Clostridium difficile is the most common nosocomial pathogen of the gastrointestinal tract and has increased in frequency over time. Typical symptoms of C. difficile infection include diarrhea, which is usually nonbloody, or colitis associated with severe abdominal pain, fever and/or gross or occult blood in the stools. Pseudomembranous colitis (PMC), the severest form of this disease, occurs as a result of a severe inflammatory response to the C. difficile toxins. This review focuses on PMC, as this severe form is associated with the greatest medical concern. Diagnosis rests on detection of C. difficile in the stool, either by culture, tissue culture assay for cytotoxin B or detection of antigens in the stool by rapid enzyme immunoassays. Oral therapy with metronidazole 250 mg 4 times a day for 10 days is the recommended first-line therapy. Vancomycin is also effective, but its use must be limited to decrease the development of vancomycin-resistant organisms such as enterococci. Vancomycin (125–500 mg 4 times a day for 10 days) should be limited to those who cannot tolerate or have not responded to metronidazole, or when metronidazole use is contraindicated, as in the first trimester of pregnancy. A therapeutic response within a few days is usual. Recurrence of symptoms after antibiotics occurs in 20% of cases and is associated with persistence of C. difficile in the stools. Further recurrences then become more likely. Therapy with antibiotics in a pulsed or tapered regimen is often effective as are efforts to normalize the fecal flora. The yeast Saccharomyces boulardii has been proven in controlled trials to reduce recurrences when given as an adjunct to antibiotic therapy. Careful hand washing and environmental decontamination are necessary to prevent epidemics.

1.
Finney JMT: Gastroenterostomy for cicatrizing ulcer of the pylorus. Bull Johns Hopkins Hosp 1983;45:53–55.
2.
George WL: Antimicrobial agent-associated colitis and diarrhea: Historical background and clinical aspects. Rev Infect Dis 1984;6:S208–213.
[PubMed]
3.
Trnka YM, LaMont JT: Clostridium difficile colitis. Adv Intern Med 1984;29:85–106.
[PubMed]
4.
Terplan K, Paine JR, Sheffer J, Egan R, Lansky H: Fulminating gastroenterocolitis caused by staphylococci. Gastroenterology 1953;24:476–509.
5.
Batts DH, Silva J, Fekety R: Staphylococcal enterocolitis; in Nelson JD, Grassi C (eds): Current Chemotherapy and Infectious Diseases. Washington, American Society of Microbiology, 1980, vol II, pp 944–945.
6.
Tedesco FJ, Barton RW, Alpers DH: Clindamycin-associated colitis: A prospective study. Ann Intern Med 1974;81:429–433.
[PubMed]
7.
Larson HE, Price AB: Pseudomembranous colitis: Presence of clostridial toxin. Lancet 1977;ii:1312–1314.
8.
Bartlett JG, Onderdonk AB, Cisneros RL, Kasper DL: Clindamycin-associated colitis due to a toxin-producing species of Clostridium in hamsters. J Infect Dis 1977;136:701–705.
[PubMed]
9.
Bartlett JG, Chang TW, Gurwith M, Gorbach SL, Onderdonk AB: Antibiotic associated pseudomembranous colitis due to toxin-reducing Clostridia. N Engl J Med 1978;298:531–534.
[PubMed]
10.
Gebhard RL, Gerding DN, Olson MM, Peterson LR, McClain CJ, Ansel HJ, Shaw MJ, Schwartz ML: Clinical and endoscopic findings in patients early in the course of Clostridium difficile-associated pseudomembranous colitis. Am J Med 1985;78:45–48.
11.
Andrejak M, Lafon B, Decocq G, Chetaille E, Dupas JL, Ducroix JP, Capron JP: Antibiotic-associated pseudomembranous colitis: Retrospective study of 48 cases diagnosed by colonoscopy (in French). Thérapie 1996;51:81–86.
[PubMed]
12.
Zwiener RJ, Belknap WM, Quan R: Severe pseudomembranous enterocolitis in a child: Case report and literature review. Pediatr Infect Dis J 1989;8:876–882.
[PubMed]
13.
Bulstrode NW, Bradbury AW, Barrett S, Standsby G, Mansfield AO, Nicolaides AN, Wolfe JH: Clostridium difficile colitis after aortic surgery. Eur J Vasc Endovasc Surg 1997;14:217–220.
