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Published: February 2013

Clostridium difficile

Thomas G. Fraser

James F. Swiencicki

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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 infection (CDI) 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 CDI 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 may be as high as 50% in hospitalized patients where CDI is endemic, 5% to 7% in residents of long-term care facilities, and generally less than 2% in ambulatory adults.2,6 Carriage rates are higher in hospitalized patients who have received antibiotics. The reported incidence of C. difficile colitis among hospitalized inpatients ranges from 3.8 to 9.5 cases per 10,000 patient days. 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 CDI 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 3-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 CDI including cephalosporins, penicillins, and the fluoroquinolones.2,10 Chemotherapeutic agents, particularly those with antimicrobial properties, have also been associated with the development of CDI.

The second step is acquisition of a toxigenic strain of C. difficile. The organism 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 ymore 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 CDI is unknown, the time from acquisition to disease is relatively short, perhaps no longer than 7 days.13 Whether a patient will develop CDI 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 (Figure 2).

Figure 2.
Risk Factors for the Development of Clostridium difficile infection
Age
Severity of illness
Antacid therapy
Cathartics
Stool softeners
Gastrointestinal surgery
Enteral feeds
Nasogastric or oral gastric tubes

Adapted from Poutanen SM, Simor AE: Clostridium difficile–associated diarrhea in adults. CMAJ 2004;171:51-58; and Thielman NM, Wilson KH: Antibiotic-associated colitis. In Mandell GL, Bennett JE, Dolin R (eds): Principles and Practice of Infectious Diseases, 6th ed, vol 1. Philadelphia: Elsevier, 2005, pp 1249-1262.

The pathogenicity of C. difficile is rooted in the fact that 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 2 potent exotoxins, toxin A (a 308-kd enterotoxin) and toxin B (a 269-kd cytotoxin).15 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-alpha (TNF-alpha) and proinflammatory interleukins that cause a large inflammatory response and ultimately the 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.15 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.15 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.

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Epidemiology

Beginning in 2002 an epidemic strain of C. difficile emerged resulting in an increase in the incidence and severity of disease.16 This more virulent strain, referred to as NAP1 or BI, 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. While the epidemic strain has been shown to be more virulent, its emergence is also most likely linked to the increased age and acuity of hospitalized patients as well as the fact that it is resistant to the respiratory fluoroquinolones, commonly used agents in hospitals today. CDI has also been increasingly recognized in patient populations previously felt to be at low risk–healthy persons in the community and pregnant women.6 One report has demonstrated that C. difficile is the most common organism responsible for hospital acquired infections in the Southeastern U.S.17

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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.2,3 Symptoms include watery, nonbloody diarrhea accompanied by lower abdominal pain and cramping (20%-33%), fever (30%-50%), and leukocytosis (50%-60%)2,3 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 syndrome, tenosynovitis, pleural effusion, empyema, and infections of prosthetic devices.18

Diarrhea can recur in up to 40% of patients with CDI.2 Re-infection with a unique strain can also occur. The incidence of this type of infection in the BI era is uncertain suggesting continued exposure to a C. difficile endemic environment as well as persistence of risk factors for disease in affected patients. Commonly, the patient has received another course of antibiotic that predisposes him or her 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. One recurrence is a risk factor for a subsequent episode.

The differential diagnosis of CDI depends on the severity of the clinical presentation. Among the diagnoses to be considered in patients with symptoms limited to diarrhea or mild colitis are antibiotic-associated diarrhea, food-borne illness caused by enteric pathogens, and viral gastroenteritis. In patients presenting with more severe disease, particularly with ileus or abdominal distention, colitis, diverticulitis, ischemic causes must be considered.

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Diagnosis

CDI 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 CDI does occur but the 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. While available tests may vary from institution to institution, some general comments can be made. For instance, testing should only be done on unformed stool and in most cases 1 test is enough. Asymptomatic patients should not be tested and “tests of cure” should not be performed.6 Patients who have been successfully treated can still shed toxin in the stool and test results can be misleading.

