DEFINITION AND CAUSES

Clostridium difficile is an obligate anaerobic, spore-producing, gram-positive rod that was first described in 1935. Its link with pseudomembranous colitis and Clostridium difficile–associated diarrhea (CDAD) was established in 1978.^1,2 It is the implicated pathogen in 20% to 30% of patients with antibiotic-associated diarrhea, 50% to 75% of those with antibiotic-associated colitis, and more than 90% of those with antibiotic-associated pseudomembranous colitis.³ CDAD is an important hospital-acquired infection associated with an increase in length of hospital stay and cost and substantial morbidity and mortality.^4,5

INCIDENCE AND PREVALENCE

Prevalence rates of C. difficile depend on the patient population, antibiotic prescribing patterns, endemic strains, and criteria used to define antibiotic-associated diarrhea.^2,6 The estimated prevalence of C. difficile colonization varies from 7% to 11% in hospitalized patients, 5% to 7% in residents of long-term care facilities, and generally less than 2% in ambulatory adults.² Carriage rates are higher in hospitalized patients who have received antibiotics. The reported incidence of C. difficile colitis among hospitalized inpatients ranges from 1 to 10 cases per 1000 discharges and it has been shown that these rates may vary over time in a given institution.⁶ These numbers likely increase in direct proportion to hospital length of stay. The incidence of CDAD is increasing.⁷

PATHOPHYSIOLOGY AND NATURAL HISTORY

The current understanding of the natural history of C. difficile infection can be conceptualized as a three-step process.⁸ As outlined in Figure 1, the first step is alteration of the normal gut flora, usually as a result of administration of an antibiotic. Clindamycin was the first antibiotic to be associated with pseudomembranous colitis, identified as a precipitant before the establishment of C. difficile as the causal pathogen.⁹ Since that initial observation, almost all antimicrobials have been associated with CDAD including the cephalosporins and the penicillins.² Recently, attention has focused on a growing link between the widespread use of fluoroquinolones and CDAD.¹⁰ Chemotherapeutic agents, particularly those with antimicrobial properties, have also been associated with the development of CDAD.

Figure 1 Pathophysiology and natural history of Clostridium difficile–associated diarrhea (CDAD).

HCW, health care worker.

The second step is acquisition of a toxigenic strain of C. difficile. It is primarily a nosocomially acquired pathogen and its spores can be found in the hospital environment, with the chance of contamination being highest for those in closest proximity to symptomatic patients.¹¹ Most disease transmission is caused by transient carriage on health care workers’ hands. The direct effect of the environment on transmission is difficult to assess, although studies have shown that the more contaminated the environment, the more likely health care workers’ hands are contaminated.¹²

Once a patient has acquired C. difficile, he or she will develop clinical disease or will remain asymptomatically colonized, the final step in the process. Although the exact incubation time for CDAD is unknown, the time from acquisition to disease is relatively short, perhaps no longer than 7 days.¹³ Whether a patient will develop CDAD once exposed to the pathogen has been shown to correlate with the ability to mount a humoral immune response.¹⁴ Further clinical risk factors for the development of acute disease have also been identified (Box 1).

The pathogenicity of C. difficile is because it is a spore-forming toxigenic organism. The spore form of the organism is resistant to gastric acid and can therefore readily pass through the stomach to the intestine, where it changes to a vegetative life cycle.² As this occurs, the organism releases two potent exotoxins, toxin A (a 308-kd enterotoxin) and toxin B (a 269-kd cytotoxin).⁶ These toxins not only open tight junctions between the cells of the intestine that result in increased vascular permeability and hemorrhage, but they also induce the production of tumor necrosis factor α and proinflammatory interleukins that cause a large inflammatory response and ultimately formation of pseudomembranes. Toxin A was previously believed to play a more important role in the development of diarrhea because animal models demonstrated more extensive tissue damage and fluid accumulation in the intestine compared with toxin B, which appeared to cause its effects only after the intestinal walls were damaged by toxin A. However, toxin A is not essential for virulence because virulent strains of C. difficile that are toxin A–negative but toxin B–positive have been described.

