Stock Ticker

Clostridioides difficile pathogenesis and control

  • Lawson, P. A., Citron, D. M., Tyrrell, K. L. & Finegold, S. M. Reclassification of Clostridium difficile as Clostridioides difficile (Hall and O’Toole 1935) Prévot 1938. Anaerobe 40, 95–99 (2016).

    Article 

    Google Scholar
     

  • Kuehne, S. A. et al. Importance of toxin A, toxin B, and CDT in virulence of an epidemic Clostridium difficile strain. J. Infect. Dis. 209, 83–86 (2014). This article showcases the role of the different CDTs in causing infection.

    Article 
    CAS 

    Google Scholar
     

  • van Prehn, J. et al. European society of clinical microbiology and infectious diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clin. Microbiol. Infect. 27, S1–s21 (2021).

    Article 

    Google Scholar
     

  • Mounsey, A., Lacy Smith, K., Reddy, V. C. & Nickolich, S. Clostridioides difficile infection: update on management. Am. Fam. Physician 101, 168–175 (2020).


    Google Scholar
     

  • Hall, I. C. & O’toole, E. Intestinal flora in new-born infants: with a description of a new pathogenic anaerobe, Bacillus difficilis. Am. J. Dis. Child. 49, 390–402 (1935).

    Article 

    Google Scholar
     

  • George, W. L., Sutter, V. L., Goldstein, E. J., Ludwig, S. L. & Finegold, S. M. Aetiology of antimicrobial-agent-associated colitis. Lancet 1, 802–803 (1978).

    Article 
    CAS 

    Google Scholar
     

  • Bartlett, J. G., Moon, N., Chang, T. W., Taylor, N. & Onderdonk, A. B. Role of Clostridium difficile in antibiotic-associated pseudomembranous colitis. Gastroenterology 75, 778–782 (1978).

    Article 
    CAS 

    Google Scholar
     

  • Tsigrelis, C. Recurrent Clostridioides difficile infection: recognition, management, prevention. Cleve. Clin. J. Med. 87, 347–359 (2020).

    Article 

    Google Scholar
     

  • Guh, A. Y. et al. Characteristics of patients with initial Clostridioides difficile infection (CDI) that are associated with increased risk of multiple CDI recurrences. Open Forum Infect. Dis. 11, ofae127 (2024).

    Article 
    PubMed Central 

    Google Scholar
     

  • Olsen, M. A., Yan, Y., Reske, K. A., Zilberberg, M. D. & Dubberke, E. R. Recurrent Clostridium difficile infection is associated with increased mortality. Clin. Microbiol. Infect. 21, 164–170 (2015).

    Article 
    CAS 

    Google Scholar
     

  • Olsen, M. A., Yan, Y., Reske, K. A., Zilberberg, M. & Dubberke, E. R. Impact of Clostridium difficile recurrence on hospital readmissions. Am. J. Infect. Control. 43, 318–322 (2015).

    Article 

    Google Scholar
     

  • Tresman, R. & Goldenberg, S. D. Healthcare resource use and attributable cost of Clostridium difficile infection: a micro-costing analysis comparing first and recurrent episodes. J. Antimicrob. Chemother. 73, 2851–2855 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Fawley, W. N. et al. Development and validation of an internationally-standardized, high-resolution capillary gel-based electrophoresis PCR-ribotyping protocol for Clostridium difficile. PLoS ONE 10, e0118150 (2015).

    Article 
    PubMed Central 

    Google Scholar
     

  • Freeman, J. et al. The changing epidemiology of Clostridium difficile infections. Clin. Microbiol. Rev. 23, 529–549 (2010).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • McDonald, L. C. et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious diseases society of America (IDSA) and Society for healthcare epidemiology of America (SHEA). Clin. Infect. Dis. 66, e1–e48 (2018).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Guh, A. Y. et al. Trends in U.S. burden of Clostridioides difficile infection and outcomes. N. Engl. J. Med. 382, 1320–1330 (2020).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Alshannaq, A. F. et al. Diverse sources and latent reservoirs of community-associated Clostridioides difficile infection. Clin. Infect. Dis. 80, 37–42 (2025).

    Article 

    Google Scholar
     

  • Worley, J. et al. Genomic determination of relative risks for Clostridioides difficile infection from asymptomatic carriage in intensive care unit patients. Clin. Infect. Dis. 73, e1727–e1736 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Gilboa, M., Baharav, N., Melzer, E., Regev-Yochay, G. & Yahav, D. Screening for asymptomatic Clostridioides difficile carriage among hospitalized patients: a narrative review. Infect. Dis. Ther. 12, 2223–2240 (2023).

    Article 
    PubMed Central 

    Google Scholar
     

  • Caballero-Flores, G., Pickard, J. M. & Núñez, G. Microbiota-mediated colonization resistance: mechanisms and regulation. Nat. Rev. Microbiol. 21, 347–360 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Dingle, K. E. et al. Effects of control interventions on Clostridium difficile infection in England: an observational study. Lancet Infect. Dis. 17, 411–421 (2017).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Slimings, C. & Riley, T. V. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J. Antimicrob. Chemother. 69, 881–891 (2014).

    Article 
    CAS 

    Google Scholar
     

  • Dingle, K. E. et al. Penicillin binding protein substitutions cooccur with fluoroquinolone resistance in epidemic lineages of multidrug-resistant Clostridioides difficile. mBio 14, e0024323 (2023).

    Article 

    Google Scholar
     

  • Webb, B. J. et al. Antibiotic exposure and risk for hospital-associated Clostridioides difficile infection. Antimicrob. Agents Chemother. 64, e02169-19 (2020).

    Article 
    PubMed Central 

    Google Scholar
     

  • Johnson, S. et al. Clinical practice guideline by the infectious diseases society of America (IDSA) and society for healthcare epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin. Infect. Dis. 73, e1029–e1044 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Buckley, A. M., Moura, I. B. & Wilcox, M. H. The potential of microbiome replacement therapies for Clostridium difficile infection. Curr. Opin. Gastroenterol. 38, 1–6 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Wilcox, M. H. et al. Changing epidemiology of Clostridium difficile infection following the introduction of a national ribotyping-based surveillance scheme in England. Clin. Infect. Dis. 55, 1056–1063 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Agnew, E. et al. Impact of testing on Clostridioides difficile infection in hospitals across Europe: a mathematical model. Clin. Microbiol. Infect. 29, 796.e1–796.e6 (2023).

    Article 

    Google Scholar
     

  • Tkalec, V. et al. Clostridioides difficile positivity rate and PCR ribotype distribution on retail potatoes in 12 European countries, January to June 2018. Eur. Surveill. 27, 2100417 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Rupnik, M. et al. Distribution of Clostridioides difficile ribotypes and sequence types across humans, animals and food in 13 European countries. Emerg. Microbes Infect. 13, 2427804 (2024).

    Article 
    PubMed Central 

    Google Scholar
     

  • Viprey, V. F. et al. A point-prevalence study on community and inpatient Clostridioides difficile infections (CDI): results from Combatting Bacterial Resistance in Europe CDI (COMBACTE-CDI), July to November 2018. Eur. Surveill. 27, 2100704 (2022). This article offers a detailed description of the rates of community and health-care-associated CDI across Europe, regardless of diagnosis.

    Article 
    CAS 

    Google Scholar
     

  • Abdrabou, A. M. M. et al. Implementation of a Clostridioides difficile sentinel surveillance system in Germany: first insights for 2019-2021. Anaerobe 77, 102548 (2022).

    Article 

    Google Scholar
     

  • Marujo, V. & Arvand, M. The largely unnoticed spread of Clostridioides difficile PCR ribotype 027 in Germany after 2010. Infect. Prev. Pract. 2, 100102 (2020).

