Comparative Genomics of Clostridium difficile

  • Sandra Janezic
  • Julian R. Garneau
  • Marc Monot
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1050)


Clostridium difficile, a gram-positive spore-forming anaerobic bacterium, has rapidly emerged as the leading cause of nosocomial diarrhoea in hospitals. The availability of genome sequences in large numbers, mainly due to the use of next-generation sequencing methods, have undoubtedly shown their immense advantages in the determination of the C. difficile population structure. The implementation of fine-scale comparative genomic approaches have paved the way to global transmission and recurrence studies, but also more targeted studies such as the PaLoc or the CRISPR/Cas systems. In this chapter, we provide an overview of the recent and significant findings on C. difficile using comparative genomics studies with implication for the epidemiology, infection control and understanding of the evolution of C. difficile.


Genomics Evolution Transmission Recurrence CRISPR/Cas Nontoxigenic strains Epidemiology 



JG was supported by a discovery grant from the Natural Sciences and Engineering Research Council of Canada (NSERC #341450-2010). SJ was supported by Slovenian Research Agency grant J4-8224.


  1. Bauer MP, Notermans DW, van Benthem BH, Brazier JS, Wilcox MH, Rupnik M, Monnet DL, van Dissel JT, Kuijper EJ, Group ES (2011) Clostridium difficile infection in Europe: a hospital-based survey. Lancet 377(9759):63–73. CrossRefGoogle Scholar
  2. Boudry P, Semenova E, Monot M, Datsenko KA, Lopatina A, Sekulovic O, Ospina-Bedoya M, Fortier LC, Severinov K, Dupuy B, Soutourina O (2015) Function of the CRISPR-Cas system of the human pathogen Clostridium difficile. MBio 6(5):e01112–e01115. PubMedPubMedCentralGoogle Scholar
  3. Braun V, Mehlig M, Moos M, Rupnik M, Kalt B, Mahony DE, von Eichel-Streiber C (2000) A chimeric ribozyme in Clostridium difficile combines features of group I introns and insertion elements. Mol Microbiol 36(6):1447–1459CrossRefPubMedCentralGoogle Scholar
  4. Brouwer MS, Roberts AP, Hussain H, Williams RJ, Allan E, Mullany P (2013) Horizontal gene transfer converts non-toxigenic Clostridium difficile strains into toxin producers. Nat Commun 4:2601. CrossRefPubMedCentralGoogle Scholar
  5. Cairns MD, Preston MD, Lawley TD, Clark TG, Stabler RA, Wren BW (2015) Genomic epidemiology of a protracted hospital outbreak caused by a toxin A-negative Clostridium difficile sublineage PCR ribotype 017 strain in London, England. J Clin Microbiol 53(10):3141–3147. CrossRefPubMedCentralGoogle Scholar
  6. Cairns MD, Preston MD, Hall CL, Gerding DN, Hawkey PM, Kato H, Kim H, Kuijper EJ, Lawley TD, Pituch H, Reid S, Kullin B, Riley TV, Solomon K, Tsai PJ, Weese JS, Stabler RA, Wren BW (2017) Comparative genome analysis and global phylogeny of the toxin variant Clostridium difficile PCR ribotype 017 reveals the evolution of two independent sublineages. J Clin Microbiol 55(3):865–876. CrossRefPubMedCentralGoogle Scholar
  7. Chowdhury G, Joshi S, Bhattacharya S, Sekar U, Birajdar B, Bhattacharyya A, Shinoda S, Ramamurthy T (2016) Extraintestinal infections caused by non-toxigenic Vibrio cholerae non-O1/non-O139. Front Microbiol 7:144. CrossRefPubMedCentralGoogle Scholar
  8. Cohen SH, Tang YJ, Silva J Jr (2000) Analysis of the pathogenicity locus in Clostridium difficile strains. J Infect Dis 181(2):659–663. CrossRefPubMedCentralGoogle Scholar
  9. Collery MM, Kuehne SA, McBride SM, Kelly ML, Monot M, Cockayne A, Dupuy B, Minton NP (2016) What’s a SNP between friends: the influence of single nucleotide polymorphisms on virulence and phenotypes of Clostridium difficile strain 630 and derivatives. Virulence 8(6):767–781. CrossRefPubMedCentralGoogle Scholar
  10. Collins DA, Hawkey PM, Riley TV (2013) Epidemiology of Clostridium difficile infection in Asia. Antimicrob Resist Infect Control 2(1):21. CrossRefPubMedCentralGoogle Scholar
  11. Davies KA, Ashwin H, Longshaw CM, Burns DA, Davis GL, Wilcox MH, group Es (2016b) Diversity of Clostridium difficile PCR ribotypes in Europe: results from the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID), 2012 and 2013. Euro Surveill 21(29).
