Introduction
Background
Clostridium difficile is a gram-positive, anaerobic, spore-forming bacillus that is responsible for the development of antibiotic-associated diarrhea and colitis. C difficile was first described in 1935 as a component of the fecal flora of healthy newborns and was initially not thought to be a pathogen. It was named difficile because it grows slowly and is difficult to culture. While early investigators noted that the bacterium produced a potent toxin, the role of C difficile in antibiotic-associated diarrhea and pseudomembranous colitis was not elucidated until the 1970s.
Endoscopic visualization of pseudomembranous colitis, a characteristic manifestation of full-blown Clostridium difficile colitis. Classic pseudomembranes are visible as raised yellow plaques ranging from 2-10 mm in diameter and scattered over the colorectal mucosa. Courtesy of Gregory Ginsberg, MD, University of Pennsylvania.
C difficile infection commonly manifests as mild-to-moderate diarrhea, occasionally with abdominal cramping. Pseudomembranes, adherent yellowish-white plaques on the intestinal mucosa, occasionally are observed. In rare cases, patients with C difficile infection can present with an acute abdomen and fulminant life-threatening colitis. Approximately 20% of individuals who are hospitalized acquire C difficile during hospitalization, and more than 30% of these patients develop diarrhea. Thus, C difficile colitis is currently one of the most common nosocomial infections.
The diagnosis of C difficile colitis should be suspected in any patient with diarrhea who has received antibiotics within the previous 2 months and/or when diarrhea occurs 72 hours or more after hospitalization.
Pathophysiology
C difficile colitis results from a disturbance of the normal bacterial flora of the colon, colonization with C difficile, and release of toxins that cause mucosal inflammation and damage. Antibiotic therapy is the key factor that alters the colonic flora. Hospitalized patients are the primary targets of C difficile infection. C difficile is present in 2-3% of healthy adults and in as many as 70% of healthy infants. Treatment of asymptomatic carriers is not recommended. Colonization occurs by the fecal-oral route. C difficile forms heat-resistant spores that can persist in the environment for several months to years. Outbreaks of C difficile diarrhea may occur in hospitals and other outpatient facilities where contamination with spores is prevalent. Normal gut flora resists colonization and overgrowth with C difficile. Antibiotic use, which suppresses the normal flora, allows proliferation of C difficile.
Pathogenic strains of C difficile produce 2 distinct toxins. Toxin A is an enterotoxin, and toxin B is a cytotoxin. Both are high–molecular weight proteins capable of binding to specific receptors on the intestinal mucosal cells. Receptor-bound toxins gain intracellular entry where they catalyze a specific alteration of Rho proteins, small glutamyl transpeptidase (GTP)–binding proteins that assist in actin polymerization, cytoskeletal architecture, and cell movement. Both toxin A and toxin B appear to play a role in the pathogenesis of C difficile colitis in humans.
Frequency
United States
C difficile infection primarily occurs in hospitalized patients, causing as many as 3 million cases of diarrhea and colitis per year. McFarland et al (1989) reported that 7% of patients admitted to a hospital and 28% of patients who were hospitalized had positive cultures for the organism. The incidence of C difficile in hospitalized patients has been on the rise, ranging from 30-40/100,000 in the 1990s to 84/100,000 by 2005. According to one report, only 20,000 cases per year are diagnosed in outpatients.
International
The incidence of C difficile as well as deaths attributable to C difficile over the past 20 years has also risen in Europe and Canada. In Canada's Estrie region of Quebec, the incidence quadrupled in 2003 to 92.2/100,000.
Mortality/Morbidity
While most patients with C difficile colitis recover without specific therapy, symptoms may be prolonged and debilitating. C difficile associated diarrhea can be a serious condition with a mortality rate as high as 25% in elderly patients who are frail. Reports that focus on patients who are more seriously ill indicate mortality rates of 10-30%. Mortality rates have also risen over the past decade and reflect an increase in admissions and the virulence for C difficile.
Several outbreaks have been caused by the North American Pulsed Field type 1 and PCR ribotype 027 (NAP1/027) strain. This virulent strain has been associated with increased production of toxins A + B, fluoroquinolone resistance, and the production of binary toxin. The role of binary toxin is not clear but it may synergistically increase the virulence of toxins A and B. Based on data from the Centers of Disease Control and Prevention, the virulent strain NAP1/027 has been reported in most states throughout the U.S. and in several countries in Europe.
Sex
C difficile colitis has no sexual predilection.
Age
C difficile infection is more common in elderly people, and old age may promote susceptibility to colonization and disease. While infants and young children frequently harbor C difficile and its toxins, clinical infection is uncommon. Cross-infection by C difficile is common in neonatal units, but neonates do not seem to develop C difficile associated diarrhea. More recently that have been more populations affected by C difficile that were believed to be low risk. These populations include young healthy persons not exposed to a hospital environment or antimicrobial therapy and young women in peripartum setting.
Clinical
History
C difficile colonization results in a wide spectrum of clinical conditions, including an asymptomatic carrier state, mild self-limited diarrhea, pseudomembranous colitis, and fulminant colitis.
- Most patients develop diarrhea during or shortly after starting antibiotics. However, 25-40% of patients may not become symptomatic for as many as 10 weeks after completing antibiotic therapy.
- Symptoms often include the following:
- Mild-to-moderate watery diarrhea that is rarely bloody
- Cramping abdominal pain
- Anorexia
- Malaise
- Fever, especially in more severe cases
Physical
- Physical examination may reveal the following:
- Fever
- Dehydration
- Lower abdominal tenderness
- Rebound tenderness - Raises the possibility of colonic perforation and peritonitis
Causes
C difficile colitis results from a disruption of the normal bacterial flora of the colon, colonization with C difficile, and release of toxins that cause mucosal inflammation and damage.