    Article 
    PubMed Central 

    Google Scholar
     

  • Berger, F. K. et al. Hospital outbreak due to Clostridium difficile ribotype 018 (RT018) in Southern Germany. Int. J. Med. Microbiol. 309, 189–193 (2019).

    Article 

    Google Scholar
     

  • Gateau, C. et al. Local outbreak of Clostridioides difficile PCR-ribotype 018 investigated by multi locus variable number tandem repeat analysis, whole genome multi locus sequence typing and core genome single nucleotide polymorphism typing. Anaerobe 60, 102087 (2019).

    Article 
    CAS 

    Google Scholar
     

  • UK Health Security Agency. Clostridioides difficile Ribotyping Network (CDRN) for England and Northern Ireland, 2018 to 2023 (UKHSA, 2024).

  • UKHSA Advisory Board. Update on Preparedness for Infectious Diseases (UKHSA, 2024).

  • Kachrimanidou, M. et al. Predominance of Clostridioides difficile PCR ribotype 181 in northern Greece, 2016-2019. Anaerobe 76, 102601 (2022).

    Article 
    CAS 

    Google Scholar
     

  • National Center for Emerging and Zoonotic Infectious Diseases. Emerging Infections Program, Healthcare-Associated Infections — Community Interface Surveillance Report, Clostridioides difficile Infection (CDI), 2021 (CDC, 2023).

  • Snydman, D. R. et al. A US-based national surveillance study for the susceptibility and epidemiology of Clostridioides difficile isolates with special reference to ridinilazole: 2020–2021. Antimicrob. Agents Chemother. 67, e0034923 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Canadian Nosocomial Infection Surveillance Program. Healthcare-associated infections and antimicrobial resistance in Canadian acute care hospitals, 2017–2021. Can. Commun. Dis. Rep. 49, 235–252 (2023).

    Article 
    PubMed Central 

    Google Scholar
     

  • Hong, S. et al. Laboratory-based surveillance of Clostridium difficile infection in Australian health care and community settings, 2013 to 2018. J. Clin. Microbiol. 58, e01552-20 (2020).

    Article 
    PubMed Central 

    Google Scholar
     

  • O’Grady, K. et al. Defining the phylogenetics and resistome of the major Clostridioides difficile ribotypes circulating in Australia. Microb. Genom. 10, 001232 (2024).

    PubMed Central 

    Google Scholar
     

  • Angulo, F. J., Ghia, C., Fletcher, M. A., Ozbilgili, E. & Morales, G. D. C. The burden of Clostridioides difficile infections in South-East Asia and the Western Pacific: a narrative review. Anaerobe 86, 102821 (2024).

    Article 
    CAS 

    Google Scholar
     

  • Brajerova, M., Zikova, J. & Krutova, M. Clostridioides difficile epidemiology in the Middle and the Far East. Anaerobe 74, 102542 (2022).

    Article 

    Google Scholar
     

  • Acuña-Amador, L., Quesada-Gómez, C. & Rodríguez, C. Clostridioides difficile in Latin America: a comprehensive review of literature (1984-2021). Anaerobe 74, 102547 (2022).

    Article 

    Google Scholar
     

  • Morales-Olvera, C. G. et al. Clostridioides Difficile in Latin America: an epidemiological overview. Curr. Microbiol. 80, 357 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Senoh, M. & Kato, H. Molecular epidemiology of endemic Clostridioides difficile infection in Japan. Anaerobe 74, 102510 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Bignardi, G. E., Hill, K., Berrington, A. & Settle, C. D. Two-stage algorithm for Clostridium difficile: glutamate-dehydrogenase-positive toxin-negative enzyme immunoassay results may require further testing. J. Hosp. Infect. 83, 347–349 (2013).

    Article 
    CAS 

    Google Scholar
     

  • Planche, T. D. et al. Differences in outcome according to Clostridium difficile testing method: a prospective multicentre diagnostic validation study of C difficile infection. Lancet Infect. Dis. 13, 936–945 (2013). This article demonstrates how different diagnostic methods correlate with clinical outcomes and was instrumental in the development of optimized two-step diagnostic algorithms.

    Article 
    PubMed Central 

    Google Scholar
     

  • Iheagwara, C. C. et al. A rare case of polymerase chain reaction-negative severe Clostridioides difficile infection. Cureus 15, e50403 (2023).

    PubMed Central 

    Google Scholar
     

  • Polage, C. R. et al. Overdiagnosis of Clostridium difficile infection in the molecular test era. JAMA Intern. Med. 175, 1792–1801 (2015).

    Article 
    PubMed Central 

    Google Scholar
     

  • Bartlett, J. G., Chang, T. W., Gurwith, M., Gorbach, S. L. & Onderdonk, A. B. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N. Engl. J. Med. 298, 531–534 (1978).

    Article 
    CAS 

    Google Scholar
     

  • Chang, T. W., Gorbach, S. L. & Bartlett, J. B. Neutralization of Clostridium difficile toxin by Clostridium sordellii antitoxins. Infect. Immun. 22, 418–422 (1978).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Trubiano, J. A. et al. Australasian society of infectious diseases updated guidelines for the management of Clostridium difficile infection in adults and children in Australia and New Zealand. Intern. Med. J. 46, 479–493 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Watkin, S., Yongblah, F., Burton, J., Hartley, J. C. & Cloutman-Green, E. Clostridioides difficile detection and infection in children: are they just small adults? J. Med. Microbiol. 73, 001816 (2024).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Dalal, R. S. & Allegretti, J. R. Diagnosis and management of Clostridioides difficile infection in patients with inflammatory bowel disease. Curr. Opin. Gastroenterol. 37, 336–343 (2021).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Crobach, M. J. et al. European society of clinical microbiology and infectious diseases: update of the diagnostic guidance document for Clostridium difficile infection. Clin. Microbiol. Infect. 22, S63–81 (2016).

    Article 

    Google Scholar
     

  • Viprey, V. F. et al. European survey on the current surveillance practices, management guidelines, treatment pathways and heterogeneity of testing of Clostridioides difficile, 2018–2019: results from the Combatting Bacterial Resistance in Europe CDI (COMBACTE-CDI). J. Hosp. Infect. 131, 213–220 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Planche, T. et al. Diagnosis of Clostridium difficile infection by toxin detection kits: a systematic review. Lancet Infect. Dis. 8, 777–784 (2008).

    Article 

    Google Scholar
     

  • Tichota-Lee, J., Jaqua-Stewart, M. J., Benfield, D., Simmons, J. L. & Jaqua, R. A. Effect of age on the sensitivity of cell cultures to Clostridium difficile toxin. Diagn. Microbiol. Infect. Dis. 8, 203–214 (1987).

    Article 
    CAS 

    Google Scholar
     

  • Lyerly, D. M., Sullivan, N. M. & Wilkins, T. D. Enzyme-linked immunosorbent assay for Clostridium difficile toxin A. J. Clin. Microbiol. 17, 72–78 (1983).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Borriello, S. P. et al. Molecular, immunological, and biological characterization of a toxin A-negative, toxin B-positive strain of Clostridium difficile. Infect. Immun. 60, 4192–4199 (1992).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Eastwood, K., Else, P., Charlett, A. & Wilcox, M. Comparison of nine commercially available Clostridium difficile toxin detection assays, a real-time PCR assay for C. difficile tcdB, and a glutamate dehydrogenase detection assay to cytotoxin testing and cytotoxigenic culture methods. J. Clin. Microbiol. 47, 3211–3217 (2009).

    Article 
    PubMed Central 

    Google Scholar
     

  • Tenover, F. C. et al. Impact of strain type on detection of toxigenic Clostridium difficile: comparison of molecular diagnostic and enzyme immunoassay approaches. J. Clin. Microbiol. 48, 3719–3724 (2010).