  12. Deltcheva E, Chylinski K, Sharma CM, Gonzales K, Chao Y, Pirzada ZA, Eckert MR, Vogel J, Charpentier E (2011) CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature 471(7340):602–607. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Deshpande A, Pasupuleti V, Thota P, Pant C, Rolston DD, Sferra TJ, Hernandez AV, Donskey CJ (2013) Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother 68(9):1951–1961. CrossRefPubMedCentralGoogle Scholar
  14. Didelot X, Eyre DW, Cule M, Ip CL, Ansari MA, Griffiths D, Vaughan A, O’Connor L, Golubchik T, Batty EM, Piazza P, Wilson DJ, Bowden R, Donnelly PJ, Dingle KE, Wilcox M, Walker AS, Crook DW, Peto TE, Harding RM (2012) Microevolutionary analysis of Clostridium difficile genomes to investigate transmission. Genome Biol 13(12):R118. CrossRefPubMedCentralGoogle Scholar
  15. Diez-Villasenor C, Almendros C, Garcia-Martinez J, Mojica FJ (2010) Diversity of CRISPR loci in Escherichia coli. Microbiology 156(Pt 5):1351–1361. PubMedPubMedCentralGoogle Scholar
  16. Dingle KE, Griffiths D, Didelot X, Evans J, Vaughan A, Kachrimanidou M, Stoesser N, Jolley KA, Golubchik T, Harding RM, Peto TE, Fawley W, Walker AS, Wilcox M, Crook DW (2011) Clinical Clostridium difficile: clonality and pathogenicity locus diversity. PLoS One 6(5):ee19993. CrossRefGoogle Scholar
  17. Dingle KE, Elliott B, Robinson E, Griffiths D, Eyre DW, Stoesser N, Vaughan A, Golubchik T, Fawley WN, Wilcox MH, Peto TE, Walker AS, Riley TV, Crook DW, Didelot X (2014) Evolutionary history of the Clostridium difficile pathogenicity locus. Genome Biol Evol 6(1):36–52. CrossRefPubMedCentralGoogle Scholar
  18. Drudy D, Harnedy N, Fanning S, Hannan M, Kyne L (2007) Emergence and control of fluoroquinolone-resistant, toxin A-negative, toxin Bpositive Clostridium difficile. Infect Control Hosp Epidemiol 28(8):932–940. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Duchene S, Holt KE, Weill FX, Le Hello S, Hawkey J, Edwards DJ, Fourment M, Holmes EC (2016) Genome-scale rates of evolutionary change in bacteria. Microb Genome 2(11):e000094. CrossRefGoogle Scholar
  20. Eckert C, Coignard B, Hebert M, Tarnaud C, Tessier C, Lemire A, Burghoffer B, Noel D, Barbut F, Group IC-RW (2013) Clinical and microbiological features of Clostridium difficile infections in France: the ICD-RAISIN 2009 national survey. Med Mal Infect 43(2):67–74. CrossRefPubMedCentralGoogle Scholar
  21. Elliott B, Dingle KE, Didelot X, Crook DW, Riley TV (2014) The complexity and diversity of the pathogenicity locus in Clostridium difficile clade 5. Genome Biol Evol 6(12):3159–3170. CrossRefPubMedCentralGoogle Scholar
  22. Eyre DW, Golubchik T, Gordon NC, Bowden R, Piazza P, Batty EM, Ip CL, Wilson DJ, Didelot X, O’Connor L, Lay R, Buck D, Kearns AM, Shaw A, Paul J, Wilcox MH, Donnelly PJ, Peto TE, Walker AS, Crook DW (2012) A pilot study of rapid benchtop sequencing of Staphylococcus aureus and Clostridium difficile for outbreak detection and surveillance. BMJ Open 2(3):e001124. CrossRefPubMedCentralGoogle Scholar
  23. Eyre DW, Cule ML, Griffiths D, Crook DW, Peto TE, Walker AS, Wilson DJ (2013a) Detection of mixed infection from bacterial whole genome sequence data allows assessment of its role in Clostridium difficile transmission. PLoS Comput Biol 9(5):e1003059. Scholar
  24. Eyre DW, Cule ML, Wilson DJ, Griffiths D, Vaughan A, O’Connor L, Ip CL, Golubchik T, Batty EM, Finney JM, Wyllie DH, Didelot X, Piazza P, Bowden R, Dingle KE, Harding RM, Crook DW, Wilcox MH, Peto TE, Walker AS (2013b) Diverse sources of C.difficile infection identified on whole-genome sequencing. N Engl J Med 369(13):1195–1205. CrossRefPubMedCentralGoogle Scholar
