Clostridium difficile infection: Epidemiology, diagnosis and understanding transmission

Nature Reviews Gastroenterology and Hepatology

Volumn 13, Issue 4, 2016, Pages 206-216

  Martin, Jessica S H ^a   Monaghan, Tanya M ^b   Wilcox, Mark H ^a  

^a LEEDS GENERAL INFIRMARY   (United Kingdom)

^b NOTTINGHAM UNIVERSITY HOSPITALS NHS TRUST   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CLOSTRIDIUM DIFFICILE TOXIN A; CLOSTRIDIUM DIFFICILE TOXIN B;

BACTERIAL SPORE; BACTERIAL STRAIN; BACTERIAL TRANSMISSION; BACTERIAL VIRULENCE; BACTERIUM CARRIER; BACTERIUM IDENTIFICATION; CLOSTRIDIUM DIFFICILE INFECTION; COLON PERFORATION; COMMUNITY ACQUIRED INFECTION; CYTOKINE RELEASE; DEATH; DIAGNOSTIC TEST; DIARRHEA; DISEASE SURVEILLANCE; DISEASE TRANSMISSION; ENVIRONMENTAL FACTOR; FECES ANALYSIS; HEALTH CARE FACILITY; HOSPITAL INFECTION; HOST SUSCEPTIBILITY; HUMAN; INFECTION CONTROL; MORBIDITY; NONHUMAN; NUCLEIC ACID AMPLIFICATION; OUTCOME ASSESSMENT; PEPTOCLOSTRIDIUM DIFFICILE; PRIORITY JOURNAL; REVIEW; SENSITIVITY AND SPECIFICITY; SEQUENCE ANALYSIS; SPORE GERMINATION; SPOROGENESIS; TOXIC MEGACOLON; VARIABLE NUMBER OF TANDEM REPEAT; CLASSIFICATION; CLOSTRIDIUM INFECTIONS; COMMUNITY-ACQUIRED INFECTIONS; CROSS INFECTION; HEALTH; ISOLATION AND PURIFICATION; TRANSMISSION;

BACTERIAL TYPING TECHNIQUES; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM INFECTIONS; COMMUNITY-ACQUIRED INFECTIONS; CROSS INFECTION; GLOBAL HEALTH; HUMANS;

EID: 84960193245     PISSN: 17595045     EISSN: 17595053     Source Type: Journal    
DOI: 10.1038/nrgastro.2016.25     Document Type: Review

References (124)

1. Wilson, K. H., et al. Gnotobiotic models for study of the microbial ecology of Clostridium difficile and Escherichia coli. J. Infect. Dis. 153, 547-551 (1986).
2. Walker, A. S., et al. Characterisation of Clostridium difficile hospital ward-based transmission using extensive epidemiological data and molecular typing. PLoS Med. 9, e1001172 (2012).
3. 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).
4. Clabots, C. R., Johnson, S., Olson, M. M., Peterson, L. R. & Gerding, D. N. Acquisition of Clostridium difficile by hospitalized patients: evidence for colonized new admissions as a source of infection. J. Infect. Dis. 166, 561-567 (1992).
5. He, M., et al. Evolutionary dynamics of Clostridium difficile over short and long time scales. Proc. Natl Acad. Sci. USA 107, 7527-7532 (2010).
6. Solomon, K. The host immune response to Clostridium difficile infection. Ther. Adv. Infect. Dis. 1, 19-35 (2013).
7. Vedantam, G., et al. Clostridium difficile infection: toxins and non-toxin virulence factors, and their contributions to disease establishment and host response. Gut Microbes 3, 121-134 (2012).
8. Walker, A. S., et al. Relationship between bacterial strain type, host biomarkers, and mortality in Clostridium difficile infection. Clin. Infect. Dis. 56, 1589-1600 (2013).
9. Solomon, K., et al. Mortality in patients with Clostridium difficile infection correlates with host pro-inflammatory and humoral immune responses. J. Med. Microbiol. 62, 1453-1460 (2013).