    Article 
    PubMed Central 

    Google Scholar
     

  • Mansfield, M. J. et al. Phylogenomics of 8,839 Clostridioides difficile genomes reveals recombination-driven evolution and diversification of toxin A and B. PLoS Pathog. 16, e1009181 (2020).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Ramírez-Vargas, G. et al. Novel clade C-I Clostridium difficile strains escape diagnostic tests, differ in pathogenicity potential and carry toxins on extrachromosomal elements. Sci. Rep. 8, 13951 (2018).

    Article 
    PubMed Central 

    Google Scholar
     

  • Shen, E. et al. Subtyping analysis reveals new variants and accelerated evolution of Clostridioides difficile toxin B. Commun. Biol. 3, 347 (2020).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Landry, M. L. et al. High agreement between an ultrasensitive Clostridioides difficile toxin assay and a C. difficile laboratory algorithm utilizing GDH-and-toxin enzyme immunoassays and cytotoxin testing. J. Clin. Microbiol. 58, e01629-19 (2020).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Sandlund, J. et al. Ultrasensitive detection of Clostridioides difficile toxins A and B by use of automated single-molecule counting technology. J. Clin. Microbiol. 56, e00908-18 (2018).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Banz, A. et al. Sensitivity of single-molecule array assays for detection of Clostridium difficile toxins in comparison to conventional laboratory testing algorithms. J. Clin. Microbiol. 56, e00452-18 (2018).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Shim, J. K., Johnson, S., Samore, M. H., Bliss, D. Z. & Gerding, D. N. Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea. Lancet 351, 633–636 (1998).

    Article 
    CAS 

    Google Scholar
     

  • Bouza, E. et al. ‘Second-look’ cytotoxicity: an evaluation of culture plus cytotoxin assay of Clostridium difficile isolates in the laboratory diagnosis of CDAD. J. Hosp. Infect. 48, 233–237 (2001).

    Article 
    CAS 

    Google Scholar
     

  • Anderson, B. M., Anderson, C. D., Van Tassell, R. L., Lyerly, D. M. & Wilkins, T. D. Purification and characterization of Clostridium difficile glutamate dehydrogenase. Arch. Biochem. Biophys. 300, 483–488 (1993).

    Article 
    CAS 

    Google Scholar
     

  • Shetty, N., Wren, M. W. & Coen, P. G. The role of glutamate dehydrogenase for the detection of Clostridium difficile in faecal samples: a meta-analysis. J. Hosp. Infect. 77, 1–6 (2011).

    Article 
    CAS 

    Google Scholar
     

  • Avni, T. et al. Molecular-based diagnosis of Clostridium difficile infection is associated with reduced mortality. Eur. J. Clin. Microbiol. Infect. Dis. 37, 1137–1142 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Longtin, Y. et al. Impact of the type of diagnostic assay on Clostridium difficile infection and complication rates in a mandatory reporting program. Clin. Infect. Dis. 56, 67–73 (2013).

    Article 

    Google Scholar
     

  • Prosty, C. et al. Clinical outcomes and management of NAAT-positive/toxin-negative Clostridioides difficile infection: a systematic review and meta-analysis. Clin. Infect. Dis. 78, 430–438 (2024).

    Article 
    CAS 

    Google Scholar
     

  • Goret, J. et al. Impact of the introduction of a nucleic acid amplification test for Clostridium difficile diagnosis on stool rejection policies. Gut Pathog. 10, 19 (2018).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Yen, C. et al. Reducing Clostridium difficile colitis rates via cost-saving diagnostic stewardship. Infect. Control. Hosp. Epidemiol. 39, 734–736 (2018).

    Article 

    Google Scholar
     

  • Davies, K. A. et al. Underdiagnosis of Clostridium difficile across Europe: the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID). Lancet Infect. Dis. 14, 1208–1219 (2014).

    Article 

    Google Scholar
     

  • Davies, K. et al. Variability in testing policies and impact on reported Clostridium difficile infection rates: results from the pilot longitudinal European Clostridium difficile infection diagnosis surveillance study (LuCID). Eur. J. Clin. Microbiol. Infect. Dis. 35, 1949–1956 (2016).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Lessa, F. C. et al. Burden of Clostridium difficile infection in the United States. N. Engl. J. Med. 372, 825–834 (2015).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Davies, K. A., Planche, T. & Wilcox, M. H. The predictive value of quantitative nucleic acid amplification detection of Clostridium difficile toxin gene for faecal sample toxin status and patient outcome. PLoS ONE 13, e0205941 (2018).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Goldenberg, S. D. & French, G. L. Lack of association of tcdC type and binary toxin status with disease severity and outcome in toxigenic Clostridium difficile. J. Infect. 62, 355–362 (2011).

    Article 

    Google Scholar
     

  • Pollock, N. R. Ultrasensitive detection and quantification of toxins for optimized diagnosis of Clostridium difficile infection. J. Clin. Microbiol. 54, 259–264 (2016).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Pollock, N. R. et al. Comparison of Clostridioides difficile stool toxin concentrations in adults with symptomatic infection and asymptomatic carriage using an ultrasensitive quantitative immunoassay. Clin. Infect. Dis. 68, 78–86 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Ford, C. D., Lopansri, B. K., Hunter, B. D., Asch, J. & Hoda, D. Multiplexed gastrointestinal PCR panels for the evaluation of diarrhea in HCT recipients. Transpl. Cell Ther. 30, 814.e1–814.e7 (2024).

    Article 
    CAS 

    Google Scholar
     

  • Langhorst, J. & Boone, J. Fecal lactoferrin as a noninvasive biomarker in inflammatory bowel diseases. Drugs Today 48, 149–161 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Barbut, F. et al. Faecal lactoferrin and calprotectin in patients with Clostridium difficile infection: a case-control study. Eur. J. Clin. Microbiol. Infect. Dis. 36, 2423–2430 (2017).

    Article 
    CAS 

    Google Scholar
     

  • Swale, A. et al. Calprotectin and lactoferrin faecal levels in patients with Clostridium difficile infection (CDI): a prospective cohort study. PLoS ONE 9, e106118 (2014).

    Article 
    PubMed Central 

    Google Scholar
     

  • Lee, S. H. et al. Fecal calprotectin predicts complete mucosal healing and better correlates with the ulcerative colitis endoscopic index of severity than with the Mayo endoscopic subscore in patients with ulcerative colitis. BMC Gastroenterol. 17, 110 (2017).

    Article 
    PubMed Central 

    Google Scholar
     

  • O’Connor, J. R., Johnson, S. & Gerding, D. N. Clostridium difficile infection caused by the epidemic BI/NAP1/027 strain. Gastroenterology 136, 1913–1924 (2009).

    Article 

    Google Scholar
     

  • Wickramage, I., Spigaglia, P. & Sun, X. Mechanisms of antibiotic resistance of Clostridioides difficile. J. Antimicrob. Chemother. 76, 3077–3090 (2021).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Vernon, J. J., Wilcox, M. H. & Freeman, J. Antimicrobial resistance progression in the United Kingdom: a temporal comparison of Clostridioides difficile antimicrobial susceptibilities. Anaerobe 70, 102385 (2021).

    Article 

    Google Scholar
     

  • National Insitute for Health and Care Excellence. Scenario: management of antibiotic associated diarrhoea. NICE https://cks.nice.org.uk/topics/diarrhoea-antibiotic-associated/management/diarrhoea-antibiotic-associated/#suspected-or-confirmed-clostridiodes-difficile-infections (2023).

  • Gonzales-Luna, A. J. et al. Reduced susceptibility to metronidazole is associated with initial clinical failure in Clostridioides difficile infection. Open Forum Infect. Dis. 8, ofab365 (2021).