  25. Eyre DW, Griffiths D, Vaughan A, Golubchik T, Acharya M, O’Connor L, Crook DW, Walker AS, Peto TE (2013c) Asymptomatic Clostridium difficile colonisation and onward transmission. PLoS One 8(11):e78445. CrossRefPubMedCentralGoogle Scholar
  26. Eyre DW, Walker AS, Freeman J, Baines SD, Fawley WN, Chilton CH, Griffiths D, Vaughan A, Crook DW, Peto TE, Wilcox MH (2013d) Short-term genome stability of serial Clostridium difficile ribotype 027 isolates in an experimental gut model and recurrent human disease. PLoS One 8(5):e63540. CrossRefPubMedCentralGoogle Scholar
  27. Eyre DW, Babakhani F, Griffiths D, Seddon J, Del Ojo EC, Gorbach SL, Peto TE, Crook DW, Walker AS (2014) Whole-genome sequencing demonstrates that fidaxomicin is superior to vancomycin for preventing reinfection and relapse of infection with Clostridium difficile. J Infect Dis 209(9):1446–1451. CrossRefPubMedCentralGoogle Scholar
  28. Eyre DW, Fawley WN, Rajgopal A, Settle C, Mortimer K, Goldenberg SD, Dawson S, Crook DW, Peto TEA, Walker AS, Wilcox MH (2017) Comparison of control of Clostridium difficile infection in six english hospitals using whole-genome sequencing. Clin Infect Dis 65:433. CrossRefPubMedCentralGoogle Scholar
  29. Forgetta V, Oughton MT, Marquis P, Brukner I, Blanchette R, Haub K, Magrini V, Mardis ER, Gerding DN, Loo VG, Miller MA, Mulvey MR, Rupnik M, Dascal A, Dewar K (2011) Fourteen-genome comparison identifies DNA markers for severe-disease-associated strains of Clostridium difficile. J Clin Microbiol 49(6):2230–2238. CrossRefPubMedCentralGoogle Scholar
  30. Griffiths D, Fawley W, Kachrimanidou M, Bowden R, Crook DW, Fung R, Golubchik T, Harding RM, Jeffery KJ, Jolley KA, Kirton R, Peto TE, Rees G, Stoesser N, Vaughan A, Walker AS, Young BC, Wilcox M, Dingle KE (2010) Multilocus sequence typing of Clostridium difficile. J Clin Microbiol 48(3):770–778. CrossRefPubMedCentralGoogle Scholar
  31. Hargreaves KR, Flores CO, Lawley TD, Clokie MR (2014) Abundant and diverse clustered regularly interspaced short palindromic repeat spacers in Clostridium difficile strains and prophages target multiple phage types within this pathogen. MBio 5(5):e01045–e01013. CrossRefPubMedCentralGoogle Scholar
  32. Hasselmayer O, Braun V, Nitsche C, Moos M, Rupnik M, von Eichel-Streiber C (2004) Clostridium difficile IStron CdISt1: discovery of a variant encoding two complete transposase-like proteins. J Bacteriol 186(8):2508–2510CrossRefPubMedCentralGoogle Scholar
  33. He M, Sebaihia M, Lawley TD, Stabler RA, Dawson LF, Martin MJ, Holt KE, Seth-Smith HM, Quail MA, Rance R, Brooks K, Churcher C, Harris D, Bentley SD, Burrows C, Clark L, Corton C, Murray V, Rose G, Thurston S, van Tonder A, Walker D, Wren BW, Dougan G, Parkhill J (2010) Evolutionary dynamics of Clostridium difficile over short and long time scales. Proc Natl Acad Sci U S A 107(16):7527–7532. CrossRefPubMedCentralGoogle Scholar
  34. He M, Miyajima F, Roberts P, Ellison L, Pickard DJ, Martin MJ, Connor TR, Harris SR, Fairley D, Bamford KB, D’Arc S, Brazier J, Brown D, Coia JE, Douce G, Gerding D, Kim HJ, Koh TH, Kato H, Senoh M, Louie T, Michell S, Butt E, Peacock SJ, Brown NM, Riley T, Songer G, Wilcox M, Pirmohamed M, Kuijper E, Hawkey P, Wren BW, Dougan G, Parkhill J, Lawley TD (2013b) Emergence and global spread of epidemic healthcareassociated Clostridium difficile. Nat Genet 45(1):109–113.
