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Clostridium difficile infection

Abstract

Infection of the colon with the Gram-positive bacterium Clostridium difficile is potentially life threatening, especially in elderly people and in patients who have dysbiosis of the gut microbiota following antimicrobial drug exposure. C. difficile is the leading cause of health-care-associated infective diarrhoea. The life cycle of C. difficile is influenced by antimicrobial agents, the host immune system, and the host microbiota and its associated metabolites. The primary mediators of inflammation in C. difficile infection (CDI) are large clostridial toxins, toxin A (TcdA) and toxin B (TcdB), and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhoea, inflammation and tissue necrosis — the major symptoms of CDI. The factors responsible for the epidemic of some C. difficile strains are poorly understood. Recurrent infections are common and can be debilitating. Toxin detection for diagnosis is important for accurate epidemiological study, and for optimal management and prevention strategies. Infections are commonly treated with specific antimicrobial agents, but faecal microbiota transplants have shown promise for recurrent infections. Future biotherapies for C. difficile infections are likely to involve defined combinations of key gut microbiota.

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Figure 1: Clostridium difficile.
Figure 2: Stages of the Clostridium difficile life cycle in the human gastrointestinal tract.
Figure 3: Innate immune response of host cells to Clostridium difficile.
Figure 4: Regulation of the Clostridium difficile toxins.
Figure 5: Structure and function of the large clostridial toxins.
Figure 6: Histopathology of Clostridium difficile infection in a mouse model.
Figure 7: Mechanism of action of Clostridium difficile transferase (binary toxin).
Figure 8: Diagnosis and treatment options for Clostridium difficile infections.
Figure 9: Faecal microbiota transplant.
Figure 10: Cost per case of Clostridium difficile infection.

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Acknowledgements

This work was partially supported by a Vidi fellowship from the Netherlands Organization for Scientific Research and a Gisela Thier Fellowship from the Leiden University Medical Center to W.K.S.; a National Institutes of Health Award AI95755 and a Burroughs Wellcome Investigator in the Pathogenesis of Infectious Disease Award to D.B.L.; and a Future Fellowship FT120100779 of the Australian Research Council to D.L. The authors thank the ESCMID Study Group for Clostridium difficile (ESGCD) for their advice and suggestions and apologize to the authors whose work could not be cited due to restrictions imposed by the format of this Primer. W. Knetsch is acknowledged for drafting the illustration used in Box 1.

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Introduction (W.K.S.); Epidemiology (M.H.W., E.J.K. and W.K.S.); Mechanisms/pathophysiology (D.B.L., D.L. and W.K.S.); Diagnosis, screening and prevention (M.H.W., E.J.K. and W.K.S.); Management (M.H.W., E.J.K. and W.K.S.); Quality of life (M.H.W., E.J.K. and W.K.S.); Outlook (W.K.S. and E.J.K.); overview of the Primer (W.K.S.).

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Correspondence to Wiep Klaas Smits.

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Competing interests

W.K.S. has performed research for Cubist. D.L. has performed research for Immuron and Adenium Biotech. D.B.L. has performed research for MedImmune and Merck. M.H.W. has received consulting fees from Abbott, Actelion Pharmaceuticals, Astellas, AstraZeneca, Bayer, Cerexa, Cubist, Durata, The European Tissue Symposium, The Medicines Company, MedImmune, Merck, Motif Biosciences, Nabriva, Optimer, Paratek, Pfizer, Roche, Sanofi Pasteur, Seres Therapeutics, Summit Pharmaceuticals, and Synthetic Biologics. M.H.W. has also received lecture fees from Abbott, Alere, Astellas, AstraZeneca, Pfizer and Hoffmann La Roche, and received grant support from Abbott, Actelion, Astellas, bioMérieux, Cubist, Da Volterra, The European Tissue Symposium, Merck and Summit Pharmaceuticals. E.J.K. has performed research for Cubist, Novartis and Qiagen, and has participated in advisory forums of Astellas, Optimer, Actelion, Pfizer, Sanofi Pasteur and Seres Therapeutics. These companies had no role in the writing of this Primer.

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Smits, W., Lyras, D., Lacy, D. et al. Clostridium difficile infection. Nat Rev Dis Primers 2, 16020 (2016). https://doi.org/10.1038/nrdp.2016.20

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