    Article 
    PubMed Central 

    Google Scholar
     

  • Freeman, J. et al. The ClosER study: results from a three-year pan-European longitudinal surveillance of antibiotic resistance among prevalent Clostridium difficile ribotypes, 2011–2014. Clin. Microbiol. Infect. 24, 724–731 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Goudarzi, M. et al. Antimicrobial susceptibility of Clostridium difficile clinical isolates in Iran. Iran. Red. Crescent Med. J. 15, 704–711 (2013).

    Article 
    PubMed Central 

    Google Scholar
     

  • European Committee on Antimicrobial Susceptibility Testing. Breakpoint Tables for Interpretation of MICs and Zone Diameters. Version 15.0 (EUCAST, 2025).

  • Peláez, T. et al. Metronidazole resistance in Clostridium difficile is heterogeneous. J. Clin. Microbiol. 46, 3028–3032 (2008).

    Article 
    PubMed Central 

    Google Scholar
     

  • Moura, I., Spigaglia, P., Barbanti, F. & Mastrantonio, P. Analysis of metronidazole susceptibility in different Clostridium difficile PCR ribotypes. J. Antimicrob. Chemother. 68, 362–365 (2013).

    Article 
    CAS 

    Google Scholar
     

  • Baines, S. D. et al. Emergence of reduced susceptibility to metronidazole in Clostridium difficile. J. Antimicrob. Chemother. 62, 1046–1052 (2008).

    Article 
    CAS 

    Google Scholar
     

  • Boekhoud, I. M. et al. Plasmid-mediated metronidazole resistance in Clostridioides difficile. Nat. Commun. 11, 598 (2020). This article describes a novel plasmid linked to metronidazole resistance in C. difficile.

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Imwattana, K., Rodríguez, C., Riley, T. V. & Knight, D. R. A species-wide genetic atlas of antimicrobial resistance in Clostridioides difficile. Microb. Genom. 7, 000696 (2021).

    CAS 
    PubMed Central 

    Google Scholar
     

  • Boekhoud, I. M. et al. Haem is crucial for medium-dependent metronidazole resistance in clinical isolates of Clostridioides difficile. J. Antimicrob. Chemother. 76, 1731–1740 (2021).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Olaitan, A. O. et al. Decoding a cryptic mechanism of metronidazole resistance among globally disseminated fluoroquinolone-resistant Clostridioides difficile. Nat. Commun. 14, 4130 (2023).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Ammam, F. et al. The functional vanGCd cluster of Clostridium difficile does not confer vancomycin resistance. Mol. Microbiol. 89, 612–625 (2013).

    Article 
    CAS 

    Google Scholar
     

  • Eubank, T. A., Gonzales-Luna, A. J., Hurdle, J. G. & Garey, K. W. Genetic mechanisms of vancomycin resistance in Clostridioides difficile: a systematic review. Antibiotics 11, 258 (2022).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Shen, W. J. et al. Constitutive expression of the cryptic vanGCd operon promotes vancomycin resistance in Clostridioides difficile clinical isolates. J. Antimicrob. Chemother. 75, 859–867 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Buddle, J. E. et al. Identification of pathways to high-level vancomycin resistance in Clostridioides difficile that incur high fitness costs in key pathogenicity traits. PLoS Biol. 22, e3002741 (2024).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Tsvetkova, K., Marvaud, J. C. & Lambert, T. Analysis of the mobilization functions of the vancomycin resistance transposon Tn1549, a member of a new family of conjugative elements. J. Bacteriol. 192, 702–713 (2010).

    Article 
    CAS 

    Google Scholar
     

  • Wu, Y. et al. Independent microevolution mediated by mobile genetic elements of individual Clostridium difficile isolates from clade 4 revealed by whole-genome sequencing. mSystems 4, e00252-18 (2019).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Pu, M. et al. Plasmid acquisition alters vancomycin susceptibility in Clostridioides difficile. Gastroenterology 160, 941–945.e8 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Saldanha, G. Z. et al. Genetic relatedness, virulence factors and antimicrobial resistance of C. difficile strains from hospitalized patients in a multicentric study in Brazil. J. Glob. Antimicrob. Resist. 22, 117–121 (2020).

    Article 

    Google Scholar
     

  • Eubank, T. A., Dureja, C., Garey, K. W., Hurdle, J. G. & Gonzales-Luna, A. J. Reduced vancomycin susceptibility in Clostridioides difficile is associated with lower rates of initial cure and sustained clinical response. Clin. Infect. Dis. 79, 15–21 (2024).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Goldstein, E. J. et al. Comparative susceptibilities to fidaxomicin (OPT-80) of isolates collected at baseline, recurrence, and failure from patients in two phase III trials of fidaxomicin against Clostridium difficile infection. Antimicrob. Agents Chemother. 55, 5194–5199 (2011).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Schwanbeck, J. et al. Characterization of a clinical Clostridioides difficile isolate with markedly reduced fidaxomicin susceptibility and a V1143D mutation in rpoB. J. Antimicrob. Chemother. 74, 6–10 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Marchandin, H. et al. In vivo emergence of a still uncommon resistance to fidaxomicin in the urgent antimicrobial resistance threat Clostridioides difficile. J. Antimicrob. Chemother. 78, 1992–1999 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Aoki, K., Takeda, S., Miki, T., Ishii, Y. & Tateda, K. Antimicrobial susceptibility and molecular characterisation using whole-genome sequencing of Clostridioides difficile collected in 82 hospitals in Japan between 2014 and 2016. Antimicrob. Agents Chemother. 63, e01259-19 (2019).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Redmond, S. N. et al. Emergence and spread of Clostridioides difficile isolates with reduced fidaxomicin susceptibility in an acute care hospital. Clin. Infect. Dis. 80, 984–991 (2025).

    Article 
    CAS 

    Google Scholar
     

  • Toth, M., Stewart, N. K., Smith, C. & Vakulenko, S. B. Intrinsic class D β-lactamases of Clostridium difficile. mBio 9, e01803-18 (2018).

    Article 
    PubMed Central 

    Google Scholar
     

  • Isidro, J. et al. Imipenem resistance in Clostridium difficile ribotype 017, Portugal. Emerg. Infect. Dis. 24, 741–745 (2018).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Sacco, M. D. et al. A unique class of Zn2+-binding serine-based PBPs underlies cephalosporin resistance and sporogenesis in Clostridioides difficile. Nat. Commun. 13, 4370 (2022).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Curry, S. R. et al. High frequency of rifampin resistance identified in an epidemic Clostridium difficile clone from a large teaching hospital. Clin. Infect. Dis. 48, 425–429 (2009).

    Article 
    CAS 

    Google Scholar
     

  • Carman, R. J., Boone, J. H., Grover, H., Wickham, K. N. & Chen, L. In vivo selection of rifamycin-resistant Clostridium difficile during rifaximin therapy. Antimicrob. Agents Chemother. 56, 6019–6020 (2012).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Dang, U. T. et al. Rifamycin resistance in Clostridium difficile is generally associated with a low fitness burden. Antimicrob. Agents Chemother. 60, 5604–5607 (2016).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Corver, J. et al. Analysis of a Clostridium difficile PCR ribotype 078 100 kilobase island reveals the presence of a novel transposon, Tn6164. BMC Microbiol. 12, 130 (2012).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Spigaglia, P., Barbanti, F. & Mastrantonio, P. Tetracycline resistance gene tet(W) in the pathogenic bacterium Clostridium difficile. Antimicrob. Agents Chemother. 52, 770–773 (2008).

