Skip to main content Accessibility help

Clostridium difficile Exposures, Colonization, and the Microbiome: Implications for Prevention

  • Sara L. Revolinski (a1) (a2) and L. Silvia Munoz-Price (a3)


New studies have been published regarding the epidemiology of Clostridium difficile in topics such as asymptomatic C. difficile colonization, community-associated C. difficile infection, environmental contamination outside healthcare settings, animal colonization, and the interactions between C. difficile and the gut microbiome. In addition to summarizing these findings, this review offers a perspective on the potential impact of high-throughput sequencing and other potential techniques on the prevention of C. difficile.

Infect Control Hosp Epidemiol 2018;39:596–602


Corresponding author

Address correspondence to L. Silvia Munoz-Price, MD, PhD, 9200 W Wisconsin Ave, Milwaukee, WI 53226 (


Hide All
1. Loo, VG, Bourgault, AM, Poirier, L, et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med 2011;365:16931703.
2. Alasmari, F, Seiler, SM, Hink, T, Burnham, CA, Dubberke, ER. Prevalence and risk factors for asymptomatic Clostridium difficile carriage. Clin Infect Dis 2014;59:216222.
3. Furuya-Kanamori, L, Clements, AC, Foster, NF, et al. Asymptomatic Clostridium difficile colonization in two Australian tertiary hospitals, 2012–2014: prospective, repeated cross-sectional study. Clin Microbiol Infect 2017;23:48.e148.e7.
4. Pires, D, Prendki, V, Renzi, G, et al. Low frequency of asymptomatic carriage of toxigenic Clostridium difficile in an acute care geriatric hospital: prospective cohort study in Switzerland. Antimicrob Resist Infect Control 2016;5:24.
5. Blixt, T, Gradel, KO, Homann, C, et al. Asymptomatic carriers contribute to nosocomial Clostridium difficile infection: a cohort study of 4,508 patients. Gastroenterology 2017;152:10311041.
6. Zacharioudakis, IM, Zervou, FN, Pliakos, EE, Ziakas, PD, Mylonakis, E. Colonization with toxinogenic C. difficile upon hospital admission, and risk of infection: a systematic review and meta-analysis. Am J Gastroenterol 2015;110:381390.
7. Kamboj, M, Sheahan, A, Sun, J, et al. Transmission of Clostridium difficile during hospitalization for allogeneic stem cell transplant. Infect Control Hosp Epidemiol 2016;37:815.
8. Bruminhent, J, Wang, ZX, Hu, C, et al. Clostridium difficile colonization and disease in patients undergoing hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2014;20:13291334.
9. Jain, T, Croswell, C, Urday-Cornejo, V, et al. Clostridium difficile colonization in hematopoietic stem cell transplant recipients: a prospective study of the epidemiology and outcomes involving toxigenic and nontoxigenic strains. Biol Blood Marrow Transplant 2016;22:157163.
10. Cannon, CM, Musuuza, JS, Barker, AK, et al. Risk of Clostridium difficile infection in hematology-oncology patients colonized with toxigenic C. difficile . Infect Control Hosp Epidemiol 2017;38:718720.
11. Gerding, DN, Meyer, T, Lee, C, et al. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. JAMA 2015;313:17191727.
12. Longtin, Y, Paquet-Bolduc, B, Gilca, R, et al. Effect of detecting and isolating Clostridium difficile carriers at hospital admission on the incidence of C. difficile infections: a quasi-experimental controlled study. JAMA Intern Med 2016;176:796804.
13. Eyre, DW, Griffiths, D, Vaughan, A, et al. Asymptomatic Clostridium difficile colonisation and onward transmission. PLoS One 2013;8:e78445.
14. Eyre, DW, Fawley, WN, Best, EL, et al. Comparison of multilocus variable-number tandem-repeat analysis and whole-genome sequencing for investigation of Clostridium difficile transmission. J Clin Microbiol 2013;51:41414149.
