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

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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

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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.

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.

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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.

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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.

The tissue culture cytotoxin assay, which detects toxin B from stool filtrate, is considered the gold standard because of its high sensitivity and specificity.² The disadvantages are its need for 24 to 48 hours for completion, as well as requiring tissue culture capability.

The most common test used to establish a diagnosis of C. difficile is an enzyme-linked immunosorbent assay (ELISA) for toxin A or toxins A and B.¹⁸ The ELISA test is less technically demanding as compared with the cytotoxin assay. Although not as sensitive as the gold standard, the test performs well and has been widely adopted by clinical microbiology laboratories. Repeated testing may improve its sensitivity, although one specimen should usually be sufficient for diagnosis.⁶

Although inexpensive and easy to perform, a latex agglutination test for glutamate dehydrogenase, or common antigen, which is an enzyme-produced in Clostridium spp. as well as other bacteria, is not recommended for use in C. difficile diagnosis. This is because of its low poor sensitivity and specificity compared with other available testing strategies.⁶

Stool culture for C. difficile is rarely performed in clinical microbiology laboratories because of inconvenience compared with other marketed tests. Culture is very sensitive but not specific, because it will not distinguish between toxigenic and nontoxigenic strains.⁶ This question can be answered if a toxin assay is added as a second step in the test. The benefits of stool culture include the ability to perform epidemiologic investigations and strain typing of isolates.

The polymerase chain reaction (PCR) assay for C. difficile toxins is currently a research method that shows promise as a more sensitive and specific test as compared with ELISA, with results similar to those of cytotoxin assays.² Its use in the clinical setting may be limited because of its cost compared with ELISA.¹⁶

Endoscopy should be considered when a rapid diagnosis is required, the patient has an ileus and stool is unable to be obtained, and other colonic diseases are being considered, such as inflammatory bowel disease.⁶ Sigmoidoscopy or colonoscopy is required to visualize the colonic mucosa to establish the diagnosis of pseudomembranous colitis. Pseudomembranes are 2- to 10-mm raised yellow plaques that may have areas of normal mucosa or may coalesce to form larger plaques. Flexible sigmoidoscopy can miss up to 10% of cases of pseudomembranous colitis. If pseudomembranes are not visualized on endoscopy, then the findings of C. difficile colitis may be nonspecific and biopsies should be taken. Endoscopy should be used judiciously in patients with fulminant colitis given the incumbent risk of perforation.²

Findings of a thickened, edematous bowel wall (thumbprinting) may be seen on abdominal plain radiographs as well as on computed tomography (CT) scans in patients with pseudomembranous colitis.^2,16 Imaging studies are adjunctive but not diagnostic, can demonstrate the extent of colon involvement, and can assist in evaluating for other diagnoses in the differential.

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Summary

• Consider CDAD infection in any patient with nosocomial diarrhea or diarrhea following recent antibiotic administration.
• A single unformed stool specimen is usually adequate for C. difficile testing.
• Most clinical laboratories use ELISA tests for C. difficile toxins because of their cost, convenience, and sensitivity.
• Endoscopy is required to establish the diagnosis of pseudomembranous colitis or when stool samples are unable to be obtained secondary to ileus.

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Treatment

The most important aspect of management of CDAD is rapid recognition of the disease and discontinuation of the inciting agent.² Historically, as many as 50% of patients will respond to stopping the precipitating antibiotic. Medical therapy for CDAD is necessary in moderate to severe disease and surgery may be necessary for severe disease. Adequate hydration and electrolyte replenishment should accompany medical and surgical therapy. Antiperistaltics should be avoided because these can exacerbate toxin-mediated damage to the mucosa.

Medical Options

Oral metronidazole, 500 mg three times daily, or vancomycin, 125 to 250 mg four times daily for 10 to 14 days is considered first-line therapy for C. difficile–associated dirarrhea.¹⁹ Both agents have been found to have similar efficacy in prospective randomized control trials.^20,21 Metronidazole is the preferred first-line therapy because of its lower cost and concerns that oral vancomycin selects for vancomycin-resistant Enterococcus.^16,19 Oral vancomycin should be reserved for those patients with intolerance to metronidazole, those who fail to respond to metronidazole, or those who have more severe disease. Recently, there have been concerns that metronidazole is inferior to vancomycin. This observational data are noteworthy but as of yet there is no evidence that metronidazole should be abandoned for this disease.^22-24 The epidemic strain that has been recently identified reminds us of the potentially severe consequences of this disease and the need for careful clinical attention. If a patient on metronidazole deteriorates, a change to vancomycin is likely warranted. It usually takes 3 or 4 days for a patient to begin to improve with appropriate therapy. To date, there has been no documentation of metronidazole or vancomycin resistance to C. difficile.