    Article 
    CAS 

    Google Scholar
     

  • Deakin, L. J. et al. The Clostridium difficile spo0A gene is a persistence and transmission factor. Infect. Immun. 80, 2704–2711 (2012).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Péchiné, S., Denève-Larrazet, C. & Collignon, A. Clostridium difficile adhesins. Methods Mol. Biol. 1476, 91–101 (2016).

    Article 

    Google Scholar
     

  • Papatheodorou, P., Minton, N. P., Aktories, K. & Barth, H. An updated view on the cellular uptake and mode-of-action of Clostridioides difficile toxins. Adv. Exp. Med. Biol. 1435, 219–247 (2024).

    Article 
    CAS 

    Google Scholar
     

  • Buddle, J. E. & Fagan, R. P. Pathogenicity and virulence of Clostridioides difficile. Virulence 14, 2150452 (2023).

    Article 
    PubMed Central 

    Google Scholar
     

  • Martins, D. et al. CD25890, a conserved protein that modulates sporulation initiation in Clostridioides difficile. Sci. Rep. 11, 7887 (2021).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • DiCandia, M. A. et al. Identification of functional Spo0A residues critical for sporulation in Clostridioides difficile. J. Mol. Biol. 434, 167641 (2022).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Lee, C. D. et al. Genetic mechanisms governing sporulation initiation in Clostridioides difficile. Curr. Opin. Microbiol. 66, 32–38 (2022).

    Article 
    CAS 

    Google Scholar
     

  • DiCandia, M. A. et al. A conserved switch controls virulence, sporulation, and motility in C. difficile. PLoS Pathog. 20, e1012224 (2024).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Edwards, A. N., Krall, E. G. & McBride, S. M. Strain-dependent RstA regulation of Clostridioides difficile toxin production and sporulation. J. Bacteriol. 202, e00586-19 (2020).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Paredes-Sabja, D., Shen, A. & Sorg, J. A. Clostridium difficile spore biology: sporulation, germination, and spore structural proteins. Trends Microbiol. 22, 406–416 (2014).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Montes-Bravo, N. et al. Role of the spore coat proteins CotA and CotB, and the spore surface protein CDIF630_02480, on the surface distribution of exosporium proteins in Clostridioides difficile 630 spores. Microorganisms 10, 1918 (2022).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Pizarro-Guajardo, M., Calderón-Romero, P., Castro-Córdova, P., Mora-Uribe, P. & Paredes-Sabja, D. Ultrastructural variability of the exosporium layer of Clostridium difficile spores. Appl. Environ. Microbiol. 82, 2202–2209 (2016).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Pizarro-Guajardo, M. et al. Characterization of the collagen-like exosporium protein, BclA1, of Clostridium difficile spores. Anaerobe 25, 18–30 (2014).

    Article 
    CAS 

    Google Scholar
     

  • Sorg, J. A. & Sonenshein, A. L. Bile salts and glycine as cogerminants for Clostridium difficile spores. J. Bacteriol. 190, 2505–2512 (2008).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Kochan, T. J. et al. Intestinal calcium and bile salts facilitate germination of Clostridium difficile spores. PLoS Pathog. 13, e1006443 (2017).

    Article 
    PubMed Central 

    Google Scholar
     

  • Francis, M. B., Allen, C. A., Shrestha, R. & Sorg, J. A. Bile acid recognition by the Clostridium difficile germinant receptor, CspC, is important for establishing infection. PLoS Pathog. 9, e1003356 (2013).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Shrestha, R., Cochran, A. M. & Sorg, J. A. The requirement for co-germinants during Clostridium difficile spore germination is influenced by mutations in yabG and cspA. PLoS Pathog. 15, e1007681 (2019).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Kevorkian, Y. & Shen, A. Revisiting the role of Csp family proteins in regulating Clostridium difficile spore germination. J. Bacteriol. 199, e00266-17 (2017).

    Article 
    PubMed Central 

    Google Scholar
     

  • Rohlfing, A. E. et al. The CspC pseudoprotease regulates germination of Clostridioides difficile spores in response to multiple environmental signals. PLoS Genet. 15, e1008224 (2019).

    Article 
    PubMed Central 

    Google Scholar
     

  • Ribis, J. W. et al. Single-spore germination analyses reveal that calcium released during Clostridioides difficile germination functions in a feedforward loop. mSphere 8, e0000523 (2023).

    Article 

    Google Scholar
     

  • Castro-Córdova, P. et al. Redistribution of the novel Clostridioides difficile spore adherence receptor E-cadherin by TcdA and TcdB increases spore binding to adherens junctions. Infect. Immun. 91, e0047622 (2023).

    Article 

    Google Scholar
     

  • Normington, C. et al. Biofilms harbour Clostridioides difficile, serving as a reservoir for recurrent infection. npj Biofilms Microbiomes 7, 16 (2021). This article demonstrates the role of. C. difficile spores in recurrent CDI and pathogen persistence in the large intestine.

    Article 
    PubMed Central 

    Google Scholar
     

  • Ðapa, T. et al. Multiple factors modulate biofilm formation by the anaerobic pathogen Clostridium difficile. J. Bacteriol. 195, 545–555 (2013).

    Article 
    PubMed Central 

    Google Scholar
     

  • Donelli, G., Vuotto, C., Cardines, R. & Mastrantonio, P. Biofilm-growing intestinal anaerobic bacteria. FEMS Immunol. Med. Microbiol. 65, 318–325 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Semenyuk, E. G. et al. Analysis of bacterial communities during Clostridium difficile infection in the mouse. Infect. Immun. 83, 4383–4391 (2015).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Smith, A. B. et al. Enterococci enhance Clostridioides difficile pathogenesis. Nature 611, 780–786 (2022).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Dubois, T. et al. A microbiota-generated bile salt induces biofilm formation in Clostridium difficile. npj Biofilms Microbiomes 5, 14 (2019).

    Article 
    PubMed Central 

    Google Scholar
     

  • Kang, J. D. et al. Bile acid 7α-dehydroxylating gut bacteria secrete antibiotics that inhibit Clostridium difficile: role of secondary bile acids. Cell Chem. Biol. 26, 27–34.e24 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Baban, S. T. et al. The role of flagella in Clostridium difficile pathogenesis: comparison between a non-epidemic and an epidemic strain. PLoS ONE 8, e73026 (2013).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • McKee, R. W., Aleksanyan, N., Garrett, E. M. & Tamayo, R. Type IV Pili promote Clostridium difficile adherence and persistence in a mouse model of infection. Infect. Immun. 86, e00943-17 (2018).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Waligora, A. J. et al. Characterization of a cell surface protein of Clostridium difficile with adhesive properties. Infect. Immun. 69, 2144–2153 (2001).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Fagan, R. P. & Fairweather, N. F. Biogenesis and functions of bacterial S-layers. Nat. Rev. Microbiol. 12, 211–222 (2014).

    Article 
    CAS 

    Google Scholar
     

  • Kirk, J. A., Banerji, O. & Fagan, R. P. Characteristics of the Clostridium difficile cell envelope and its importance in therapeutics. Microb. Biotechnol. 10, 76–90 (2017).

    Article 
    CAS 

    Google Scholar
     

  • Tasteyre, A., Barc, M. C., Collignon, A., Boureau, H. & Karjalainen, T. Role of FliC and FliD flagellar proteins of Clostridium difficile in adherence and gut colonization. Infect. Immun. 69, 7937–7940 (2001).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Merrigan, M. M. et al. Surface-layer protein A (SlpA) is a major contributor to host-cell adherence of Clostridium difficile. PLoS ONE 8, e78404 (2013).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Calabi, E., Calabi, F., Phillips, A. D. & Fairweather, N. F. Binding of Clostridium difficile surface layer proteins to gastrointestinal tissues. Infect. Immun. 70, 5770–5778 (2002).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Kirk, J. A. et al. New class of precision antimicrobials redefines role of Clostridium difficile S-layer in virulence and viability. Sci. Transl Med. 9, eaah6813 (2017).

