Clostridium difficile infection pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Pathophysiology
Bacteriology
Clostridia are motile bacteria that are ubiquitous in nature and are especially prevalent in soil. Under the microscope after Gram staining, they appear as long drumsticks with a bulge located at their terminal ends. Clostridium difficile cells are Gram positive. Clostridium shows optimum growth when plated on blood agar at human body temperatures. When the environment becomes stressed, however, the bacteria produce spores that tolerate the extreme conditions that the active bacteria cannot. First described by Hall and O'Toole in 1935, "the difficult clostridium" was resistant to early attempts at isolation and grew very slowly in culture.[1] C. difficile is a commensal bacterium of the human intestine in a minority of the population. . In small numbers it does not result in disease of any significance. Antibiotics, especially those with a broad spectrum of activity, cause disruption of normal intestinal flora, leading to an overgrowth of C. difficile. This leads to pseudomembranous colitis.
C. difficile is resistant to most antibiotics. It flourishes under these conditions. It is transmitted from person to person by the fecal-oral route. Because the organism forms heat-resistant spores, it can remain in the hospital or nursing home environment for long periods of time. It can be cultured from almost any surface in the hospital. Once spores are ingested, they pass through the stomach unscathed because of their acid-resistance. They change to their active form in the colon and multiply. It has been observed that several disinfectants commonly used in hospitals may fail to kill the bacteria, and may actually promote spore formation. However, disinfectants containing bleach are effective in killing the organisms[2].
Patients are rarely infected unless the normal flora of the intestinal tract has been altered by antibiotics. Following colonization C. diff releases two cytotoxins, A and B:
- The cytotoxins bind to receptors on intestinal epithelial cells.
- The cytotoxins usually result in acute inflammatory infiltrate, leading to cell necrosis and shedding.
- A shallow ulcer results, from which serum proteins, mucus, and inflammatory cells emanate, leading to the appearance of a pseudomembrane.
- Some strains do not produce toxin.
Toxins
Pathogenic C. difficile strains produce various toxins. The most well-characterized are enterotoxin (toxin A) and cytotoxin (toxin B).[3] These two toxins are both responsible for the diarrhea and inflammation seen in infected patients, although their relative contributions have been debated by researchers. Another toxin, binary toxin, has also been described, but its role in disease is not yet fully understood.[4]
Role in Disease
With the introduction of broad-spectrum antibiotics in the latter half of the twentieth century, antibiotic-associated diarrhea became more common. Pseudomembranous colitis was first described as a complication of C. difficile infection in 1978,[5] when a toxin was isolated from patients suffering from pseudomembranous colitis and Koch's postulates were met.
Clostridium Difficile Infection (CDI), can range in severity from asymptomatic to severe and life threatening, and many deaths have been reported, especially amongst the aged. People are most often infected in hospitals, nursing homes, or institutions, although C. difficile infection in the community, outpatient setting is increasing. Clostridium difficile associated diarrhea (aka CDAD) has been linked to use of broad-spectrum antibiotics such as cephalosporins and clindamycin, though the use of quinolones is now probably the most likely culprit, which are frequently used in hospital settings. Frequency and severity of C. difficile colitis remains high and seems to be associated with increased death rates. Immunocompromised status and delayed diagnosis appear to result in elevated risk of death. Early intervention and aggressive management are key factors to recovery.
The rate of Clostridium difficile acquisition is estimated to be 13 percent in patients with hospital stays of up to two weeks and 50 percent in those with hospital stays longer than four weeks.
Increasing rates of community-acquired Clostridium difficile-associated infection/disease (CDAD) has also been linked to the use of medication to suppress gastric acid production: H2-receptor antagonists increased the risk twofold, and proton pump inhibitors threefold, mainly in the elderly. It is presumed that increased gastric pH, (alkalinity), leads to decreased destruction of spores.[6]
References
- ↑ Hall I, O'Toole E (1935). "Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, Bacillus difficilis". Am J Dis Child. 49: 390.
- ↑ "Cleaning agents 'make bug strong'". BBC News Online. 3 April 2006. Retrieved 2007-01-11.
- ↑
- ↑ Barth H, Aktories K, Popoff M, Stiles B (2004). "Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins". Microbiol Mol Biol Rev. 68 (3): 373–402, table of contents. PMID 15353562.
- ↑ Larson H, Price A, Honour P, Borriello S (1978). "Clostridium difficile and the aetiology of pseudomembranous colitis". Lancet. 1 (8073): 1063–6. PMID 77366.
- ↑ Dial S, Delaney J, Barkun A, Suissa S (2005). "Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease". JAMA. 294 (23): 2989–95. PMID 16414946.