  35. Janezic S, Rupnik M (2015) Genomic diversity of Clostridium difficile strains. Res Microbiol 166(4):353–360. CrossRefPubMedCentralGoogle Scholar
  36. Janezic S, Marin M, Martin A, Rupnik M (2015) A new type of toxin A-negative, toxin B-positive Clostridium difficile strain lacking a complete tcdA gene. J Clin Microbiol 53(2):692–695. CrossRefPubMedCentralGoogle Scholar
  37. Janezic S, Potocnik M, Zidaric V, Rupnik M (2016) Highly divergent Clostridium difficile strains isolated from the environment. PLoS One 11(11):e0167101. CrossRefPubMedCentralGoogle Scholar
  38. Janvilisri T, Scaria J, Thompson AD, Nicholson A, Limbago BM, Arroyo LG, Songer JG, Grohn YT, Chang YF (2009) Microarray identification of Clostridium difficile core components and divergent regions associated with host origin. J Bacteriol 191(12):3881–3891. CrossRefPubMedCentralGoogle Scholar
  39. Jhung MA, Thompson AD, Killgore GE, Zukowski WE, Songer G, Warny M, Johnson S, Gerding DN, McDonald LC, Limbago BM (2008) Toxinotype V Clostridium difficile in humans and food animals. Emerg Infect Dis 14(7):1039–1045. CrossRefPubMedCentralGoogle Scholar
  40. Kelly CP (2012) Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect 18(Suppl 6):21–27. CrossRefPubMedCentralGoogle Scholar
  41. Khanna S, Pardi DS (2012) Clostridium difficile infection: new insights into management. Mayo Clin Proc 87(11):1106–1117. CrossRefPubMedCentralGoogle Scholar
  42. Knetsch CW, Terveer EM, Lauber C, Gorbalenya AE, Harmanus C, Kuijper EJ, Corver J, van Leeuwen HC (2012) Comparative analysis of an expanded Clostridium difficile reference strain collection reveals genetic diversity and evolution through six lineages. Infect Genet Evol 12(7):1577–1585. CrossRefPubMedCentralGoogle Scholar
  43. Knight DR, Elliott B, Chang BJ, Perkins TT, Riley TV (2015) Diversity and evolution in the genome of Clostridium difficile. Clin Microbiol Rev 28(3):721–741. CrossRefPubMedCentralGoogle Scholar
  44. Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A, Minton NP (2010) The role of toxin A and toxin B in Clostridium difficile infection. Nature 467(7316):711–713. CrossRefPubMedCentralGoogle Scholar
  45. Kuijper EJ, Barbut F, Brazier JS, Kleinkauf N, Eckmanns T, Lambert ML, Drudy D, Fitzpatrick F, Wiuff C, Brown DJ, Coia JE, Pituch H, Reichert P, Even J, Mossong J, Widmer AF, Olsen KE, Allerberger F, Notermans DW, Delmee M, Coignard B, Wilcox M, Patel B, Frei R, Nagy E, Bouza E, Marin M, Akerlund T, Virolainen-Julkunen A, Lyytikainen O, Kotila S, Ingebretsen A, Smyth B, Rooney P, Poxton IR, Monnet DL (2008) Update of Clostridium difficile infection due to PCR ribotype 027 in Europe, 2008. Euro Surveill 13(31):18942Google Scholar
  46. Kumar N, Miyajima F, He M, Roberts P, Swale A, Ellison L, Pickard D, Smith G, Molyneux R, Dougan G, Parkhill J, Wren BW, Parry CM, Pirmohamed M, Lawley TD (2016) Genome-based infection tracking reveals dynamics of Clostridium difficile transmission and disease recurrence. Clin Infect Dis 62(6):746–752. CrossRefPubMedCentralGoogle Scholar