[PubMed]
14.
Freiman JP, Graham DJ, Green L: Pseudomembranous colitis associated with single-dose cephalosporin prophylaxis. JAMA 1989;262:902.
15.
Gerding DN, Olson MM, Peterson LR, Teasley DG, Gebhard RL, Schwartz ML, Lee JT Jr: Clostridium difficile-associated diarrhea and colitis in adults. Arch Intern Med 1986;146:95–100.
[PubMed]
16.
Jobe BA, Grasley A, Deveney KE, Deveney CW, Sheppard BC: Clostridium difficile colitis: An increasing hospital-acquired illness. Am J Surg 1995;169:480–484.
[PubMed]
17.
Triadafilopoulos G, Hallstone AE: Acute abdomen as the first presentation of pseudomembranous colitis. Gastroenterology 1991;101:685–691.
[PubMed]
18.
Burke GW, Wilson ME, Mehrez IO: Absence of diarrhea in toxic megacolon complicating Clostridium difficile pseudomembranous colitis. Am J Gastroenterol 1988;83:304–307.
[PubMed]
19.
Coyne JD, Dervan PA, Haboubi NY: Involvement of the appendix in pseudomembranous colitis. J Clin Pathol 1997;50:70–71.
[PubMed]
20.
Lipsett PA, Samantaray DK, Tam ML, Bartlett JG, Lillemoe KD: Pseudomembranous colitis: A surgical disease? Surgery 1994;116:491–496.
[PubMed]
21.
Lofgren RP, Tadlock LM, Soltis RD: Acute oligoarthritis associated with Clostridium difficile pseudomembranous colitis. Arch Intern Med 1984;144:617–619.
[PubMed]
22.
Mogyorosi A, Carley MD: Hemolytic-uremic syndrome associated with pseudomembranous colitis caused by Clostridium difficile (letter). Nephron 1997;76:491.
[PubMed]
23.
Rooney N, Variend S, Taitz LS: Haemolytic uraemic syndrome and pseudomembranous colitis. Pediatr Nephrol 1988;2:415–418.
[PubMed]
24.
Fekety R: Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Am J Gastroenterol 1997;92:739–750.
[PubMed]
25.
Jacobs J, Rudensky B, Dresner J, Berman A, Sonnenblick M, van Dijk Y, Yinnon AM: Comparison of four laboratory tests for diagnosis of Clostridium difficile-associated diarrhea. Eur J Microbiol Infect Dis 1996;15:561–566.
26.
Staneck JL, Weckbach LS, Allen SD, Siders JA, Gilligan PH, Coppitt G, Kraft JA, Willis DH: Multicenter evaluation of four methods for Clostridium difficile detection: ImmunoCard C. difficile, cytotoxin assay, culture and latex agglutination. J Clin Microbiol 1996;34:2718–2721.
[PubMed]
27.
Barbut F, Petit J-C: Laboratoriy methods for detecting the toxins of Clostridium difficile; in Rambaud J-C, LaMont JT (eds): Updates on Clostridium difficile.Paris, Springer France, 1996, pp 93–104.
28.
Johnson LL, McFarland LV, Dearing P, Raisys V, Schoenknecht FD: Identification of Clostridium difficile in stool specimens by culture-enhanced gas-liquid chromatography. J Clin Microbiol 1989;27:2218–2221.
[PubMed]
29.
Olson MM, Shanholtzer CJ, Lee JT Jr, Gerding DN: 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.
[PubMed]
30.
McFarland LV: Clostridium difficile-associated disease; in Surawicz, Owen RL (eds): Gastrointestinal and Hepatic Infections. Philadelphia, Saunders Co, 1995, pp 153–175.
31.
Morris JB, Zollinger RM, Stellato TA: Role of surgery in antibiotic-induced pseudomembranous enterocolitis. Am J Surg 1989;160:535–539.
32.
Seppälä K, Hjelt L, Sipponen P: Colonoscopy in the diagnosis of antibiotic associated colitis: A prospective study. Scand J Gastroenterol 1981;16:465–468.
[PubMed]
33.
Tedesco FJ: Antibiotic-associated pseudomembranous colitis with negative proctosigmoidoscopic examination. Gastroenterology 1979;77:295–297.
