Clostridium difficile Infections

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Introduction

Clostridium difficile is a Gram positive, anaerobic, sporulating bacterium that can be found in human intestinal normal flora [1]. C. difficile was originally named Bacillus difficilis in 1935 in recognition of the difficulty of its isolation. It is most commonly known for causing C. difficile infections (CDIs) as an opportunistic pathogen, resulting in diarrhea and pseudomembranous colitis [2]. While the literature on the healthcare costs of CDI is lacking, a more recent 2008 estimate on the costs in the US for CDIs was set at $4.8 billion [3] and does not include the costs for long term care.

Epidemiology

Transmission and Prevalence

Transmission of C. difficile is done via the fecal-oral route through the acquisition of C. difficile spores [4]. Primarily, spore transmission is considered to be from human-to-human but there is mounting evidence demonstrating the possibility of a zoonotic origin as well as a connection to ingestion from food [5]. CDIs were also viewed exclusively as nosocomial infections but recent emergence of CDIs in populations considered to be of low risk [6] has created a distinction between hospital-acquired and community-acquired CDIs. In Canada, a study on hospital reported CDIs has shown that there was no significance difference in prevalence of nosocomial CDIs within regions of Canada [7].

Risk Factors

There are several risk factors involved with CDIs [8]. Since C. difficile can be found in the normal flora of the gut, alterations in the balance of gut microbiota, also known as dysbiosis, can allow the bacterium to widely colonize the gut and cause a symptomatic infection. This is usually established through the use of broad spectrum antibiotics or multiple antibiotics. Another major factor is the healthcare setting in which C. difficile presence is prevalent, in particular hospitals. Other risk factors include age, where older individuals are at a higher risk of infection, gastric acid suppression and presence of inflammatory bowel disease. Also, a past study has demonstrated an association between patient age and strain type with CDI outcome, implicating their strong roles as determinants [9].

Clinical Presentation and Diagnosis

Symptoms

Carriers of C. difficile may be asymptomatic or symptomatic which creates a distinction between colonization, the former, and infection, the latter [10]. Symptoms include different severities of diarrhea, fever, loss of appetite, abdominal pain, colitis and pseudomembranous colitis [10,11].

Diagnostic Tests

No single, unambiguous method has been identified as an effective diagnostic test [11]. However current techniques employed focus on identifying virulence related toxins and their respective genes, as not all strains of C. difficile carry these toxins. Thus, simply culturing C. difficile from the patient is not sufficient as evidence of a CDI. A positive case of CDI includes both the presentation of clinical symptoms as well as positive identification of C. difficile toxins, toxigenic C. difficile or pseudomembranous colitis [12].

Molecular Pathogenesis

Toxins

The primary virulence factors for C. difficile are toxin A (TcdA) and toxin B (TcdB) [13]. All pathogenic strains of C. difficile carry the TcdB gene and only some carry both. So far, none are found to carry the TcdA gene alone. These genes are found at a location known as the Pathogenicity Locus (PaLoc) [14]. As C. difficile proliferates in the gut during colonization, these toxins accumulate and bind to the host cells. Then, they are brought into the cytoplasm. TcdA and TcdB have a glucosyl-transferase domain that glucosylates GTPases in the cell and inactivate them. GTPases are involved in host cell signalling pathways and cytoskeletal structure, so disrupting GTPases will also disrupt these two functions. More importantly, the toxins indirectly break down the tight junctions of the epithelium which causes the intestine to be more permeable. Presence of these toxins also cause the host cells to release cytokines [13], eliciting an immune response from the human host. Neutrophil recruitment results in further epithelial damage as inflammation ensues.

Other Virulence Factors

Other supporting virulence factors include a binary toxin, a S-layer and peptidoglycan structure [14]. Only some C. difficile strains carry the binary toxin which is known C. difficile transferase (CDT). CDT directly alters the cytoskeleton and studies have shown that it may aid with host cell attachment. S-layer also appears to have a role in adherence and is composed of many surface-layer proteins A (SlpA) arranged in a crystal lattice structure. The variability in the peptidoglycan structure of C. difficile allows it to resist the degradative effects of lysozyme and the targeting of its synthesis by β-lactam antibiotics. Also of note are the key proteins involved in germination and sporulation. CSpB is involved in removing the spore cortex during germination [13] and Spo0A is involved in the regulation of sporulation [14]. Both processes share similarities with the model organism Bacillis subtilis.

Treatment

Antibiotics

The orally administered antibiotics vancomycin and metronidazole are the primary therapeutic drugs of choice for treatment of CDIs [15]. However, as CDIs are generally induced through the use of broad spectrum antibiotics, further usage of broad spectrum antibiotics during the treatment will decrease the effectiveness and possible aggravate the issue. Recently, the novel RNA polymerase inhibitor antibiotic fidaxomicin has shown promise as an alternative to these traditional antibiotics [16]. Clinically, fidaxomicin is as effective as vancomycin and shows minimal absorption in patients. Minimizing absorption of the antibiotics in the gut allows them to more effectively function in the destruction of bacteria.

Alternatives

Microbial resistance to metronidazole and restricted use of vancomycin as treatment options for CDIs has created a need for alternate options [17]. One possibility is the application bacteriophage [17]. An in vitro study on the effects of bacteriophage ΦCD27 on C. difficile has shown a significant reduction in cell number upon treatment. Another option is the use of bacteriocins [18]. Thuricin CD, produced by Bacillus thuringiensis, was found to share similar minimum inhibitory concentrations to metronidazole and vancomycin when applied to C. difficile but benefits from the reduced effects on the gut microbiota. A final, perhaps more readily debated, option of note is the fecal microbiota transplant (FMT) [19]. The goal of FMT is to correct dysbiosis by re-establishing a stable gut microbiota, thus solving the problems relating to CDIs. While FMT shows promising results clinically, critics have indicated the need for randomized control trials [19] and the need to address the potential safety issues of FMT [20].

References

1. Office of Laboratory Security, PHAC. Available at: http://www.phac-aspc.gc.ca.ezproxy.library.ubc.ca/lab-bio/res/psds-ftss/msds36e-eng.php. Accessed 10/31, 2013.

2. Depestel DD, Aronoff DM. Epidemiology of Clostridium difficile Infection. J Pharm Pract. 2013;26:464-475.

3. Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin Infect Dis. 2012;55 Suppl 2:S88-92.

4. Public Health Agency of Canada (PHAC). Available at: http://www.phac-aspc.gc.ca.ezproxy.library.ubc.ca/id-mi/cdiff-eng.php. Accessed 10/31, 2013.

5. Hoover DG, Rodriguez-Palacios A. Transmission of Clostridium difficile in foods. Infect Dis Clin North Am. 2013;27:675-685.

6. Garg S, Mirza YR, Girotra M, et al. Epidemiology of Clostridium difficile-Associated Disease (CDAD): A Shift from Hospital-Acquired Infection to Long-Term Care Facility-Based Infection. Dig Dis Sci. 2013.

7. Simor AE, Williams V, McGeer A, et al. Prevalence of colonization and infection with methicillin-resistant staphylococcus aureus and vancomycin-resistant enterococcus and of clostridium difficile infection in Canadian hospitals. Infect Control Hosp Epidemiol. 2013;34:687-693.

8. Knight CL, Surawicz CM. Clostridium difficile Infection. Med Clin North Am. 2013;97:523-36, ix.

9. Miller M, Gravel D, Mulvey M, et al. Health care-associated Clostridium difficile infection in Canada: patient age and infecting strain type are highly predictive of severe outcome and mortality. Clin Infect Dis. 2010;50:194-201.

10. Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/hai/organisms/cdiff/cdiff_faqs_hcp.html. Accessed 10/31, 2013.

11. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478-98; quiz 499.

12. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431-455.

13. Peniche AG, Savidge TC, Dann SM. Recent insights into Clostridium difficile pathogenesis. Curr Opin Infect Dis. 2013;26:447-453.

14. Vedantam G, Clark A, Chu M, McQuade R, Mallozzi M, Viswanathan VK. Clostridium difficile infection: toxins and non-toxin virulence factors, and their contributions to disease establishment and host response. Gut Microbes. 2012;3:121-134.

15. Rea MC, Alemayehu D, Ross RP, Hill C. Gut solutions to a gut problem: bacteriocins, probiotics and bacteriophage for control of Clostridium difficile infection. J Med Microbiol. 2013;62:1369-1378.

16. Sears P, Ichikawa Y, Ruiz N, Gorbach S. Advances in the treatment of Clostridium difficile with fidaxomicin: a narrow spectrum antibiotic. Ann N Y Acad Sci. 2013;1291:33-41.

17. Meader E, Mayer MJ, Steverding D, Carding SR, Narbad A. Evaluation of bacteriophage therapy to control Clostridium difficile and toxin production in an in vitro human colon model system. Anaerobe. 2013;22:25-30.

18. Rea MC, Alemayehu D, Ross RP, Hill C. Gut solutions to a gut problem: bacteriocins, probiotics and bacteriophage for control of Clostridium difficile infection. J Med Microbiol. 2013;62:1369-1378.

19. Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108:500-508.

20. Brandt LJ. American Journal of Gastroenterology Lecture: Intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of ‘‘C. difficile’’ infection. Am J Gastroenterol. 2013;108:177-185.