  47. Kurka H, Ehrenreich A, Ludwig W, Monot M, Rupnik M, Barbut F, Indra A, Dupuy B, Liebl W (2014) Sequence similarity of Clostridium difficile strains by analysis of conserved genes and genome content is reflected by their ribotype affiliation. PLoS One 9(1):e86535. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Lemee L, Dhalluin A, Pestel-Caron M, Lemeland JF, Pons JL (2004) Multilocus sequence typing analysis of human and animal Clostridium difficile isolates of various toxigenic types. J Clin Microbiol 42(6):2609–2617. CrossRefPubMedCentralGoogle Scholar
  49. Lim SK, Stuart RL, Mackin KE, Carter GP, Kotsanas D, Francis MJ, Easton M, Dimovski K, Elliott B, Riley TV, Hogg G, Paul E, Korman TM, Seemann T, Stinear TP, Lyras D, Jenkin GA (2014) Emergence of a ribotype 244 strain of Clostridium difficile associated with severe disease and related to the epidemic ribotype 027 strain. Clin Infect Dis 58(12):1723–1730. CrossRefGoogle Scholar
  50. Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S, Bourgault AM, Nguyen T, Frenette C, Kelly M, Vibien A, Brassard P, Fenn S, Dewar K, Hudson TJ, Horn R, Rene P, Monczak Y, Dascal A (2005) A predominantly clonal multi-institutional outbreak of Clostridium difficile associated diarrhea with high morbidity and mortality. N Engl J Med 353(23):2442–2449. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Lyras D, O’Connor JR, Howarth PM, Sambol SP, Carter GP, Phumoonna T, Poon R, Adams V, Vedantam G, Johnson S, Gerding DN, Rood JI (2009) Toxin B is essential for virulence of Clostridium difficile. Nature 458(7242):1176–1179. CrossRefPubMedCentralGoogle Scholar
  52. Mac Aogain M, Moloney G, Kilkenny S, Kelleher M, Kelleghan M, Boyle B, Rogers TR (2015) Whole-genome sequencing improves discrimination of relapse from reinfection and identifies transmission events among patients with recurrent Clostridium difficile infections. J Hosp Infect 90(2):108–116. CrossRefPubMedCentralGoogle Scholar
  53. Makarova KS, Haft DH, Barrangou R, Brouns SJ, Charpentier E, Horvath P, Moineau S, Mojica FJ, Wolf YI, Yakunin AF, van der Oost J, Koonin EV (2011) Evolution and classification of the CRISPR-Cas systems. Nat Rev Microbiol 9(6):467–477. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Makarova KS, Wolf YI, Koonin EV (2013) The basic building blocks and evolution of CRISPR-CAS systems. Biochem Soc Trans 41(6):1392–1400. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Marsden GL, Davis IJ, Wright VJ, Sebaihia M, Kuijper EJ, Minton NP (2010) Array comparative hybridisation reveals a high degree of similarity between UK and European clinical isolates of hypervirulent Clostridium difficile. BMC Genomics 11:389. CrossRefPubMedCentralGoogle Scholar
  56. Mawer DPC, Eyre DW, Griffiths D, Fawley WN, Martin JSH, Quan TP, Peto TEA, Crook DW, Walker AS, Wilcox MH (2017) Contribution to Clostridium difficile transmission of symptomatic patients with toxigenic strains who are fecal toxin negative. Clin Infect Dis 64(9):1163–1170. CrossRefPubMedCentralGoogle Scholar
  57. McDonald LC, Killgore GE, Thompson A, Owens RC Jr, Kazakova SV, Sambol SP, Johnson S, Gerding DN (2005) An epidemic, toxin genevariant strain of Clostridium difficile. N Engl J Med 353(23):2433–2441. CrossRefPubMedCentralGoogle Scholar
  58. Monot M, Eckert C, Lemire A, Hamiot A, Dubois T, Tessier C, Dumoulard B, Hamel B, Petit A, Lalande V, Ma L, Bouchier C, Barbut F, Dupuy B (2015) Clostridium difficile: new insights into the evolution of the pathogenicity locus. Sci Rep 5:15023. CrossRefPubMedCentralGoogle Scholar