[PubMed]
34.
Price AB, Davies DR: Pseudomembranous colitis. J Clin Pathol 1977;30:1–12.
[PubMed]
35.
Nathan MA, Seabold JE, Brown BP, Bushnell DL: Colonic localization of labelet leukocytes in critically ill patients: Scintigraphic detection of pseudomembranous colitis. Clin Nucl Med 1995;20:99–106.
[PubMed]
36.
Dignan CR, Greenson JK: Can ischemic colitis be differentiated from C. difficile colitis in biopsy specimens? Am J Surg Pathol 1997;21:700–710.
37.
Boland GW, Lee MJ, Cats A, Mueller PR: Pseudomembranous colitis: Diagnostic sensitivity of the abdominal plain radiograph. Clin Radiol 1994;49:473–475.
[PubMed]
38.
Watanabe H, Uchida R, Kurita S, Sato A, Ohishi K, Rikitomi N, Nagatake T: A case of pseudomembranous enterocolitis which diagnosis was delayed in the outpatient clinic (in Japanese). Kansenshogaku Zasshi 1997;71:83–86.
[PubMed]
39.
Whitehead R: Colitis: Problems in definition and diagnosis. Virchows Arch A Pathol Anat 1990;417:187–190.
[PubMed]
40.
Uc A, Mitros FA, Kao SCS, Sanders KD: Pseudomembranous colitis with Escherichia coli O157:H7. J Pediatr Gatroenterol Nutr 1997;24:623–625.
41.
Elmer GW, Surawicz CM, McFarland LV: Biotherapeutic agents: A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–876.
[PubMed]
42.
Borriello SP: Pathogenesis of Clostridium difficile infection of the gut. J Med Microbiol 1990;33:207–215.
[PubMed]
43.
Bongaerts GPA, Lyerly DM: Role of toxins A and B in the pathogenesis of Clostridium difficile disease. Microb Pathogens 1994;17:1–12.
44.
Tucker KD, Carrig PE, Wilkins TD: Toxin A of Clostridium difficile is a potent cytotoxin. J Clin Microbiol 1990;28:869–871.
[PubMed]
45.
Guerrant RL, Lima AAM, Thielman NM, Steiner TS, Fonteles MC: Diarrhea, demography and cell signaling: Lessons from microbial toxins. Trans Am Clin Climatol Assoc 1997;108:149–164.
46.
Riegler M, Sedivy R, Pothoulakis C, Hamilton G, Zacherl J, Bischof G, Cosentini E, Feil W, Schiessel R, LaMont JT, Wenzl E: Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro. J Clin Invest 1995;95:2004–2011.
[PubMed]
47.
Smith JA, Cooke DL, Hyde S, Borriello SP, Long RC: Clostridium difficile toxin A binding to human intestinal epithelial cells. J Med Microbiol 1997;40:953–958.
48.
LaMont JT: Recent advances in the structure and function of Clostridium difficile toxins; in Rambaud J-C, LaMont JT (eds): Updates on Clostridium difficile. Paris, Springer France, 1996, pp 73–82.
49.
Just I, Fritz G, Aktories K, Giry M, Popoff MR, Boquet P, Hegenbarth S, von Eichel-Streiber C: Clostridium difficile toxin B acts on the GTP-binding protein Rho. J Biol Chem 1994;269:10706–10712.
[PubMed]
50.
Hecht G, Pothoulakis C, LaMont JT, Madara JL: Clostridium difficile toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers. J Clin Invest 1988;82:1516–1524.
[PubMed]
51.
Rothman SW, Brown JE, Diecidue A, Foret DA: Differential cytotoxic effects of toxins A and B isolated from Clostridium difficile. Infect Immun 1984;46:324–331.
[PubMed]
52.
Bradbury AW, Barrett S: Surgical aspects of Clostridium difficile colitis. Br J Surg 1997;84:150–159.
[PubMed]
53.
Branka JE, Vallette C, Jarry A, Boullanna C, Lamarre P, Van PN, Laboisse CL: Early functional effects of Clostridium difficile toxin A on human colonocytes. Gastroenterology 1997;112:1887–1894.
[PubMed]
54.