Table 1: Tests Used for the Diagnosis of Clostridium difficile–Associated Diarrhea2,6
Test Sensitivity (%) Specificity (%) Advantages Disadvantages
Cytotoxin assay 80-90 99-100 Standard highly sensitive and specific; considered as gold standard Takes 24-48 hr to complete; requires tissue culture facility; cost; detects only toxin B
ELISA toxin test 65-85 95-100 Fast (2-6 hr), easy to perform, high specificity Not as sensitive as cytotoxin assay
Stool culture 90-100 98-100 Allows strain typing in epidemics Takes 2-5 days to complete; labor intensive; not specific for toxin-producing bacteria
Latex agglutination assay for glutamate dehydrogenase 58-68 80-96 Fast, inexpensive, easy to perform Poor sensitivity and specificity needed to establish diagnosis; requires confirmatory test
PCR assay toxin gene detection 92-97 100 Excellent sensitivity and specificity compared with cytotoxin assay Research test only; no commercial assays available
Endoscopy 51 ~100 Diagnostic of pseudomembranous colitis; can be used without need to collect stool sample Cost; invasive test; risk of perforation

ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction.


Data from: Poutanen SM, Simor AE: Clostridium difficile–associated diarrhea in adults. CMAJ 2004;171:51-58;. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepn J, Wilcox MH. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 updated by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431-455.

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 (GDH), 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 poor sensitivity and specificity compared with other available testing strategies. Strategies incorporating GDH assays as a screen followed by confirmatory testing with a more specific test have had mixed results. The logistical effects of this type of testing on infection prevention protocols must also be considered.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.

Polymerase chain reaction (PCR) assays for C. difficile toxins are increasingly being adopted by hospitals. These tests are more sensitive and specific as compared with ELISA.6 This testing approach provides rapid results but requires the clinical microbiology lab to have a molecular diagnostics infrastructure.

Endoscopy is an adjunctive test that 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 Imaging studies are also considered adjunctive but not diagnostic, can demonstrate the extent of colon involvement, and can assist in evaluating for other diagnoses in the differential.

Summary
  • Consider CDI 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. PCR is an emerging modality.
  • 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 CDI 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, however the emerging trends of CDI demonstrate that this is a potentially devastating infection that requires treatment. In addition to medical therapy, colonic resection 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 3 times daily is considered first-line therapy for mild-to-moderate C. difficile infection.6 Both metronidazole and vancomycin have been found to have similar efficacy in prospective randomized control trials.19,20 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.21 Recently, there have been concerns that metronidazole is inferior to vancomycin with clinically slower response rates. This observational data is 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.

Older agents with activity against CDI include bacitracin, fusidic acid, and teicoplanin. None are currently used in routine daily practice. Nitazoxanide has been shown to be similar to metronidazole for the treatment of mild-to-moderate CDI.25 Fidaxomicin has recently been approved for the treatment of CDI. It has shown to be non-inferior to vancomycin for the treatment of non-severe disease and to be associated with a decrease risk of recurrent disease for patients infected with non-BI strains of the organism.26

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.6 (Figure 3). Timely surgical and infectious disease consultations are critical for the complicated disease in these patients. Intravenous vancomycin is not effective in C. difficile infection because the drug is not excreted in the colon.

Figure 3.
Management of Clostridium difficile infection (CDI)
Metronidazole, 500 mg PO tid for 10 days (preferred)
Vancomycin, 125-250 mg PO qid for 10 days if metronidazole-intolerant or if patient fails to respond to metronidazole
For Moderate to Severe Disease:
White blood cell count >20,000/mm3, acute renal failure, abdominal distention, hemodynamic instability.
Vancomycin orally or via nasogastric tube, 500 mg q6h; vancomycin enema, 500 mg q6h
CDI with ileus or critical illness
Surgical and infectious disease consultation
Metronidazole, 500 mg q6h IV

Adapted from Olson MM, Shanholtzer CJ, Lee JT, et al: Ten years of prospective Clostridium difficile-associated disease surveillance and treatment at the Minneapolis VA Medical Center 1982-1991. Infect Control Hosp Epidemiol 1994;15:371-381; and from Apisarnthanarak A, Razavi B, Mundy LM: Adjunctive intracolonic vancomycin for severe Clostridium difficile colitis: case series and review of the literature. Clin Infect Dis. 2002;35(6):690-696.

CDI can recur after treatment with metronidazole or vancomycin with rates ranging from 15% to 30%.2 A first relapse should be treated with the same antimicrobial used in the initial regimen.6 Beyond the first relapse continued use of metronidazole is discouraged due to the cumulative risk of peripheral neuropathy. A taper and pulse strategy with vancomycin is an option that is commonly employed. Another strategy is that of the "rifaximin chaser" wherein a course of this agent follows a course of treatment─usually vancomycin.27 Finally, attempts to reconstitute the protective flora with fecal infusions via nasogastric tube or rectally have been reported to have great success. Continued work in this area is expected given the rise of technology that helps us understand the fecal microbiome.28,29

Surgical Options

Early surgical consultation should be considered for severe CDI, 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%.