15. Didelot, X, Eyre, DW, Cule, M, et al. Microevolutionary analysis of Clostridium difficile genomes to investigate transmission. Genome Biol 2012;13:R118.
16. Eyre, DW, Cule, ML, Wilson, DJ, et al. Diverse sources of C. difficile infection identified on whole-genome sequencing. N Engl J Med 2013;369:11951205.
17. Khanna, S, Pardi, DS, Aronson, SL, et al. The epidemiology of community-acquired Clostridium difficile infection: a population-based study. Am J Gastroenterol 2012;107:8995.
18. Lessa, FC, Winston, LG, McDonald, LC. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015;372:23692370.
19. Lessa, FC, Mu, Y, Winston, LG, et al. Determinants of Clostridium difficile infection incidence across diverse United States geographic locations. Open Forum Infect Dis 2014;1:ofu048.
20. Kotila, SM, Mentula, S, Ollgren, J, Virolainen-Julkunen, A, Lyytikainen, O. Community- and healthcare-associated Clostridium difficile infections, Finland, 2008–2013. Emerg Infect Dis 2016;22:17471753.
21. Furuya-Kanamori, L, Yakob, L, Riley, TV, et al. Community-acquired Clostridium difficile infection, Queensland, Australia. Emerg Infect Dis 2016;22:16591661.
22. Eyre, DW, Tracey, L, Elliott, B, et al. Emergence and spread of predominantly community-onset Clostridium difficile PCR ribotype 244 infection in Australia, 2010 to 2012. Euro Surveill 2015;20:21059.
23. Fawley, WN, Davies, KA, Morris, T, Parnell, P, Howe, R, Wilcox, MH. Enhanced surveillance of Clostridium difficile infection occurring outside hospital, England, 2011 to 2013. Euro Surveill 2016;21(29): doi: 10.2807/1560-7917.ES.2016.21.29.30295.
24. Naggie, S, Miller, BA, Zuzak, KB, et al. A case-control study of community-associated Clostridium difficile infection: no role for proton pump inhibitors. Am J Med 2011;124:276277.
25. Kuntz, JL, Chrischilles, EA, Pendergast, JF, Herwaldt, LA, Polgreen, PM. Incidence of and risk factors for community-associated Clostridium difficile infection: a nested case-control study. BMC Infect Dis 2011;11:194.
26. Wilcox, MH, Mooney, L, Bendall, R, Settle, CD, Fawley, WN. A case-control study of community-associated Clostridium difficile infection. J Antimicrob Chemother 2008;62:388396.
27. Deshpande, A, Pasupuleti, V, Thota, P, et al. Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother 2013;68:19511961.
28. Chitnis, AS, Holzbauer, SM, Belflower, RM, et al. Epidemiology of community-associated Clostridium difficile infection, 2009 through 2011. JAMA Intern Med 2013;173:13591367.
29. Kim, KH, Fekety, R, Batts, DH, et al. Isolation of Clostridium difficile from the environment and contacts of patients with antibiotic-associated colitis. J Infect Dis 1981;143:4250.
30. Sethi, AK, Al-Nassir, WN, Nerandzic, MM, Bobulsky, GS, Donskey, CJ. Persistence of skin contamination and environmental shedding of Clostridium difficile during and after treatment of C. difficile infection. Infect Control Hosp Epidemiol 2010;31:2127.
31. Sethi, AK, Al-Nassir, WN, Nerandzic, MM, Donskey, CJ. Skin and environmental contamination with vancomycin-resistant Enterococci in patients receiving oral metronidazole or oral vancomycin treatment for Clostridium difficile-associated disease. Infect Control Hosp Epidemiol 2009;30:1317.
32. Pepin, J, Gonzales, M, Valiquette, L. Risk of secondary cases of Clostridium difficile infection among household contacts of index cases. J Infect 2012;64:387390.
33. Loo, VG, Brassard, P, Miller, MA. Household transmission of Clostridium difficile to family members and domestic pets. Infect Control Hosp Epidemiol 2016;37:13421348.
34. Stoesser, N, Eyre, DW, Quan, TP, et al. Epidemiology of Clostridium difficile in infants in Oxfordshire, UK: risk factors for colonization and carriage, and genetic overlap with regional C. difficile infection strains. PLoS One 2017;12:e0182307.