  59. Moura I, Spigaglia P, Barbanti F, Mastrantonio P (2013) Analysis of metronidazole susceptibility in different Clostridium difficile PCR ribotypes. J Antimicrob Chemother 68(2):362–365. CrossRefPubMedCentralGoogle Scholar
  60. Moura I, Monot M, Tani C, Spigaglia P, Barbanti F, Norais N, Dupuy B, Bouza E, Mastrantonio P (2014) Multidisciplinary analysis of a nontoxigenic Clostridium difficile strain with stable resistance to metronidazole. Antimicrob Agents Chemother 58(8):4957–4960. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Peng L, Pei J, Pang H, Guo Y, Lin L, Huang R (2014) Whole genome sequencing reveals a novel CRISPR system in industrial Clostridium acetobutylicum. J Ind Microbiol Biotechnol 41(11):1677–1685. CrossRefPubMedCentralGoogle Scholar
  62. Pepin J, Valiquette L, Alary ME, Villemure P, Pelletier A, Forget K, Pepin K, Chouinard D (2004) Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ 171(5):466–472. CrossRefPubMedCentralGoogle Scholar
  63. Pepin J, Valiquette L, Cossette B (2005) Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ 173(9):1037–1042. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Pougach K, Semenova E, Bogdanova E, Datsenko KA, Djordjevic M, Wanner BL, Severinov K (2010) Transcription, processing and function Of CRISPR cassettes in Escherichia coli. Mol Microbiol 77(6):1367–1379. CrossRefPubMedCentralGoogle Scholar
  65. Quesada-Gomez C, Lopez-Urena D, Chumbler N, Kroh HK, Castro-Pena C, Rodriguez C, Orozco-Aguilar J, Gonzalez-Camacho S, Rucavado A, Guzman-Verri C, Lawley TD, Lacy DB, Chaves-Olarte E (2016) Analysis of TcdB proteins within the hypervirulent clade 2 reveals an impact of RhoA glucosylation on Clostridium difficile proinflammatory activities. Infect Immun 84(3):856–865. CrossRefPubMedCentralGoogle Scholar
  66. Richter H, Zoephel J, Schermuly J, Maticzka D, Backofen R, Randau L (2012) Characterization of CRISPR RNA processing in Clostridium thermocellum and Methanococcus maripaludis. Nucleic Acids Res 40(19):9887–9896. CrossRefPubMedCentralGoogle Scholar
  67. Rupnik M (2008) Heterogeneity of large clostridial toxins: importance of Clostridium difficile toxinotypes. FEMS Microbiol Rev 32(3):541–555. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Rupnik M, Widmer A, Zimmermann O, Eckert C, Barbut F (2008) Clostridium difficile toxinotype V, ribotype 078, in animals and humans. J Clin Microbiol 46(6):2146. CrossRefPubMedPubMedCentralGoogle Scholar
  69. Scaria J, Ponnala L, Janvilisri T, Yan W, Mueller LA, Chang YF (2010) Analysis of ultra low genome conservation in Clostridium difficile. PLoS One 5(12):e15147. CrossRefPubMedCentralGoogle Scholar
  70. Sebaihia M, Wren BW, Mullany P, Fairweather NF, Minton N, Stabler R, Thomson NR, Roberts AP, Cerdeno-Tarraga AM, Wang H, Holden MT, Wright A, Churcher C, Quail MA, Baker S, Bason N, Brooks K, Chillingworth T, Cronin A, Davis P, Dowd L, Fraser A, Feltwell T, Hance Z, Holroyd S, Jagels K, Moule S, Mungall K, Price C, Rabbinowitsch E, Sharp S, Simmonds M, Stevens K, Unwin L, Whithead S, Dupuy B, Dougan G, Barrell B, Parkhill J (2006) The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome. Nat Genet 38(7):779–786. CrossRefPubMedCentralGoogle Scholar