10. He, M., et al. Emergence and global spread of epidemic healthcare-associated Clostridium difficile. Nat. Genet. 45, 109-113 (2013).
11. Eyre, D. W., et al. Diverse sources of C. difficile infection identified on whole-genome sequencing. N. Engl. J. Med. 369, 1195-1205 (2013).
12. Bartlett, J. G., Onderdonk, A. B., Cisneros, R. L. & Kasper, D. L. Clindamycin-associated colitis due to a toxin-producing species of Clostridium in hamsters. J. Infect. Dis. 136, 701-705 (1977).
13. Archibald, L. K., Banerjee, S. N. & Jarvis, W. R. Secular trends in hospital-acquired Clostridium difficile disease in the United States, 1987-2001. J. Infect. Dis. 189, 1585-1589 (2004).
14. Freeman, J., et al. The changing epidemiology of Clostridium difficile infections. Clin. Microbiol. Rev. 23, 529-549 (2010).
15. 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).
16. Centre for Disease Control and Prevention. Clostridium difficile infection [online], http://www.cdc.gov/hai/ organisms/cdiff/cdiff-infect.html (2015).
17. Loo, V. G., et al. A predominantly clonal multiinstitutional outbreak of Clostridium difficileassociated diarrhea with high morbidity and mortality. N. Engl. J. Med. 353, 2442-2449 (2005).
18. Jones, A., Kuijper, E. & Wilcox, M. Clostridium difficile: a European perspective. J. Infect. 66, 115-128 (2013).
19. Curry, S. R., et al. Use of multilocus variable number of tandem repeats analysis genotyping to determine the role of asymptomatic carriers in Clostridium difficile transmission. Clin. Infect. Dis. 57, 1094-1102 (2013).
20. McFarland, L. V., Mulligan, M. E., Kwok, R. Y. & Stamm, W. E. Nosocomial acquisition of Clostridium difficile infection. N. Engl. J. Med. 320, 204210 (1989).
21. Loo, V. G., et al. Host and pathogen factors for Clostridium difficile infection and colonization. N. Engl. J. Med. 365, 1693-1703 (2011).
22. Chang, V. T. & Nelson, K. The role of physical proximity in nosocomial diarrhea. Clin. Infect. Dis. 31, 717-722 (2000).
23. Chitnis, A. S., et al. Epidemiology of communityassociated Clostridium difficile infection, 2009 through 2011. JAMA Intern. Med. 173, 1359-1367 (2013).
24. Zacharioudakis, I. M., et al. Colonization with toxinogenic C. difficile upon hospital admission, and risk of infection: a systematic review and metaanalysis. Am. J. Gastroenterol. 110, 381-390 (2015).
25. Khanna, S., et al. The epidemiology of communityacquired Clostridium difficile infection: a populationbased study. Am. J. Gastroenterol. 107, 89-95 (2011).
26. Jury, L. A., et al. Outpatient healthcare settings and transmission of Clostridium difficile. PLoS ONE 8, e70175 (2013).
27. Hensgens, M. P., et al. Clostridium difficile infection in the community: a zoonotic disease? Clin. Microbiol. Infect. 18, 635-645 (2012).
28. Lessa, F. C., et al. Burden of Clostridium difficile infection in the United States. N. Engl. J. Med. 372, 825-834 (2015).
29. Kufelnicka, A. M. & Kirn, T. J. Effective utilization of evolving methods for the laboratory diagnosis of Clostridium difficile infection. Clin. Infect. Dis. 52, 1451-1457 (2011).
30. Goorhuis, A., et al. Emergence of Clostridium difficile infection due to a new hypervirulent strain, polymerase chain reaction ribotype 078. Clin. Infect. Dis. 47, 1162-1170 (2008).
31. Bacci, S., et al. Binary toxin and death after Clostridium difficile infection. Emerg. Infect. Dis. 17, 976 (2011).
32. Gerding, D. N., et al. Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance. Gut Microbes. 5, 15-27 (2014).
33. 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).
34. Public Health England. Clostridium difficile Ribotyping Network (CDRN) for England and Northern Ireland 2011-2013 report. The National Archives [online], http://webarchive.nationalarchives.gov.uk/20140714084352/http://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb-C/1317140658987 (2014).