35. Anderson, DJ, Rojas, LF, Watson, S, et al. Identification of novel risk factors for community-acquired Clostridium difficile infection using spatial statistics and geographic information system analyses. PLoS One 2017;12:e0176285.
36. Fry, PR, Thakur, S, Abley, M, Gebreyes, WA. Antimicrobial resistance, toxinotype, and genotypic profiling of Clostridium difficile isolates of swine origin. J Clin Microbiol 2012;50:23662372.
37. Knetsch, CW, Connor, TR, Mutreja, A, et al. Whole-genome sequencing reveals potential spread of Clostridium difficile between humans and farm animals in the Netherlands, 2002 to 2011. Euro Surveill 2014;19:20954.
38. Keessen, EC, Harmanus, C, Dohmen, W, Kuijper, EJ, Lipman, LJ. Clostridium difficile infection associated with pig farms. Emerg Infect Dis 2013;19:10321034.
39. Zidaric, V, Zemljic, M, Janezic, S, Kocuvan, A, Rupnik, M. High diversity of Clostridium difficile genotypes isolated from a single poultry farm producing replacement laying hens. Anaerobe 2008;14:325327.
40. Rodriguez-Palacios, A, Stampfli, HR, Duffield, T, et al. Clostridium difficile PCR ribotypes in calves, Canada. Emerg Infect Dis 2006;12:17301736.
41. Rodriguez-Palacios, A, Staempfli, HR, Duffield, T, Weese, JS. Clostridium difficile in retail ground meat, Canada. Emerg Infect Dis 2007;13:485487.
42. Stone, NE, Sidak-Loftis, LC, Sahl, JW, et al. More than 50% of Clostridium difficile isolates from pet dogs in Flagstaff, USA, carry toxigenic genotypes. PLoS One 2016;11:e0164504.
43. Orden, C, Neila, C, Blanco, JL, et al. Recreational sandboxes for children and dogs can be a source of epidemic ribotypes of Clostridium difficile . Zoonoses Public Health 2018;65:8895.
44. Rodriguez, C, Taminiau, B, van, BJ, Delmee, M, Daube, G. Clostridium difficile in food and animals: a comprehensive review. Adv Exp Med Biol 2016;932:6592.
45. Rodriguez-Palacios, A, Ilic, S, LeJeune, JT. Clostridium difficile with moxifloxacin/clindamycin resistance in vegetables in Ohio, USA, and prevalence meta-analysis. J Pathog 2014;2014:158601.
46. al, SN, Brazier, JS. The distribution of Clostridium difficile in the environment of South Wales. J Med Microbiol 1996;45:133137.
47. Kotila, SM, Pitkanen, T, Brazier, J, et al. Clostridium difficile contamination of public tap water distribution system during a waterborne outbreak in Finland. Scand J Public Health 2013;41:541545.
48. Britton, RA, Young, VB. Role of the intestinal microbiota in resistance to colonization by Clostridium difficile . Gastroenterology 2014;146:15471553.
49. Britton, RA, Young, VB. Interaction between the intestinal microbiota and host in Clostridium difficile colonization resistance. Trends Microbiol 2012;20:313319.
50. Buffie, CG, Pamer, EG. Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol 2013;13:790801.
51. Lynch, SV, Pedersen, O. The human intestinal microbiome in health and disease. N Engl J Med 2016;375:23692379.
52. Young, VB. The role of the microbiome in human health and disease: an introduction for clinicians. BMJ 2017;356:j831.
53. Schubert, AM, Rogers, MA, Ring, C, et al. Microbiome data distinguish patients with Clostridium difficile infection and non-C. difficile-associated diarrhea from healthy controls. MBio 2014;5:e0102114.
54. Zhang, L, Dong, D, Jiang, C, Li, Z, Wang, X, Peng, Y. Insight into alteration of gut microbiota in Clostridium difficile infection and asymptomatic C. difficile colonization. Anaerobe 2015;34:17.
55. Buffie, CG, Bucci, V, Stein, RR, et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile . Nature 2015;517:205208.
56. Studer, N, Desharnais, L, Beutler, M, et al. Functional intestinal bile acid 7alpha-dehydroxylation by Clostridium scindens associated with protection from Clostridium difficile infection in a gnotobiotic mouse model. Front Cell Infect Microbiol 2016;6:191.
