Clostridium difficile (C. difficile) is a Gram-positive bacillus and an anaerobic, spore-bearing bacterium present in the environment that is capable of colonizing and propagating in the human gut.
C. difficile infection (CDI) is a frequently acquired nosocomial intestinal infection, increasing severity has been reported, and CDI has a high mortality and morbidity rate. Clinical disease symptoms range from moderate diarrhea to toxic megacolon, colonic perforation, or even death. In both its 2013[1] and 2019[2] reports on antimicrobial resistance, the US Centers for Disease Control and Prevention rated CDI as an urgent health threat, the highest level. Community-associated CDI has become more frequent[3] and is linked to sources of C. difficile in animals and the environment. Thus, over the last two decades, CDI has emerged as an important One Health issue[4]. Vancomycin and fidaxomicin remain the first line antibiotics for treatment of non-severe CDI, though due to lower recurrence rates, infectious disease society guidelines now favour use of fidaxomicin[5].
C. difficile is taxonomically distinct from many other well-known clostridia, with a diverse population structure. Based on multi-locus sequence type, there are eight recognized monophyletic groups or “clades” of C. difficile. Strains within these clades show many unique clinical, microbiological, and ecological features[6]. Critical to the pathogenesis of CDI is the expression of the large clostridial toxins, TcdA and TcdB, and, in some strains, binary toxin (CDT), encoded by two separate chromosomal loci, the PaLoc and CdtLoc, respectively[7]. Clade 1 (C1) contains over 200 toxigenic and non-toxigenic sequence types (STs) including many of the most prevalent strains causing CDI worldwide, for example, ST2, ST8, and ST17[6]. Several highly virulent CDT-producing strains, including ST1 (PCR ribotype [RT] 027), a lineage associated with major hospital outbreaks in North America, Europe, and Latin America, are found in clade 2 (C2). Strains of ribotype 027 were responsible for 51% and 84% of CDI cases in the United States and Canada in 2005, respectively[8, 9]. Comparatively little is known about clade 3 (C3), although it contains ST5 (RT 023), a toxigenic CDT-producing strain with characteristics that may make laboratory detection difficult. C. difficile ST37 (RT 017) is found in clade 4 (C4) and, despite the absence of a toxin A gene, is responsible for much of the endemic CDI burden in Asia. Clade 5 (C5) contains several CDT-producing strains including ST11 (RTs 078, 126, and others), which are highly prevalent in production animals worldwide[10]. The remaining so-called “cryptic” clades (C-I, C-II, and C-III), first described in 2012, contain over 50 STs from clinical and environmental sources[11]. The evolution of the cryptic clades is poorly understood. Clade C-I strains can cause CDI, due to atypical toxin gene architecture, they may not be detected, thus their prevalence may have been underestimated[6, 11].
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[1] CDC. Antibiotic Resistance Threats in the United States, 2013[EB/OL]. (http://www.cdc.gov/drugresistance/threat-report-2013/)
[2] CDC. Antibiotic Resistance Threats in the United States, 2019[EB/OL]. (https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf)
[3] Guh A Y, Mu Y, Winston L G, et al. Trends in U.S. Burden of Clostridioides difficile Infection and Outcomes[J]. N Engl J Med, 2020, 382(14): 1320-1330.
[4] Lim S C, Knight D R, Riley T V. Clostridium difficile and One Health[J]. Clin Microbiol Infect, 2020, 26(7): 857-863.
[5] Clarke L M, Allegretti J R. Review article: The epidemiology and management of Clostridioides difficile infection-A clinical update[J]. Aliment Pharmacol Ther, 2024, 59(11): 1335-1349.
[6] Knight D R, Elliott B, Chang B J, et al. Diversity and Evolution in the Genome of Clostridium difficile[J]. Clin Microbiol Rev, 2015, 28(3): 721-41.
[7] Chandrasekaran R, Lacy D B. The role of toxins in Clostridium difficile infection[J]. FEMS Microbiol Rev, 2017, 41(6): 723-750.
[8] Mcdonald L C, Killgore G E, Thompson A, et al. An epidemic, toxin gene-variant strain of Clostridium difficile[J]. The New England journal of medicine, 2005, (23): 353.
[9] Jacek, Czepiel, Mirosław, et al. Clostridium difficile infection: review[J]. European Journal of Clinical Microbiology & Infectious Diseases Official Publication of the European Society of Clinical Microbiology, 2019, 38(7): 1211-1221.
[10] Knight D R, Imwattana K, Kullin B, et al. Major genetic discontinuity and novel toxigenic species in Clostridioides difficile taxonomy[J]. Elife, 2021, 10: e64325.
[11] Ramírez-Vargas G, López-Ureña D, Badilla A, et al. Novel Clade C-I Clostridium difficile strains escape diagnostic tests, differ in pathogenicity potential and carry toxins on extrachromosomal elements[J]. Sci Rep, 2018, 8(1): 13951.