35. Hensgens, M. P., et al. Clostridium difficile infection in an endemic setting in the Netherlands. Eur. J. Clin. Microbiol. Infect. Dis. 30, 587-593 (2011).
36. Tenover, F. C., et al. Comparison of strain typing results for Clostridium difficile isolates from North America. J. Clin. Microbiol. 49, 1831-1837 (2011).
37. Ahmetagic, S., et al. Clostridium difficile infection in hospitalized patients at University Clinical Center Tuzla, Bosnia and Herzegovina: a 4 year experience. Mater. Sociomed. 25, 153 (2013).
38. Rupnik, M., et al. Diversity of C. difficile PCR ribotypes isolated from hospitalised patients in Slovenia during two-winter-month period. Zdravniški Vestnik 82, 739-745 (2013).
39. Lim, S. K., et al. 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, 1723-1730 (2014).
40. Eyre, D. W., et al. Emergence and spread of predominantly community-onset Clostridium difficile PCR ribotype 244 infection in Australia, 2010 to 2012. Euro Surveill. 20, 21059 (2015).
41. De Almeida, M., et al. Severe Clostridium difficile infection in New Zealand associated with an emerging strain, PCR-ribotype 244. N. Z. Med. J. 126, 9-14 (2013).
42. Cheng, A. C., et al. Control of fluoroquinolone resistance through successful regulation, Australia. Emerg. Infecti. Diseases 18, 1453 (2012).
43. Collins, D. A., Hawkey, P. M. & Riley, T. V. Epidemiology of Clostridium difficile infection in Asia. Antimicrob. Resist. Infect.Control 2, 21 (2013).
44. Waslawski, S., et al. Clostridium difficile ribotype diversity at six health care institutions in the United States. J. Clin. Microbiol. 51, 1938-1941 (2013).
45. Foster, N., et al. Epidemiology of Clostridium difficile infection in two tertiary-care hospitals in Perth, Western Australia: a cross-sectional study. New Microbes New Infect. 2, 64-71 (2014).
46. Griffiths, D., et al. Multilocus sequence typing of Clostridium difficile. J. Clin. Microbiol. 48, 770-778 (2010).
47. Lemee, L., et al. Multilocus sequence typing analysis of human and animal Clostridium difficile isolates of various toxigenic types. J. Clin. Microbiol. 42, 2609-2617 (2004).
48. O'Neill, G. L., Ogunsola, F. T., Brazier, J. S. & Duerden, B. I. Modification of a PCR ribotyping method for application as a routine typing scheme for Clostridium difficile. Anaerobe 2, 205-209 (1996).
49. Didelot, X., et al. Microevolutionary analysis of Clostridium difficile genomes to investigate transmission. Genome Biol. 13, R118 (2012).
50. Chakra, C., et al. Risk factors for recurrence, complications and mortality in Clostridium difficile infection: a systematic review. PloS ONE 9, e98400 (2014).
51. Skraban, J., et al. Gut microbiota patterns associated with colonization of different Clostridium difficile ribotypes. PloS ONE 8, e58005 (2013).
52. Rea, M. C., et al. Clostridium difficile carriage in elderly subjects and associated changes in the intestinal microbiota. J. Clin. Microbiol. 50, 867-875 (2012).
53. Littman, D. R. & Pamer, E. G. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 10, 311-323 (2011).
54. Yakob, L., et al. Mechanisms of hypervirulent Clostridium difficile ribotype 027 displacement of endemic strains: an epidemiological model. Sci. Rep. 5, 12666 (2015).
55. Awad, M. M., Johanesen, P. A., Carter, G. P., Rose, E. & Lyras, D. Clostridium difficile virulence factors: insights into an anaerobic spore-forming pathogen. Gut microbes 5, 579-593 (2014).
56. Smits, W. K. Hype or hypervirulence: a reflection on problematic C. difficile strains. Virulence 4, 592-596 (2013).
57. Britton, R. A. & Young, V. B. Interaction between the intestinal microbiota and host in Clostridium difficile colonization resistance. Trends Microbiol. 20, 313-319 (2012).