57. Chang, JY, Antonopoulos, DA, Kalra, A, et al. Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis 2008;197:435438.
58. Knecht, H, Neulinger, SC, Heinsen, FA, et al. Effects of beta-lactam antibiotics and fluoroquinolones on human gut microbiota in relation to Clostridium difficile associated diarrhea. PLoS One 2014;9:e89417.
59. Lewis, BB, Buffie, CG, Carter, RA, et al. Loss of microbiota-mediated colonization resistance to Clostridium difficile infection with oral vancomycin compared with metronidazole. J Infect Dis 2015;212:16561665.
60. Abujamel, T, Cadnum, JL, Jury, LA, et al. Defining the vulnerable period for re-establishment of Clostridium difficile colonization after treatment of C. difficile infection with oral vancomycin or metronidazole. PLoS One 2013;8:e76269.
61. Taur, Y, Jenq, RR, Perales, MA, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 2014;124:11741182.
62. Ross, CL, Spinler, JK, Savidge, TC. Structural and functional changes within the gut microbiota and susceptibility to Clostridium difficile infection. Anaerobe 2016;41:3743.
63. Theriot, CM, Koenigsknecht, MJ, Carlson, PE Jr, et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun 2014;5:3114.
64. Jump, RL, Polinkovsky, A, Hurless, K, et al. Metabolomics analysis identifies intestinal microbiota-derived biomarkers of colonization resistance in clindamycin-treated mice. PLoS One 2014;9:e101267.
65. Allegretti, JR, Kearney, S, Li, N, et al. Recurrent Clostridium difficile infection associates with distinct bile acid and microbiome profiles. Aliment Pharmacol Ther 2016;43:11421153.
66. Weingarden, AR, Chen, C, Bobr, A, et al. Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection. Am J Physiol Gastrointest Liver Physiol 2014;306:G310G319.
67. Seekatz, AM, Aas, J, Gessert, CE, et al. Recovery of the gut microbiome following fecal microbiota transplantation. MBio 2014;5:e0089314.
68. Perez-Cobas, AE, Gosalbes, MJ, Friedrichs, A, et al. Gut microbiota disturbance during antibiotic therapy: a multiomic approach. Gut 2013;62:15911601.
69. Crofts, TS, Gasparrini, AJ, Dantas, G. Next-generation approaches to understand and combat the antibiotic resistome. Nat Rev Microbiol 2017;15:422434.
70. Halpin, AL, de Man, TJ, Kraft, CS, et al. Intestinal microbiome disruption in patients in a long-term acute care hospital: a case for development of microbiome disruption indices to improve infection prevention. Am J Infect Control 2016;44:830836.
71. Borriello, SP, Barclay, FE. An in-vitro model of colonisation resistance to Clostridium difficile infection. J Med Microbiol 1986;21:299309.
72. Obrenovich, ME, Tima, M, Polinkovsky, A, Zhang, R, Emancipator, SN, Donskey, CJ. Targeted metabolomics analysis identifies intestinal microbiota-derived urinary biomarkers of colonization resistance in antibiotic-treated mice. Antimicrob Agents Chemother 2017;61(8):pii e0047717.
73. Lawes, T, Lopez-Lozano, JM, Nebot, CA, et al. Effect of a national 4C antibiotic stewardship intervention on the clinical and molecular epidemiology of Clostridium difficile infections in a region of Scotland: a nonlinear time-series analysis. Lancet Infect Dis 2017;17:194206.
74. Dingle, KE, Didelot, X, Quan, TP, et al. Effects of control interventions on Clostridium difficile infection in England: an observational study. Lancet Infect Dis 2017;17:411421.
75. Revolinski, SL, Wainaina, N, Graham, MB, Munoz-Price, LS. Vertical antimicrobial stewardship to reduce C. difficile colitis in colonized patients. In: Program and abstracts of the Spring Meeting of the Society for Healthcare Epidemiology of America (SHEA); May 18–20, 2016; Atlanta, GA. Abstract 8236.


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed