful in severe cases to identify complications.

The cornerstone of the diagnosis of C. difficile colitis is identification of C. difficile toxins in the stool. Culture assays are considered to be the gold standard, based on the demonstration of toxin B cytopathic effects on cell culture monolayers. This test carries great specificity and sensitivity, detecting minimal toxin concentrations. Unfortunately, cell culture tests are expensive, time-consuming, and rarely used in clinical practice.

The most preferred diagnostic method in C. difficile colitis is the enzyme-linked immunosorbent assay (ELISA), based on toxin detection in the stool. Today, most commercially available methods detect both A and B toxins, obviating the problems of missing certain C. difficile strains that produce only toxin B. ELISA is fast, relatively inexpensive, and has excellent specificity; its sensitivity, however, is 75% to 85%. Serial stool determinations on different days are suggested for suspected cases with initial negative results.

The latex agglutination test is based on the detection of the enzyme glutamate dehydrogenase rather than on C. difficile toxin. Nontoxigenic strains of C. difficile, as well as other colonic organisms, may produce this enzyme. Latex agglutination tests are rarely used today because of their lack of specificity.

Endoscopy is a rapid but invasive and expensive diagnostic test for C. difficile colitis. Often, nonspecific findings of colitis such as edema, erythema, and loss of vascular pattern are the only findings. In cases of pseudomembranous colitis, endoscopy is diagnostic, because it may reveal typical raised, yellow nodules over areas of normal mucosa or minimal erythema. In more severe cases, coalescent nodules forming extensive areas of pseudomembranes over a background of inflammation and ulcerations are found (Fig. 2). In most cases, pseudomembranes are distributed throughout the colon and are readily identified within the reach of the sigmoidoscope. In a few cases, the pseudomembranes are confined to the right colon. Endoscopy should be used with caution and reserved for patients with severe colitis of unclear cause in whom a prompt diagnosis is needed.

Figure 2 Pseudomembranous colitis.

A, Multiple yellow coalescent plaques throughout the colonic mucosa, typical findings for pseudomembranous colitis. B, Flat raised lesions that vary in size with intervening hyperemic mucosa.

(From Feldman M, Friedman LS, Brandt LJ [eds]: Sleisenger and Fordtran’s Gastrointestinal and Liver Diseases, 8th ed. Philadelphia, WB Saunders, 2006.)

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