58. Sorg, J. A. & Sonenshein, A. L. Bile salts and glycine as cogerminants for Clostridium difficile spores. J. Bacteriol. 190, 2505-2512 (2008).
59. 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).
60. Heap, J. T., Pennington, O. J., Cartman, S. T., Carter, G. P. & Minton, N. P. The ClosTron: a universal gene knock-out system for the genus Clostridium. Microbiol. Methods 70, 452-464 (2007).
61. Rosenbusch, K. E., Bakker, D., Kuijper, E. J. & Smits, W. K. C. difficile 630Δerm Spo0A regulates sporulation, but does not contribute to toxin production, by direct high-affinity binding to target DNA. PloS ONE 7, e48608 (2012).
62. Mackin, K. E., Carter, G. P., Howarth, P., Rood, J. I. & Lyras, D. Spo0A differentially regulates toxin production in evolutionarily diverse strains of Clostridium difficile. PLoS ONE 8, e79666 (2013).
63. Underwood, S., et al. Characterization of the sporulation initiation pathway of Clostridium difficile and its role in toxin production. J. Bacteriol. 191, 7296-7305 (2009).
64. Deakin, L. J., et al. The Clostridium difficile spo0A gene is a persistence and transmission factor. Infect. Immun. 80, 2704-2711 (2012).
65. 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).
66. Shen, A. Clostridium difficile toxins: mediators of inflammation. J. Innate Immun. 4, 149-158 (2012).
67. Ng, J., et al. Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome. Gastroenterology 139, 542-552.e3 (2010).
68. Xu, H., et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 513, 237-241 (2014).
69. Buonomo, E. L., et al. Role of interleukin 23 signaling in Clostridium difficile colitis. J. Infect. Dis. 208, 917-920 (2013).
70. Madan, R. & Petri, W. A. Jr. Immune responses to Clostridium difficile infection. Trends Mol. Med. 18, 658-666 (2012).
71. Kelly, C. P. & Kyne, L. The host immune response to Clostridium difficile. J. Med. Microbiol. 60, 1070-1079 (2011).
72. El Feghaly, R. E., et al. Markers of intestinal inflammation, not bacterial burden, correlate with clinical outcomes in Clostridium difficile infection. Clin. Infect. Dis. 56, 1713-1721 (2013).
73. Kyne, L., Warny, M., Qamar, A. & Kelly, C. P. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N. Engl. J. Med. 342, 390-397 (2000).
74. Kyne, L., Warny, M., Qamar, A. & Kelly, C. P. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 357, 189-193 (2001).
75. Monaghan, T. M., Robins, A., Knox, A., Sewell, H. F. & Mahida, Y. R. Circulating antibody and memory B-Cell responses to C. difficile toxins A and B in patients with C. difficile-associated diarrhoea, inflammatory bowel disease and cystic fibrosis. PLoS ONE 8, e74452 (2013).
76. 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).
77. Martin, J., et al. Investigating Clostridium difficile transmission using whole genome sequencing (WGS): few cases follow direct contact with a symptomatic donor (abstract). Program and abstracts of the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy [online], http://www.icaaconline.com/php/icaac2013abstracts/data/papers/2013/late/2013-K-168a.htm (2013).
78. Rutala, W. A. & Weber, D. J. Role of the hospital environment in disease transmission with a focus on Clostridium difficile. Healthc. Infect. 18, 18-22 (2013).
79. Friedman, N. D., et al. Prevalence of Clostridium difficile colonization among healthcare workers. BMC Infect. Dis. 13, 459 (2013).
80. Säll, O., Johansson, K. & Norén, T. Low colonization rates of Clostridium difficile among patients and healthcare workers at Örebro University Hospital in Sweden. APMIS 123, 240-244 (2015).
81. Cohen, S. H., et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect. Control Hosp. Epidemiol. 31, 431-455 (2010).
82. Hensgens, M. P. M., et al. Diarrhoea in general practice: when should a Clostridium difficile infection be considered? Results of a nested case-control study. Clin. Microbiol. Infect. 20, O1067-O1074 (2014).