    Article 
    PubMed Central 

    Google Scholar
     

  • Lanzoni-Mangutchi, P. et al. Structure and assembly of the S-layer in C. difficile. Nat. Commun. 13, 970 (2022).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Wang, S. et al. Revealing roles of S-layer protein (SlpA) in Clostridioides difficile pathogenicity by generating the first slpA gene deletion mutant. Microbiol. Spectr. 12, e0400523 (2024).

    Article 

    Google Scholar
     

  • Kirby, J. M. et al. Cwp84, a surface-associated cysteine protease, plays a role in the maturation of the surface layer of Clostridium difficile. J. Biol. Chem. 284, 34666–34673 (2009).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Péchiné, S. et al. Immunological properties of surface proteins of Clostridium difficile. J. Med. Microbiol. 54, 193–196 (2005).

    Article 

    Google Scholar
     

  • Wright, A., Drudy, D., Kyne, L., Brown, K. & Fairweather, N. F. Immunoreactive cell wall proteins of Clostridium difficile identified by human sera. J. Med. Microbiol. 57, 750–756 (2008).

    Article 
    CAS 

    Google Scholar
     

  • Zhou, Q. et al. The cwp66 gene affects cell adhesion, stress tolerance, and antibiotic resistance in Clostridioides difficile. Microbiol. Spectr. 10, e0270421 (2022).

    Article 

    Google Scholar
     

  • Schöttelndreier, D., Langejürgen, A., Lindner, R. & Genth, H. Low density lipoprotein receptor-related protein-1 (LRP1) is involved in the uptake of Clostridioides difficile toxin A and serves as an internalizing receptor. Front. Cell Infect. Microbiol. 10, 565465 (2020).

    Article 
    PubMed Central 

    Google Scholar
     

  • Tao, L. et al. Frizzled proteins are colonic epithelial receptors for C. difficile toxin B. Nature 538, 350–355 (2016).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Gupta, P. et al. Functional defects in Clostridium difficile TcdB toxin uptake identify CSPG4 receptor-binding determinants. J. Biol. Chem. 292, 17290–17301 (2017).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • LaFrance, M. E. et al. Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity. Proc. Natl Acad. Sci. USA 112, 7073–7078 (2015).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Luo, J. et al. TFPI is a colonic crypt receptor for TcdB from hypervirulent clade 2 C. difficile. Cell 185, 980–994.e15 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Manion, J. et al. C. difficile intoxicates neurons and pericytes to drive neurogenic inflammation. Nature 622, 611–618 (2023).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Lyras, D. et al. Toxin B is essential for virulence of Clostridium difficile. Nature 458, 1176–1179 (2009).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Mileto, S. J. et al. Clostridioides difficile infection damages colonic stem cells via TcdB, impairing epithelial repair and recovery from disease. Proc. Natl Acad. Sci. USA 117, 8064–8073 (2020).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Lv, X. et al. De novo design of mini-protein binders broadly neutralizing Clostridioides difficile toxin B variants. Nat. Commun. 15, 8521 (2024).

    Article 
    PubMed Central 

    Google Scholar
     

  • Eckert, C. et al. Prevalence and pathogenicity of binary toxin-positive Clostridium difficile strains that do not produce toxins A and B. New Microbes New Infect. 3, 12–17 (2015).

    Article 
    CAS 

    Google Scholar
     

  • Gerding, D. N., Johnson, S., Rupnik, M. & Aktories, K. Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance. Gut Microbes 5, 15–27 (2014).

    Article 

    Google Scholar
     

  • Lyon, S. A., Hutton, M. L., Rood, J. I., Cheung, J. K. & Lyras, D. CdtR regulates TcdA and TcdB production in Clostridium difficile. PLoS Pathog. 12, e1005758 (2016).

    Article 
    PubMed Central 

    Google Scholar
     

  • Dong, Q. et al. Virulence and genomic diversity among clinical isolates of ST1 (BI/NAP1/027) Clostridioides difficile. Cell Rep. 42, 112861 (2023).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Meza-Torres, J. et al. Clostridioides difficile binary toxin CDT induces biofilm-like persisting microcolonies. Gut Microbes 17, 2444411 (2025).

    Article 

    Google Scholar
     

  • Nabukhotna, K. et al. Purified CDT toxins and a clean deletion within the CDT locus provide novel insights into the contribution of binary toxin in cellular inflammation and Clostridioides difficile infection. PLoS Pathog. 20, e1012568 (2024).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Simpson, M. et al. Clostridioides difficile binary toxin binding component increases virulence in a Hamster model. Open Forum Infect. Dis. 10, ofad040 (2023).

    Article 
    PubMed Central 

    Google Scholar
     

  • Nhu, N. T. Q. et al. Flagellar switch inverted repeats impact heterogeneity in flagellar gene expression and thus C. difficile RT027/MLST1 virulence. Cell Rep. 44, 115830 (2025).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Trzilova, D., Anjuwon-Foster, B. R., Torres Rivera, D. & Tamayo, R. Rho factor mediates flagellum and toxin phase variation and impacts virulence in Clostridioides difficile. PLoS Pathog. 16, e1008708 (2020).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Warren Norris, M. A. H., Plaskon, D. M. & Tamayo, R. Phase variation of flagella and toxins in Clostridioides difficile is mediated by selective Rho-dependent termination. J. Mol. Biol. 436, 168456 (2024).

    Article 
    CAS 

    Google Scholar
     

  • Trzilova, D., Warren, M. A. H., Gadda, N. C., Williams, C. L. & Tamayo, R. Flagellum and toxin phase variation impacts intestinal colonization and disease development in a mouse model of Clostridioides difficile infection. Gut Microbes 14, 2038854 (2022).

    Article 
    PubMed Central 

    Google Scholar
     

  • Kelly, C. P. & Kyne, L. The host immune response to Clostridium difficile. J. Med. Microbiol. 60, 1070–1079 (2011).

    Article 
    CAS 

    Google Scholar
     

  • Gupta, S. B. et al. Antibodies to toxin B are protective against Clostridium difficile infection recurrence. Clin. Infect. Dis. 63, 730–734 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Rigo, I. et al. The impact of existing total anti-toxin B IgG immunity in outcomes of recurrent Clostridioides difficile infection. Anaerobe 87, 102842 (2024).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Janoir, C. Virulence factors of Clostridium difficile and their role during infection. Anaerobe 37, 13–24 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Di Bella, S. et al. Clostridioides difficile infection: history, epidemiology, risk factors, prevention, clinical manifestations, treatment, and future options. Clin. Microbiol. Rev. 37, e0013523 (2024).

    Article 

    Google Scholar
     

  • Abt, M. C. et al. Innate immune defenses mediated by two ILC subsets are critical for protection against acute Clostridium difficile infection. Cell Host Microbe 18, 27–37 (2015).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Saleh, M. M. & Petri, W. A. Jr. Type 3 immunity during Clostridioides difficile infection: too much of a good thing? Infect. Immun. 88, e00306–19 (2019).

    Article 
    PubMed Central 

    Google Scholar
     

  • Pruss, K. M. & Sonnenburg, J. L. C. difficile exploits a host metabolite produced during toxin-mediated disease. Nature 593, 261–265 (2021).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Pi, H. et al. Clostridioides difficile ferrosome organelles combat nutritional immunity. Nature 623, 1009–1016 (2023).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Cowardin, C. A. et al. The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. Nat. Microbiol. 1, 16108 (2016).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Berg, G. et al. Microbiome definition re-visited: old concepts and new challenges. Microbiome 8, 103 (2020).