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 CDI 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

Clostridium difficile is perhaps the quintessential hospital acquired pathogen in that it is an antibiotic-driven disease, affects those sick for other reasons, is resistant to multiple antibiotics, and, through its spore form persisting in the environment, being resistant to routine disinfection products. A full discussion of strategies is beyond the scope of this work and can be found elsewhere.6 Figure 4 summarizes basic principles for the prevention of CDI. Primary to controlling CDI is the prompt recognition, testing, and treatment of patients with disease. Standard precautions must be employed for all patients. For those recognized as having CDI, use of contact precautions is currently recommended. In settings of increased disease activity the routine use of hypochlorite containing disinfectants should be considered. Finally, judicious use of antimicrobials─minimizing the duration and number of antibiotics used when possibile─is critical to preventing CDI.

Figure 4.
Recommendations for the Prevention of Clostridium difficile Infection
Promptly test patients suspected of having CDI.
Standard precautions for all patients.
Contact precautions–gown and glove–for those with CDI.
Judicious use of antimicrobials for all patients.
Consider using hypochlorite containing environmental disinfectant in areas with increased rates.

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Suggested Readings

  • Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepn J, Wilcox MH: Clinical practice guidelines for Clostridium difficile infection in adults: 2010 updated by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31: 431-455.
  • Gerding DN, Johnson SJ: Management of Clostridium difficile infection: thinking inside and outside the box. Clin Infect Dis 2010;51:1306-1313
  • .
  • 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.
  • McFarland LV, Elmer GW, Suarawicz CM: Breaking the cycle: Treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002;97:1769-1775.
  • 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.

References

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  3. Kelly CP, Pothoulakis C, Lamont JT: Clostridium difficile colitis. N Engl J Med 1994;330:257-262.
  4. Duberberke ER, Butler AM, Reske KA, et al: Attributable outcomes of endemic Clostridium difficile-associated disease in nonsurgical patients. Emerg Infect Dis 2008;14: 1032-1038.
  5. Kyne L, Hamel MB, Plavaram R, Kelly CP: Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis 2002;34:346-353.
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  9. Tedesco FJ, Barone RW, Alpers DH: Clindamycin-associated colitis: A prospective study. Annals Int Med 1974;81:429-433.
  10. Muto CA, Pokrywka M, Shutt K, et al: A large outbreak 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.
  11. McFarland LV, Mulligan ME, Kwok RYY, Stamm WE: Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989;320:204-210.
  12. Samore MH, Venkataraman L, DeGirolami PC, et al: Clinical and molecular epidemiology of sporadic and clustered cases of nosocomial Clostridium difficile diarrhea. Am J Med 1996;100:32-40.
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  14. Kyne L, Warny M, Qamar A, Kelly CP: Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin a. N Engl J Med 2000;342:390-397.
  15. Voth DE, Ballard JD: Clostridium difficile toxins: Mechanism of action and role in disease. Clin Microbiol Rev 2005;18:247-263.
  16. 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.
  17. Miller BA, Chen LF, Sexton DJ, Anderson DJ: Comparison of the burdens of hospital onset, healthcare facility-associated Clostridium difficile infection, and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol 2011;32:387-390.
  18. Jacobs A, Barnard K, Fishel R, et al: Extracolonic manifestations of Clostridium difficile infections. Medicine 2001;80:88-101.
  19. Teasley DG, Gerding DN, Olson MM, et al: Perspective randomized trial of metronidazole versus vancomycin for Clostridium difficile–associated diarrhea and colitis. Lancet 1983;2:1043-1046.
  20. Wenisch C, Parschalk B, Hassenhundl M, et al: Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile–associated diarrhea. Clin Infect Dis 1996;22:813-818.
  21. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB: A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45:302-307.
  22. Comparison of clinical and microbiological response to treatment of Clostridium difficile-associated disease with metronidazole and vancomycin. Clin Infect Dis 2008;47:56-62.
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  25. Musher DM, Logan N, Hamill RJ, et al: Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis 2006;43:421-427.
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  28. Persky SE, Brandt LJ: Treatment of recurrent Clostridium difficile–associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol 2000;95:3283-3285.
  29. van Nood E, Vrieze A, Nieuwdorp M, et al: Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. N Engl J Med. 2013 Jan 16. [Epub ahead of print]. PMID: 23323867.

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