83. Guerrero, D. M., et al. Clostridium difficile infection in a Department of Veterans Affairs long-term care facility. Infect. Control Hosp. Epidemiol. 32, 513-515 (2011).
84. Chang, H. T., et al. Onset of symptoms and time to diagnosis of Clostridium difficile-associated disease following discharge from an acute care hospital. Infect. Control Hosp. Epidemiol. 28, 926-931 (2007).
85. Arvand, M., et al. High prevalence of Clostridium difficile colonization among nursing home residents in Hesse, Germany. PloS ONE 7, e30183 (2012).
86. Kim, J. H., Toy, D. & Muder, R. R. Clostridium difficile infection in a long-term care facility: hospitalassociated illness compared with long-term care-associated illness. Infect. Control Hosp. Epidemiol. 32, 656-660 (2011).
87. Ziakas, P. D., et al. Asymptomatic carriers of toxigenic C. difficile in long-term care facilities: a meta-analysis of prevalence and risk factors. PloS ONE 10, e0117195 (2015).
88. Wilcox, M., Mooney, L., Bendall, R., Settle, C. & Fawley, W. A case-control study of communityassociated Clostridium difficile infection. J. Antimicrob. Chemother. 62, 388-396 (2008).
89. Stoesser, N., et al. Molecular epidemiology of Clostridium difficile strains in children compared with that of strains circulating in adults with Clostridium difficile-associated infection. J. Clin. Microbiol. 49, 3994-3996 (2011).
90. Rousseau, C., et al. Clostridium difficile carriage in healthy infants in the community: a potential reservoir for pathogenic strains. Clin. Infect. Dis. 55, 1209-1215 (2012).
91. Rodriguez-Palacios, A., Borgmann, S., Kline, T. R. & LeJeune, J. T. Clostridium difficile in foods and animals: history and measures to reduce exposure. Animal Health Res. Rev. 14, 11-29 (2013).
92. Knetsch, C. W., et al. Whole genome sequencing reveals potential spread of Clostridium difficile between humans and farm animals in the Netherlands, 2002 to 2011. Euro Surveill. 19, 20954 (2014).
93. Keessen, E. C., Harmanus, C., Dohmen, W., Kuijper, E. J. & Lipman, L. J. Clostridium difficile infection associated with pig farms. Emerg. Infect. Dis. 19, 1032-1034 (2013).
94. Gould, L. H. & Limbago, B. Clostridium difficile in food and domestic animals: a new foodborne pathogen? Clin. Infect. Dis. 51, 577-582 (2010).
95. Al Saif, N. & Brazier, J. The distribution of Clostridium difficile in the environment of South Wales. J. Med. Microbiol. 45, 133-137 (1996).
96. Alam, M. J., Anu, A., Walk, S. T. & Garey, K. W. Investigation of potentially pathogenic Clostridium difficile contamination in household environs. Anaerobe 27, 31-33 (2014).
97. Wilcox, M. H. Overcoming barriers to effective recognition and diagnosis of Clostridium difficile infection. Clin. Microbiol. Infect. 18 (Suppl. 6), 13-20 (2012).
98. Dubberke, E. R., et al. Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections. J. Clin. Microbiol. 49, 2887-2893 (2011).
99. Elliott, B., et al. The complexity and diversity of the Pathogenicity Locus in Clostridium difficile clade 5. Genome Biol. Evol. 6, 3159-3170 (2014).
100. Brouwer, M. S., et al. Horizontal gene transfer converts non-toxigenic Clostridium difficile strains into toxin producers. Nat. Commun. 4, 2601 (2013).
101. Braun, V., Hundsberger, T., Leukel, P., Sauerborn, M. & von Eichel-Streiber, C. Definition of the single integration site of the pathogenicity locus in Clostridium difficile. Gene 181, 29-38 (1996).
102. 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).
103. Baker, I., Leeming, J. P., Reynolds, R., Ibrahim, I. & Darley, E. Clinical relevance of a positive molecular test in the diagnosis of Clostridium difficile infection. J. Hosp. Infect. 84, 311315 (2013).