    Article 
    PubMed Central 

    Google Scholar
     

  • Ivanov, I. I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337–349 (2008).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Cash, H. L., Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).

    Article 
    CAS 

    Google Scholar
     

  • Cario, E., Gerken, G. & Podolsky, D. K. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132, 1359–1374 (2007).

    Article 
    CAS 

    Google Scholar
     

  • De Vadder, F. et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156, 84–96 (2014).

    Article 

    Google Scholar
     

  • Hugon, P. et al. A comprehensive repertoire of prokaryotic species identified in human beings. Lancet Infect. Dis. 15, 1211–1219 (2015).

    Article 

    Google Scholar
     

  • The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

    Article 
    PubMed Central 

    Google Scholar
     

  • Shin, J. H. et al. Bacteroides and related species: the keystone taxa of the human gut microbiota. Anaerobe 85, 102819 (2024).

    Article 
    CAS 

    Google Scholar
     

  • Sorbara, M. T. & Pamer, E. G. Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them. Mucosal Immunol. 12, 1–9 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Kommineni, S. et al. Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract. Nature 526, 719–722 (2015).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Buffie, C. G. et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517, 205–208 (2015). This study demonstrates a specific bile-acid mediated mechanistic pathway by which C. scindens contributes to gut microbiota colonization resistance against. C. difficile.

    Article 
    CAS 

    Google Scholar
     

  • Girinathan, B. P. et al. In vivo commensal control of Clostridioides difficile virulence. Cell Host Microbe 29, 1693–1708.e7 (2021).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Pruss, K. M. et al. Oxidative ornithine metabolism supports non-inflammatory C. difficile colonization. Nat. Metab. 4, 19–28 (2022).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Arrieta-Ortiz, M. L. et al. Predictive regulatory and metabolic network models for systems analysis of Clostridioides difficile. Cell Host Microbe 29, 1709–1723.e5 (2021).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Theriot, C. M. & Young, V. B. Microbial and metabolic interactions between the gastrointestinal tract and Clostridium difficile infection. Gut Microbes 5, 86–95 (2014).

    Article 

    Google Scholar
     

  • Berkell, M. et al. Microbiota-based markers predictive of development of Clostridioides difficile infection. Nat. Commun. 12, 2241 (2021).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Vijay, A. & Valdes, A. M. Role of the gut microbiome in chronic diseases: a narrative review. Eur. J. Clin. Nutr. 76, 489–501 (2022).

    Article 
    CAS 

    Google Scholar
     

  • von Schwartzenberg, R. J. et al. Caloric restriction disrupts the microbiota and colonization resistance. Nature 595, 272–277 (2021).

    Article 

    Google Scholar
     

  • Denny, J. E., Flores, J. N., Mdluli, N. V. & Abt, M. C. Standard mouse diets lead to differences in severity in infectious and non-infectious colitis. mBio 16, e0330224 (2025).

    Article 

    Google Scholar
     

  • Seekatz, A. M. et al. Restoration of short chain fatty acid and bile acid metabolism following fecal microbiota transplantation in patients with recurrent Clostridium difficile infection. Anaerobe 53, 64–73 (2018).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Seekatz, A. M. et al. Recovery of the gut microbiome following fecal microbiota transplantation. mBio 5, e00893-14 (2014).

    Article 
    PubMed Central 

    Google Scholar
     

  • Gulati, M., Singh, S. K., Corrie, L., Kaur, I. P. & Chandwani, L. Delivery routes for faecal microbiota transplants: available, anticipated and aspired. Pharmacol. Res. 159, 104954 (2020).

    Article 

    Google Scholar
     

  • Tariq, R., Pardi, D. S., Bartlett, M. G. & Khanna, S. Low cure rates in controlled trials of fecal microbiota transplantation for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Clin. Infect. Dis. 68, 1351–1358 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Littmann, E. R. et al. Host immunity modulates the efficacy of microbiota transplantation for treatment of Clostridioides difficile infection. Nat. Commun. 12, 755 (2021).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Dehlholm-Lambertsen, E. et al. Cost savings following faecal microbiota transplantation for recurrent Clostridium difficile infection. Ther. Adv. Gastroenterol. 12, 1756284819843002 (2019).

    Article 

    Google Scholar
     

  • Zellmer, C. et al. Shiga toxin-producing Escherichia coli transmission via fecal microbiota transplant. Clin. Infect. Dis. 72, e876–e880 (2021).

    Article 
    CAS 

    Google Scholar
     

  • DeFilipp, Z. et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N. Engl. J. Med. 381, 2043–2050 (2019).

    Article 

    Google Scholar
     

  • Theriot, C. M., Bowman, A. A. & Young, V. B. Antibiotic-induced alterations of the gut microbiota alter secondary bile acid production and allow for Clostridium difficile spore germination and outgrowth in the large intestine. mSphere 1, e00045-15 (2016).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Lee, C. et al. Safety of fecal microbiota, live-jslm (REBYOTA) in individuals with recurrent Clostridioides difficile infection: data from five prospective clinical trials. Ther. Adv. Gastroenterol. 16, 17562848231174277 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Khanna, S. et al. Efficacy and safety of RBX2660 in PUNCH CD3, a phase III, randomized, double-blind, placebo-controlled trial with a bayesian primary analysis for the prevention of recurrent Clostridioides difficile infection. Drugs 82, 1527–1538 (2022). This phase III, double-blind, randomized, placebo-controlled clinical trial demonstrates that RBX2660 is a safe and effective treatment to reduce recurrent CDI following standard-of-care antibiotic therapy, with a sustained response.

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Feuerstadt, P. et al. SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection. N. Engl. J. Med. 386, 220–229 (2022). This phase III, double-blind, randomized, placebo-controlled clinical trial demonstrates that administration of SER-109 following standard-of-care antibiotic therapy was superior in preventing recurrence of symptoms than placebo.

    Article 
    CAS 

    Google Scholar
     

  • Cohen, S. H. et al. Extended follow-up of microbiome therapeutic SER-109 through 24 weeks for recurrent Clostridioides difficile infection in a randomized clinical trial. JAMA 328, 2062–2064 (2022).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Wilcox, M. H. et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N. Engl. J. Med. 376, 305–317 (2017).

    Article 
    CAS 

    Google Scholar
     

  • Tkaczyk, C. et al. Anti-toxin B neutralizing monoclonal antibody AZD5148 provides protection in a Clostridioides difficile gnotobiotic piglet model. Open Forum Infect. Dis. 12, ofae631.1244 (2025).

    Article 
    PubMed Central 

    Google Scholar
     

  • Hutton, M. L. et al. Bovine antibodies targeting primary and recurrent Clostridium difficile disease are a potent antibiotic alternative. Sci. Rep. 7, 3665 (2017).

    Article 
    PubMed Central 

    Google Scholar
     

  • Gerding, D. N. et al. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. JAMA 313, 1719–1727 (2015).

    Article 

    Google Scholar
     

  • Johnson, S. et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin. Infect. Dis. 59, 345–354 (2014).

    Article 
    CAS 

    Google Scholar
     

  • Daley, P. et al. Surotomycin versus vancomycin in adults with Clostridium difficile infection: primary clinical outcomes from the second pivotal, randomized, double-blind, phase 3 trial. J. Antimicrob. Chemother. 72, 3462–3470 (2017).

