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Clostridium difficile infection: new developments in epidemiology and pathogenesis

Key Points

  • This article reviews the latest clinical and fundamental research data on the important human pathogen Clostridium difficile.

  • The clinical aspects of C. difficile infection (CDI) that are discussed include description of the disease spectrum and severity, and the signs, symptoms and clinical pathogenesis of CDI. An overview of the available treatment options for CDI is also given, including discussion of the problems associated with each therapeutic approach and new recommendations for treatment based on disease severity and the numbers of recurrences. CDI prevention is also discussed. Prevention methods include preventing acquisition of C. difficile spores by patients (using barrier and cleaning methods) and reducing the risk of symptomatic infection if the organism is encountered, primarily by avoidance of unnecessary use of antimicrobials.

  • The laboratory diagnosis and characterization of C. difficile is also reviewed. The main detection methods and diagnostic tests, including the recent development of molecular testing and two-step diagnostic protocols, are discussed. The main molecular typing techniques used for C. difficile and the importance of antibiotic resistance testing are described.

  • The changing epidemiology of CDI is reviewed. Important changes in the epidemiology of CDI have been observed over the past five years, especially increased infection rates in hospitals, increased disease severity, and increased rates and mortality with patient age. Most of these changes are presumed to be driven by presence of a new epidemic strain, C. difficile BI/NAP1/027. Changes in host populations (human versus animal populations with previous low risk), a possible increase in community associated disease, and new risk factors have also been observed.

  • The known C. difficile virulence factors (TcdA and TcdB) and newly recognized virulence factors and their role in pathogenesis are discussed.

  • The role of antibiotics in the development of CDI is discussed in relation to the susceptibility of C. difficile to antibiotics taken by the patient. The implication of the resistance of C. difficile to the fluoroquinolone class of antibiotics, and fluoroquinolones as an increasing risk factor for CDI, are discussed.

Abstract

Clostridium difficile is now considered to be one of the most important causes of health care-associated infections. C. difficile infections are also emerging in the community and in animals used for food, and are no longer viewed simply as unpleasant complications that follow antibiotic therapy. Since 2001, the prevalence and severity of C. difficile infection has increased significantly, which has led to increased research interest and the discovery of new virulence factors, and has expanded and focused the development of new treatment and prevention regimens. This Review summarizes the recent epidemiological changes in C. difficile infection, our current knowledge of C. difficile virulence factors and the clinical outcomes of C. difficile infection.

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Figure 1: Model for the acquisition of Clostridium difficile infection (CDI).
Figure 2: The effect of antibiotics on the normal gut flora and the risk of Clostridium difficile infection (CDI).
Figure 3: Toxins produced by Clostridium difficile.
Figure 4: The clinical outcome of Clostridium difficile infection.
Figure 5: Clostridium difficile pathogenesis.

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Acknowledgements

M.R. was supported by EU grant 223585, ERA NET PathoGenoMics grant and ARRS grant J3-0194-0377-08.

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Competing interests

Dale N. Gerding has received research grants from ViroPharma, Optimer, Merck, GOJO Industries, Cepheid and Massachusetts Biological Laboratories. He is a consultant or advisory board member for ViroPharma, Optimer, Merck, GOJO Industries, Cepheid and BD GeneOhm. He currently holds patents for C. difficile prevention that are licensed to ViroPharma.

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Glossary

Pseudomembranous colitis

Found in some (generally the more severe cases) but not all patients with Clostridium difficile infection, and refers to changes on the inner surface of the lining of the large intestine (colon). Characteristically, the colon is inflamed and has visible patches caused by an inflammatory membrane that consists of red and white blood cells, fibrin and bacteria.

Leukocytosis

A term used to refer to an individual with an increased number of white blood cells. A common explanation for leukocytosis is infection, and in general the higher the number of white blood cells (particularly neutrophils) in the blood the greater the severity of the infection.

Toxic megacolon

An uncommon condition that occurs in only the most severe cases of Clostridium difficile infection. The large bowel (colon) becomes dangerously inflamed and dilated, and can eventually perforate.

Ribotype

Characterized by the pattern of amplified intergenic regions in the ribosomal RNA operons present in Clostridium difficile in multiple copies.

Toxinotype

A group of C. difficile strains with identical changes in the toxin-coding region known as the pathogenicity locus (PaLoc).

Heteroresistance

A type of resistance in which some but not all of the cells in a population are resistant to an antibiotic; the remainder retain their susceptibility to the antibiotic.

Negative predictive value

A measurement (usually expressed as a percentage) of all negative test results that are truly negative.

Positive predictive value

A measurement (usually expressed as a percentage) of all positive test results that are truly positive.

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Rupnik, M., Wilcox, M. & Gerding, D. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 7, 526–536 (2009). https://doi.org/10.1038/nrmicro2164

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