104. Goldenberg, S. D., Cliff, P. R. & French, G. L. Laboratory diagnosis of Clostridium difficile infection. J. Clin. Microbiol. 48, 3048-3049 (2010).
105. Polage, C. R., et al. Overdiagnosis of Clostridium difficile infection in the molecular test era. JAMA Intern. Med. 175, 1792-1801 (2015).
106. Dallal, R. M., et al. Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications. Ann. Surg. 235, 363-372 (2002).
107. Guerrero, D. M., et al. Clinical and infection control implications of Clostridium difficile infection with negative enzyme immunoassay for toxin. Clin. Infect. Dis. 53, 287-290 (2011).
108. Crobach, M., Dekkers, O., Wilcox, M. & Kuijper, E. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): Data review and recommendations for diagnosing Clostridium difficile infection (CDI). Clin. Microbiol. Infect. 15, 1053-1066 (2009).
109. Surawicz, C. M., et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am. J. Gastroenterol. 108, 478-498 (2013).
110. UK Department of Health. Clostridium difficile: updated guidance on the diagnosis and reporting. UK Government website [online] https://www.gov.uk/government/publications/updated-guidance-on-thediagnosis- and-reporting-of-clostridium-difficile (2012).
111. Alcala, L., et al. Laboratory diagnosis of Clostridium difficile infection in Spain: a population-based survey. J. Hosp. Infect. 79, 13-17 (2011).
112. Burdette, S. D. & Bernstein, J. M. Does the nose know? The odiferous diagnosis of Clostridium difficileassociated diarrhea. Clin. Infect. Dis. 44, 1142-1142 (2007).
113. Huber, C. A., Foster, N. F., Riley, T. V. & Paterson, D. L. Clostridium difficile typing methods: challenges for standardization. J. Clin. Microbiol. 51, 2810-2814 (2013).
114. Eyre, D. W., et al. Comparison of multilocus variablenumber tandem-repeat analysis and whole-genome sequencing for investigation of Clostridium difficile transmission. J. Clin. Microbiol. 51, 4141-4149 (2013).
115. Eyre, D. W., et al. A pilot study of rapid benchtop sequencing of Staphylococcus aureus and Clostridium difficile for outbreak detection and surveillance. BMJ Open 2, e001124 (2012).
116. Didelot, X., Bowden, R., Wilson, D. J., Peto, T. E. & Crook, D. W. Transforming clinical microbiology with bacterial genome sequencing. Nat. Rev. Genet. 13, 601-612 (2012).
117. Reil, M., et al. Recognition of Clostridium difficile PCRribotypes 001, 027 and 126/078 using an extended MALDI-TOF MS system. Eur. J. Clin. Microbiol. Infect. Dis. 30, 1431-1436 (2011).
118. 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).
119. Carroll, K. C. Tests for the diagnosis of Clostridium difficile infection: the next generation. Anaerobe 17, 170-174 (2011).
120. Noren, T., Alriksson, I., Andersson, J., Akerlund, T. & Unemo, M. Rapid and sensitive loop-mediated isothermal amplification test for Clostridium difficile detection challenges cytotoxin B cell test and culture as gold standard. J. Clin. Microbiol. 49, 710-711 (2011).
121. O'Horo, J. C., Jones, A., Sternke, M., Harper, C. & Safdar, N. Molecular techniques for diagnosis sof Clostridium difficile infection: systematic review and meta-analysis. Mayo Clin. Proc. 87, 643-651 (2012).
122. Kim, J., et al. Epidemiology of Clostridium difficile infections in a tertiary-care hospital in Korea. Clin. Microbiol. Infect. 19, 521-527 (2013).
123. Huang, H., et al. Distinct ribotypes and rates of antimicrobial drug resistance in Clostridium difficile from Shanghai and Stockholm. Clin. Microbiol. Infect. 15, 1170-1173 (2009).
124. Plaza-Garrido, Á., et al. Predominance of Clostridium difficile ribotypes 012, 027 and 046 in a university hospital in Chile, 2012. Epidemiol. Infect 22, 14 (2015).