The genes that encode toxins A, tcdA, and B, tcdB, are found on the pathogenicity locus in C. difficile. These genes are situated in close proximity on this locus and are transcribed in the same direction.³⁶ Three other genes, tcdC, tcdD, and tcdE, are also located on the pathogenicity locus and are believed to play a role in regulation of toxin production.³⁶ The tcdC gene lies downstream of tcdA and is transcribed in the opposite direction from tcdA and tcdB. It functions as a negative regulator of toxin production. The tcdD gene is found upstream from tcdB and is believed to be a major positive regulator of toxins A and B production. The tcdE gene lies between tcdA and tcdB and is believed to facilitate the release of toxins A and B through permeabilization of the C. difficile cell wall.

Recently, there has been the emergence of a new epidemic strain of C. difficile responsible for increases in the incidence and severity of disease.¹⁵ This strain is characterized by the deletion of tcdC and the hyperproduction of toxins A and B. It is also characterized by the production of binary toxin, as well as a more resistant antimicrobial susceptibility pattern. The significance of binary toxin production is still being investigated.

SIGNS AND SYMPTOMS

C. difficile infection manifests as a spectrum of disease, including asymptomatic carriage, simple antibiotic-associated diarrhea, pseudomembranous colitis, and fulminant colitis with toxic megacolon.¹⁶ Symptoms include watery, nonbloody diarrhea accompanied by lower abdominal pain and cramping (20%-33%), fever (30%-50%), and leukocytosis (50%-60%).⁶ Nausea, malaise, anorexia, hypoalbuminemia, and occult colonic bleeding may also be present. Fulminant colitis is characterized by a toxic appearance, fever, diffuse abdominal pain, and distention. These patients may develop toxic megacolon and paralytic ileus, with little or no diarrhea, which ultimately can result in colonic perforation and peritonitis with substantial mortality.² The incidence of severe disease has increased recently.

Extracolonic manifestations of C. difficile infection have been described. They are rare and include bacteremia, splenic abscess, osteomyelitis, reactive arthritis: Reiter’s syndrome, tenosynovitis, pleural effusion, empyema, and infections of prosthetic devices.¹⁷

Recurrent diarrhea can occur in up to 40% of patients with CDAD.² Re-infection accounts for almost 50% of these cases, which suggests continued exposure to a C. difficile endemic environment as well as persistence of risk factors for disease in affected patients. Commonly, patients have received another course of antibiotics that predisposes to the second episode. The intraluminal presence of C. difficile spores likely contributes to recurrence of symptoms in those with true relapses. Most relapses will occur within 1 month of the end of therapy. Relapse caused by antibiotic resistance is not common. One recurrence is a risk factor for a subsequent episode.

The differential diagnosis of CDAD depends on the severity of the clinical presentation. Considerations in those with symptoms limited to diarrhea or mild colitis should include antibiotic-associated diarrhea, food-borne illness caused by enteric pathogens, and viral gastroenteritis. In those presenting with more severe disease, particularly with ileus or abdominal distention, colitis, diverticulitis, and other causes of a surgical abdomen must be considered ischemic.

DIAGNOSIS

CDAD should be considered in any currently or recently hospitalized patient treated with antibiotics who develops diarrhea. This holds for residents of long-term care facilities or rehabilitation centers. Community-acquired CDAD does occur but the vast majority of patients will have had recent exposure in a traditional health care setting.

Table 1 outlines the tests used for the diagnosis of C. difficile. No single best testing algorithm has been established for the diagnosis of CDAD, but some broad comments can be made. Typically, a single unformed stool specimen is sufficient to detect C. difficile toxins; however, repeat testing may be required.^2,6 Multiple specimens on the same day are seldom useful. Patients successfully treated can still shed toxin in their stool and therefore testing cure specimens should not be done because the results can be misleading.

Table 1 Tests Used for the Diagnosis of Clostridium difficile–Associated Diarrhea^2,6,16,19

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