    Article 
    CAS 

    Google Scholar
     

  • Gerding, D. N. et al. Cadazolid for the treatment of Clostridium difficile infection: results of two double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials. Lancet Infect. Dis. 19, 265–274 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Okhuysen, P. C. et al. A randomized, double-blind, phase 3 safety and efficacy study of ridinilazole versus vancomycin for treatment of Clostridioides difficile infection: clinical outcomes with microbiome and metabolome correlates of response. Clin. Infect. Dis. 78, 1462–1472 (2024).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Fujimoto, K. & Uematsu, S. Phage therapy for Clostridioides difficile infection. Front. Immunol. 13, 1057892 (2022).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Riley, T. V., Lyras, D. & Douce, G. R. Status of vaccine research and development for Clostridium difficile. Vaccine 37, 7300–7306 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Donskey, C. J. et al. CLOVER (CLOstridium difficile Vaccine Efficacy tRial) study: a phase 3, randomized trial investigating the efficacy and safety of a detoxified toxin A/B vaccine in adults 50 years and older at increased risk of Clostridioides difficile infection. Clin. Infect. Dis. 79, 1503–1511 (2024).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Alameh, M. G. et al. A multivalent mRNA-LNP vaccine protects against Clostridioides difficile infection. Science 386, 69–75 (2024).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Wasels, F., Spigaglia, P., Barbanti, F. & Mastrantonio, P. Clostridium difficile erm(B)-containing elements and the burden on the in vitro fitness. J. Med. Microbiol. 62, 1461–1467 (2013).

    Article 
    CAS 

    Google Scholar
     

  • Stojković, V. et al. cfr(B), cfr(C), and a new cfr-like gene, cfr(E), in Clostridium difficile strains recovered across Latin America. Antimicrob. Agents Chemother. 64, e01074-19 (2019).

    Article 
    PubMed Central 

    Google Scholar
     

  • Ackermann, G. et al. Resistance to moxifloxacin in toxigenic Clostridium difficile isolates is associated with mutations in gyrA. Antimicrob. Agents Chemother. 45, 2348–2353 (2001).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Drudy, D. et al. High-level resistance to moxifloxacin and gatifloxacin associated with a novel mutation in gyrB in toxin-A-negative, toxin-B-positive Clostridium difficile. J. Antimicrob. Chemother. 58, 1264–1267 (2006).

    Article 
    CAS 

    Google Scholar
     

  • Sandhu, B. K., Edwards, A. N., Anderson, S. E., Woods, E. C. & McBride, S. M. Regulation and anaerobic function of the Clostridioides difficile β-lactamase. Antimicrob. Agents Chemother. 64, e01496-19 (2019).

    Article 
    PubMed Central 

    Google Scholar
     

  • Lyras, D. et al. Chloramphenicol resistance in Clostridium difficile is encoded on Tn4453 transposons that are closely related to Tn4451 from Clostridium perfringens. Antimicrob. Agents Chemother. 42, 1563–1567 (1998).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Persson, S. et al. Sentinel surveillance and epidemiology of Clostridioides difficile in Denmark, 2016 to 2019. Eur. Surveill. 27, 2200244 (2022).

    Article 

    Google Scholar
     

  • European Centre for Disease Prevention and Control. Clostridioides difficile Infections — Annual Epidemiological Report for 2018–2020 (ECDC, 2024).

  • Azimirad, M. et al. Clostridioides difficile ribotypes 001 and 126 were predominant in Tehran healthcare settings from 2004 to 2018: a 14-year-long cross-sectional study. Emerg. Microbes Infect. 9, 1432–1443 (2020).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Kullin, B., Abratt, V. R., Reid, S. J. & Riley, T. V. Clostridioides difficile infection in Africa: a narrative review. Anaerobe 74, 102549 (2022).

    Article 

    Google Scholar
     

  • Griffiths, D. et al. Multilocus sequence typing of Clostridium difficile. J. Clin. Microbiol. 48, 770–778 (2010).

    Article 
    CAS 

    Google Scholar
     

  • Huber, C. A., Foster, N. F., Riley, T. V. & Paterson, D. L. Challenges for standardization of Clostridium difficile typing methods. J. Clin. Microbiol. 51, 2810–2814 (2013).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • European Centre for Disease Prevention and Control. Study Protocol for a Survey of Whole Genome Sequencing of Clostridioides difficile Isolates from Tertiary Acute Care Hospitals, EU/EEA, 2022–2023 (ECDC, 2024).

  • Baktash, A. et al. Comparison of whole-genome sequence-based methods and PCR ribotyping for subtyping of Clostridioides difficile. J. Clin. Microbiol. 60, e0173721 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Knight, D. R. et al. Major genetic discontinuity and novel toxigenic species in Clostridioides difficile taxonomy. eLlife 10, e64325 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Miles-Jay, A. et al. Longitudinal genomic surveillance of carriage and transmission of Clostridioides difficile in an intensive care unit. Nat. Med. 29, 2526–2534 (2023).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Newcomer, E. P. et al. Genomic surveillance of Clostridioides difficile transmission and virulence in a healthcare setting. mBio 15, e0330023 (2024).

    Article 

    Google Scholar
     

  • Coia, C. W., Banks, A. L., Cottom, L. & Fitzpatrick, F. The need for European surveillance of CDI. Adv. Exp. Med. Biol. 1435, 13–31 (2024).

    Article 
    CAS 

    Google Scholar
     

  • UK Health Security Agency. Annual Epidemiological Commentary: Gram-Negative, MRSA, MSSA Bacteraemia and C. difficile Infections, Up to and Including Financial Year 2022 to 2023 (UKHSA, 2024).

  • Australian Commission on Safety and Quality in Health Care. Monitoring Clostridioides difficile Infection (CDI) in Australia. Clostridioides difficile Infection — 2020 and 2021 Data Snapshot (ACSQHC, 2023).

  • Choi, K. B. et al. Trends in Clostridioides difficile infection rates in Canadian hospitals during the coronavirus disease 2019 (COVID-19) pandemic. Infect. Control. Hosp. Epidemiol. 44, 1180–1183 (2023).

    Article 

    Google Scholar
     

  • Karampatakis, T. et al. Implication of COVID-19 pandemic on the incidence of Clostridioides difficile infection in a Greek tertiary hospital. J. Med. Microbiol. https://doi.org/10.1099/jmm.0.001689 (2023).

  • Maldonado-Barrueco, A. et al. Increase of healthcare-onset Clostridioides difficile infection in adult population since SARS-CoV-2 pandemic: a retrospective cohort study in a tertiary care hospital from 2019 to 2022. Anaerobe 86, 102836 (2024).

    Article 
    CAS 

    Google Scholar
     

  • Vehreschild, M. et al. Trends in the epidemiology of Clostridioides difficile infection in Germany. Infection 51, 1695–1702 (2023).

    Article 

    Google Scholar
     

  • Tossens, B. et al. Impact of the COVID-19 pandemic on Clostridioides difficile infection in a tertiary healthcare institution in Belgium. Acta Clin. Belg. 78, 459–466 (2023).

    Article 

    Google Scholar
     

  • Merchante, N. et al. Impact of COVID19 pandemic on the incidence of health-care associated Clostridioides difficile infection. Anaerobe 75, 102579 (2022).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • European Centre for Disease Prevention and Control. Point Prevalence Survey of Healthcare-Associated Infections and Antimicrobial Use in European Acute Care Hospitals — 2002–2023 (ECDC, 2024).

  • Feuerstadt, P., Theriault, N. & Tillotson, G. The burden of CDI in the United States: a multifactorial challenge. BMC Infect. Dis. 23, 132 (2023).

    Article 
    PubMed Central 

    Google Scholar
     

  • Source link

    Get RawNews Daily

    Stay informed with our RawNews daily newsletter email

    Kristin Cavallari and Lauren Conrad Hash It Out on ‘Laguna Beach’ Reunion

    Iran proposes regional military alliance excluding US and Israel. Again.

    Angels Announce 11 Roster Moves

    Nicholas Brendon’s Lawyers Move to Keep Odd Legal Battle Alive After His Death