In patients who are unable to tolerate oral medications or who have severe ileus, IV metronidazole in combination with intracolonic vancomycin via nasogastric tube is appropriate.²⁶ In addition, vancomycin enemas have been used for the patient with severe disease and ileus (Box 2). Timely surgical and infectious disease consultations are critical for these complicated patients. IV vancomycin is not efficacious in C. difficile infection because the drug is not excreted in the colon.^2,16

CDAD can recur after treatment with metronidazole or vancomycin.¹⁹ A first relapse should be treated with the same antimicrobial used in the initial regimen.¹⁶ Multiple relapses have been treated with various medical regimens, including pulsed and tapered metronidazole and vancomycin, combinations with rifampin, colestipol, or cholestyramine.^{16,19,25,27,28} Small case series have shown IV immunoglobulin to be helpful in both recurrent and severe disease.²⁹ Studies using adjunctive probiotics such as Saccharomyces boulardii and Lactobacillus GG have had mixed results.³⁰ The lack of standardization of probiotic preparations makes endorsement of these approaches difficult. There are also reports of severe consequences of this adjunctive therapy.³¹ Finally, attempts to reconstitute the protective flora with fecal infusions via nasogastric tube or rectally have been reported to have great success.^32,33

Newer agents in the treatment of C. difficile are currently in development. These include not only antimicrobials but also toxin-neutralizing agents and vaccines.

Surgical Options

Early surgical consultation should be considered for severe CDAD, especially if toxic megacolon is present, because operative intervention can be lifesaving.⁶ Various surgical procedures have been described, including diversion of fecal stream by ileostomy, decompressive colostomy, or subtotal colectomy, the procedure of choice with toxic megacolon. Cases requiring surgery carry high mortality rates, ranging from 30% to over 50%.

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Summary

• Oral metronidazole remains the preferred initial agent in the treatment of C. difficile–associated diarrhea.
• Oral vancomycin should be considered if the patient fails to respond to metronidazole or has severe disease.
• The severely ill patient with CDAD requires a multidisciplinary approach, and surgery may be lifesaving.
• The first relapse should be treated with the same antimicrobial used for the initial therapy.
• Recurrent infection can be difficult to manage and includes various treatment strategies.

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Prevention

Box 3 reviews practice guidelines for the prevention of CDAD. The proper use of antibiotics is essential for prevention. Institutional antimicrobial restriction of agents associated with an increased risk of C. difficile (e.g., clindamycin, cephalosporins) can be effective in controlling outbreaks.^34,35

The Centers for Disease Control and Prevention has recommended measures to prevent the nosocomial transmission of C. difficile. These can be found at http://www.cdc.gov/ncidod/dhqp/id_CdiffFAQ_HCP.html.

Institution of these measures requires an ongoing surveillance program to identify patients with CDAD. Patients should be placed in a private room, if possible, particularly if they have fecal incontinence. If private rooms are not available, cohorting of affected patients is acceptable. Hands should be washed with soap and water or alcohol hand rub after contact with infected patients. In outbreak settings, the preferential use of soap and water should be considered, because alcohol rubs may not be as effective in removing spores from the hands. Gloves should be worn when entering the room of a patient with CDAD. Gowns should be worn for significant patient contact. Equipment should be dedicated whenever possible. Meticulous cleaning of all environmental surfaces must be ensured and, if ongoing cross-transmission occurs, a hypochlorite-based solution is recommended.

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Suggested Readings

• Gerding DN, Johnson S, Peterson LR, et al: Clostridium difficile–associated diarrhea and colitis. Infect Control Hosp Epidemiol. 1995, 16: 459-477.
• Johnson S, Gerding GN. Clostridium difficile–associated diarrhea. Clin Infect Dis. 1998, 26: 1027-1036.
• McDonald LC, Killgore GE, Thompson A, et al: An epidemic, toxin gene–variant strain of Clostridium difficile. N Engl J Med. 2005, 353: 2433-2441.
• McFarland LV, Mulligan ME, Kwok RYY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med. 1989, 320: 204-210.
• McFarland LV, Surawicz CM, Stamm WE. Risk factors for Clostridium difficile carriage and C. difficile–associated diarrhea in a cohort of hospitalized patients. J Infect Dis. 1990, 162: 678-684.
• Muto CA, Pokrywka M, Shutt K, et al: A large outbfeak of Clostridium difficile–associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol. 2005, 26: 273-280.
• Poutanen SM, Simor AE. Clostridium difficile–associated diarrhea in adults. CMAJ. 2004, 171: 51-58.
• Shim JK, Johnson S, Samore MH, et al: Primary symptomless colonization by Clostridium difficile and decreased risk of subsequent diarrhea. Lancet. 1998, 351: 633-636.
• Thielman NM, Wilson KH. Antibiotic-associated colitis. 6th edIn: Mandell GL, Bennett JE, Dolin R (eds): Principles and Practice of Infectious Diseases. vol 1: 2005, Philadelphia: Elsevier, 1249-1262.