Rocha MF, Maia ME, Bezerra LR, Lyerly DM, Guerrant RL, Ribeiro RA, Lima AA: Clostridium difficile toxin A induces the release of neutrophil chemotactic factors from rat peritoneal macrophages: Role of interleukin-1beta, tumor necrosis factor alpha and leukotrienes. Infect Immun 1997;65:2740–2746.
[PubMed]
55.
Burakoff R, Zhao L, Celifarco AJ, Rose KL, Donovan V, Pothoulakis C, Percy WH: Effects of purified Clostridium difficile toxin A on rabbit distal colon. Gastroenterology 1995;109:348–354.
[PubMed]
56.
Kelly CP, Becker S, Linevsky JK, Joshi MA, O’Keane JC, Dickey BF, LaMont JT, Pothoulakis C: Neutrophil recruitment in Clostridium difficile toxin A enteritis in the rabbit. J Clin Invest 1994:93:1257–1265.
[PubMed]
57.
Schnitt SJ, Antonioli DA, Goldman H: Massive mural edema in severe pseudomembranous colitis. Arch Pathol Lab Med 1983;107:211–213.
[PubMed]
58.
Arnon SS, Mills DC, Day PA, Henrickson RV, Sullivan NM, Wilkins TD: Rapid death of infant rhesus monkeys injected with Clostridium difficile toxins A and B: Physiologic and pathologic basis. J Pediatr 1984;104:34–40.
[PubMed]
59.
Percy WH, Christensen J: Antibiotic depression of evoked and spontaneous responses of opossum distal colonic muscularis mucosae in vitro: A factor in antibiotic-associated colitis? Gastroenterology 1985;88:964–970.
[PubMed]
60.
Pothoulakis C, Castagliuolo I, LaMont JT, Jaffer A, O’Keane JC, Snider RM, Leeman SE: CP-96,345, a substance P antagonist, inhibits rat intestinal responses to Clostridium difficile toxin A but not cholera toxin. Proc Natl Acad Sci USA 1994;91:947–951.
[PubMed]
61.
Silva J Jr: Update on pseudomembranous colitis. West J Med 1989;151:644–648.
[PubMed]
62.
Bramdev A: Pseudomembranous colitis: A clinicopathological review of 7 cases. S Afr Med J 1989;76:221–223.
[PubMed]
63.
Byrd RP Jr, Roy TM, Ossorio MA, Fields CL: Delayed onset of pseudomembranous colitis after rifampin therapy. South Med J 1997;90:644–646.
[PubMed]
64.
Trexler F, Fraser TG, Jones MP: Fulminant pseudomembranous colitis caused by clindamycin phosphate vaginal cream. Am J Gastroenterol 1997;92:2112–2113.
[PubMed]
65.
Takao T, Nishida M, Maeda Y, Takao K, Oka M: The study of continuous infusion chemotherapy with low-dose cisplatin and 5-fluorouracil for patients with primary liver cancer (in Japanese). Gan To Kagaku Ryoho 1997;24:1724–1727.
[PubMed]
66.
Trevisani F, Simoncini M, Alampi G, Bernardi M: Colitis associated to chemotherapy with 5-fluorouracil. Hepatogastroenterology 1997;44:710–712.
[PubMed]
67.
Yokoyama T, Kondo H, Yokota T, Tokue Y, Sito D, Shimada Y, Sugihara K: Colonoscopy for frank bloody stools associated with cancer chemotherapy. Jpn J Clin Oncol 1997;27:111–114.
[PubMed]
68.
Qualman SJ, Petric M, Karmali MA, Smith CR, Hamilton SR: Clostridium difficile invasion and toxin circulation in fatal pediatric pseudomembranous colitis. Am J Clin Pathol 1990;94:410–416.
[PubMed]
69.
Zamora S, Copes MJ, Scott RB, Mueller DL: Clostridium difficile, pseudomembranous enterocolitis: Striking CT and sonographic features in a pediatric patient. Eur J Radiol 1996;23:104–106.
[PubMed]
70.
Fekety R, Silva J, Kauffman C, Buggy B, Derry HG: Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: Comparison of two dosage regimens. Am J Med 1989;86:15–19.
71.
Teasley DG, Olson MM, Gebhard RL, Gerding DN, Peterson LR, Schwartz MJ, Lee JT Jr: Prospective randomised trial of metronidazole versus vancomycin for Clostridium difficile-associated diarrhoea and colitis. Lancet 1983;2:1043–1046.