- The chief risk factor for the disease is prior exposure to antibiotics.
- The most common antibiotics implicated in C difficile colitis include cephalosporins (especially second and third generation), ampicillin/amoxicillin, and clindamycin.
- Less commonly implicated antibiotics are the macrolides (ie, erythromycin, clarithromycin, azithromycin) and other penicillins.
- Agents occasionally reported to cause the disease include aminoglycosides, fluoroquinolones, trimethoprim-sulfamethoxazole, metronidazole, chloramphenicol, tetracycline, imipenem, and meropenem.
- Even brief exposure to any single antibiotic can cause C difficile colitis.
- A prolonged antibiotic course or the use of 2 or more antibiotics increases the risk of disease.
- Even antibiotics traditionally used to treat C difficile colitis have been shown to cause disease.
- Other risk factors include the following:
- Advanced age (>60 y)
- Hospitalization (particularly sharing a hospital room with an infected patient, intensive care unit stays, and prolonged hospital stays)
- Rarer associations include the following:
- Gastric acid suppressive therapy (proton pump inhibitors)
- Antineoplastic agents, principally methotrexate
- Hemolytic-uremic syndrome
- Malignancies
- Intestinal ischemia
- Renal failure
- Necrotizing enterocolitis
- Hirschsprung disease
- Inflammatory bowel disease
- Nonsurgical gastrointestinal procedures, including nasogastic tubes
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References
Sailhamer EA, Carson K, Chang Y, et al. Fulminant Clostridium difficile colitis: patterns of care and predictors of mortality. Arch Surg. May 2009;144(5):433-9; discussion 439-40. [Medline].
Miller AT, Tabrizian P, Greenstein AJ, et al. Long-term follow-up of patients with fulminant Clostridium difficile colitis. J Gastrointest Surg. May 2009;13(5):956-9. [Medline].
Bartlett JG. Pseudomembranous enterocolitis and antibiotic-associated colitis. In: Feldman M, Scharschmidt BF, Sleisenger MH, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 6th ed. Philadelphia, Pa:. WB Saunders Co;1998:1633-1647.
Cleary RK. Clostridium difficile-associated diarrhea and colitis: clinical manifestations, diagnosis, and treatment. Dis Colon Rectum. Nov 1998;41(11):1435-49. [Medline].
Fekety R. Guidelines for the diagnosis and management of Clostridium difficile- associated diarrhea and colitis. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. May 1997;92(5):739-50. [Medline].
Gilbert DN, Moellering RC, Sande MA. The Sanford Guide to Antimicrobial Therapy. 13th ed. Hyde Park, Vt:. Antimicrobial Therapy;2000:12.
Johnson S, Gerding DN. Clostridium difficile--associated diarrhea. Clin Infect Dis. May 1998;26(5):1027-34; quiz 1035-6. [Medline].
Jones EM, Kirkpatrick BL, Feeney R. Hospital-acquired Clostridium difficile diarrhoea. Lancet. Apr 19 1997;349(9059):1176-7. [Medline].
Kelly CP, LaMont JT. Clostridium difficile infection. Annu Rev Med. 1998;49:375-90. [Medline].
Kelly CP, LaMont JT. Clostridium difficile--more difficult than ever. N Engl J Med. Oct 30 2008;359(18):1932-40. [Medline].
Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med. Jan 27 1994;330(4):257-62. [Medline].
Lyerly DM, Wilkins TD. Clostridium difficile. Infections of the Gastrointestinal Tract. 1995;867-891.
McDonald CL, Gerding DN, Johnson S,. "Clostridium difficile: Changing Diagnosis, Epidemiology, and Treatment" The content of this virtual lecture is derived from a satellite symposium presented on April 7, 2008, during the 18th Annual SHEA Scientific Meeting. Available at http://www.rmei.com/CDI010/.
McFarland LV, Mulligan ME, Kwok RY. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med. Jan 26 1989;320(4):204-10. [Medline].
Schneeweiss S, Korzenik J, Solomon DH, et al. Infliximab and other immunomodulating drugs in patients with inflammatory bowel disease and the risk of serious bacterial infections. Aliment Pharmacol Ther. Aug 2009;30(3):253-64. [Medline].
Sonnenberg A. Similar geographic variations of mortality and hospitalization associated with IBD and Clostridium difficile colitis. Inflamm Bowel Dis. Jul 27 2009;epub ahead of print. [Medline].
Starr J. Clostridium difficile associated diarrhoea: diagnosis and treatment. BMJ. Sep 3 2005;331(7515):498-501. [Medline].
Further Reading
Keywords
C difficile, gut flora, antibiotic-associated diarrhea, pseudomembranous colitis, cephalosporins, ampicillin, amoxicillin, clindamycin, macrolides, erythromycin, clarithromycin, azithromycin, aminoglycosides, fluoroquinolones, trimethoprim-sulfamethoxazole, metronidazole, chloramphenicol, tetracycline, imipenem, meropenem, Clostridium Difficile colitis, C Difficile colitis, nosocomial infections, fulminant life-threatening colitis, toxin A, enterotoxin, toxin B, cytotoxin, C difficile infection, cramping abdominal pain, mild-to-moderate watery diarrhea, colonic perforation, peritonitis, hemolytic-uremic syndrome, necrotizing enterocolitis, Hirschsprung disease, inflammatory bowel disease