  71. Shin BM, Kuak EY, Yoo SJ, Shin WC, Yoo HM (2008) Emerging toxin A-B+ variant strain of Clostridium difficile responsible for pseudomembranous colitis at a tertiary care hospital in Korea. Diagn Microbiol Infect Dis 60(4):333–337. CrossRefPubMedCentralGoogle Scholar
  72. Sim JH, Truong C, Minot SS, Greenfield N, Budvytiene I, Lohith A, Anikst V, Pourmand N, Banaei N (2017) Determining the cause of recurrent Clostridium difficile infection using whole genome sequencing. Diagn Microbiol Infect Dis 87(1):11–16. CrossRefPubMedPubMedCentralGoogle Scholar
  73. Spigaglia P, Barbanti F, Mastrantonio P, European Study Group on Clostridium difficile (2011) Multidrug resistance in European Clostridium difficile clinical isolates. J Antimicrob Chemother 66(10):2227–2234. CrossRefPubMedCentralGoogle Scholar
  74. Stabler RA, Gerding DN, Songer JG, Drudy D, Brazier JS, Trinh HT, Witney AA, Hinds J, Wren BW (2006) Comparative phylogenomics of Clostridium difficile reveals clade specificity and microevolution of hypervirulent strains. J Bacteriol 188(20):7297–7305. CrossRefPubMedCentralGoogle Scholar
  75. Stabler RA, He M, Dawson L, Martin M, Valiente E, Corton C, Lawley TD, Sebaihia M, Quail MA, Rose G, Gerding DN, Gibert M, Popoff MR, Parkhill J, Dougan G, Wren BW (2009a) Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium. Genome Biol 10(9):R102. CrossRefPubMedCentralGoogle Scholar
  76. Stabler RA, Dawson LF, Valiente E, Cairns MD, Martin MJ, Donahue EH, Riley TV, Songer JG, Kuijper EJ, Dingle KE, Wren BW (2012) Macro and micro diversity of Clostridium difficile isolates from diverse sources and geographical locations. PLoS One 7:e31559. CrossRefPubMedCentralGoogle Scholar
  77. Valiente E, Dawson LF, Cairns MD, Stabler RA, Wren BW (2012) Emergence of new PCR ribotypes from the hypervirulent Clostridium difficile 027lineage. J Med Microbiol 61(Pt 1):49–56. CrossRefGoogle Scholar
  78. Vedantam G, Clark A, Chu M, McQuade R, Mallozzi M, Viswanathan VK (2012) Clostridium difficile infection: toxins and non-toxin virulence factors, and their contributions to disease establishment and host response. Gut Microbes 3(2):121–134. CrossRefPubMedCentralGoogle Scholar
  79. Vonberg RP, Kuijper EJ, Wilcox MH, Barbut F, Tull P, Gastmeier P, European Cd-ICG, European Centre for Disease P, Control, van den Broek PJ, Colville A, Coignard B, Daha T, Debast S, Duerden BI, van den Hof S, van der Kooi T, Maarleveld HJ, Nagy E, Notermans DW, O’Driscoll J, Patel B, Stone S, Wiuff C (2008) Infection control measures to limit the spread of Clostridium difficile. Clin Microbiol Infect 14(Suppl 5):2–20.
  80. Warny M, Pepin J, Fang A, Killgore G, Thompson A, Brazier J, Frost E, McDonald LC (2005) Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 366(9491):1079–1084. CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Sandra Janezic
    • 1
    • 2
  • Julian R. Garneau
    • 3
    • 4
  • Marc Monot
    • 3
    • 4
    • 5
  1. 1.National Laboratory for Health, Environment and Food (NLZOH)MariborSlovenia
  2. 2.University of Maribor, Faculty of MedicineMariborSlovenia
  3. 3.Département de MicrobiologieInstitut Pasteur, Laboratoire Pathogenèse des bactéries anaérobiesParisFrance
  4. 4.Département de Microbiologie et d’infectiologie, Faculté de Médecine et des Sciences de la SantéUniversité de SherbrookeSherbrookeCanada
  5. 5.Université Paris Diderot, Sorbonne Paris CitéParisFrance

Personalised recommendations