[PubMed]
72.
Edmond MB, Ober JF, Weinbaum DL, Pfaller MA, Hwang T, Sanford MD, Wenzel RP: Vancomycin-resistant Enterococcus faecium bacteremia: Risk factors for infection. Clin Infect Dis 1995;20:1134–1136.
[PubMed]
73.
Young GP, Ward PB, Bayley N, Gordon D, Higgins G, Trapani JA, McDonald MI, Labrooy J, Hecker R: Antibiotic-associated colitis due to Clostridium difficile: Double-blind comparison of vancomycin with bacitracin. Gastroenterology 1985;89:1038–1045.
[PubMed]
74.
Cronberg S, Castor B, Thoren A: Fusidic acid for the treatment of antibiotic-associated colitis induced by Clostridium difficile. Infection 1984;12:276–279.
[PubMed]
75.
DeLalla F, Nicolin R, Rionaldi E, Scarpelini P, Rigoli R, Manfrin V, Tramarin A: Prospective study of oral teicoplanin versus oral vancomycin for therapy of pseudomembranous colitis and Clostridium difficile-associated diarrhea. Antimicrob Agents Chemother 1992;36:2192–2195.
[PubMed]
76.
Kleinfeld DI, Sharpe RJ, Donta ST: Parenteral therapy for antibiotic-associated pseudomembranous colitis (letter). J Infect Dis 1988;157:389.
[PubMed]
77.
Oliva SL, Guglielmo BJ, Jacobs R, Pons VG: Failure of intravenous vancomycin and intravenous metronidazole to prevent or treat antibiotic-associated pseudomembranous colitis. J Infect Dis 1989;159:1154–1155.
[PubMed]
78.
Bolton RP, Culshaw MA: Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile. Gut 1986;27:1169–1172.
[PubMed]
79.
Guzman R, Kirkpatrick J, Forward K, Lim F: Failure of parenteral metronidazole in the treatment of pseudomembranous colitis. J Infect Dis 1988;158:1146–1147.
[PubMed]
80.
Fekety R, Shah AB: Diagnosis and treatment of Clostridium difficile colitis. JAMA 1993;269:71–75.
[PubMed]
81.
Prendergast TM, Marini CP, D’Angelo AS, Sher ME, Cohen JR: Surgical patients with pseudomembranous colitis: Factors affecting progress. Surgery 1994;116:768–774.
[PubMed]
82.
Toothaker RD, Elmer GW: Prevention of clindamycin-induced mortality in hamsters by Saccharomyces boulardii. Antimicrob Agents Chemother 1984;26:552–556.
[PubMed]
83.
Elmer GW, McFarland LV: Suppression by Saccharomyces boulardii of toxigenic Clostridium difficile overgrowth after vancomycin treatment in hamsters. Antimicrob Agents Chemother 1987;31:129–131.
[PubMed]
84.
Surawicz CM, McFarland LV, Elmer G, Chinn J: Treatment of recurrent Clostridium difficile colitis with vancomycin and Saccharomyces boulardii. Am J Gastroenterol 1989;84:1285–1287.
[PubMed]
85.
McFarland LV, Surawicz CM, Greenberg RN, Fekety R, Elmer GW, Moyer KA, Melcher SA, Bowen KE, Cox JL, Noorani Z, Harrington G, Rubin M, Greenwald D: A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994:271:1913–1918.
[PubMed]
86.
Seal DV, Borriello SP, Barclay F, Welch A, Piper M, Bonnycastle M: Treatment of relapsing Clostridium difficile diarrhoea by administration of non-toxigenic strain. Eur J Clin Microbiol 1987;67:51–53.
87.
Schwaan A, Sjolin S, Trottestam U, Aronsson B: Relapsing C. difficile enterocolitis cured by rectal infusion of normal feces. Scand J Infect Dis 1984;16:211–215.
[PubMed]
88.
Tvede M, Rask-Madsen J: Bacteriotherapy for chronic relapsing Clostridium difficile diarrhea in six patients. Lancet 1989;i:1156–1160.
89.
Gorbach SL, Chang TW, Goldin B: Successful treatment of relapsing Clostridium difficile colitis with Lactobacillus GG (letter). Lancet 1987;ii:1519.
You do not currently have access to this content.