Purpose of Review
Colonization resistance refers to the innate defense provided by the indigenous microbiota against colonization by pathogenic organisms. We aim to describe how this line of defense is deployed against Clostridium difficile and what the implications are for interventions directed by Antimicrobial Stewardship Programs.
The indigenous microbiota provides colonization resistance through depletion of nutrients, prevention of access to adherence sites within the gut mucosa, production of inhibitory substances, and stimulation of the host’s immune system. The ability to quantify colonization resistance could provide information regarding periods of maximal vulnerability to colonization with pathogens and also allow the identification of mechanisms of restoration of colonization resistance. Methods utilized to determine the composition of the gut microbiota include sequencing technologies and measurement of concentration of specific bacterial metabolites.
Use of innovations in the quantification of colonization resistance can expand the role of Antimicrobial Stewardship from prevention of disruption of the indigenous microbiota to restoration of colonization resistance.
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Centers for Disease Control and Prevention. What do we know about antibiotic use in hospitals. In: Antibiotic prescribing and use. 2017. https://www.cdc.gov/antibiotic-use/stewardship-report/hospital.html. Accessed 16 Dec 2017.
Lawley TD, Walker AW. Intestinal colonization resistance. Immunology. 2013;138:1–11.
Bohnhoff M, Miller CP. Enhanced susceptibility to Salmonella infection in streptomycin-treated mice. J Infect Dis. 1962;111:117–27.
Ross CL, Spinler JK, Savidge TC. Structural and functional changes within the gut microbiota and susceptibility to Clostridium difficile infection. Anaerobe. 2016;41:37–43.
Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006;124:837–48.
Freter R, Brickner H, Botney M, Cleven D, Aranki A. Mechanisms that control bacterial populations in continuous-flow culture models of mouse large intestinal flora. Infect Immun. 1983;39:676–85.
Wilson KH, Perini F. Role of competition for nutrients in suppression of Clostridium difficile by the colonic microflora. Infect Immun. 1988;56:2610–4.
Juge N. Microbial adhesins to gastrointestinal mucus. Trends Microbiol. 2012;20:30–9.
Johansson ME, Larsson JM, Hansson GC. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4659–65.
Buffie CG, Pamer EG. Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol. 2013;13:790–801.
Marteyn B, Scorza FB, Sansonetti PJ, Tang C. Breathing life into pathogens: the influence of oxygen on bacterial virulence and host responses in the gastrointestinal tract. Cell Microbiol. 2011;13:171–6.
Dobson A, Cotter PD, Ross RP, Hill C. Bacteriocin production: a probiotic trait? Appl Environ Microbiol. 2012;78:1–6.
Donskey CJ. The role of the intestinal tract as a reservoir and source for transmission of nosocomial pathogens. Clin Infect Dis. 2004;39:219–26.
Britton RA, Young VB. Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology. 2014;146:1547–53.
Martin JS, Monaghan TM, Wilcox MH. Clostridium difficile infection: epidemiology, diagnosis and understanding transmission. Nat Rev Gastroenterol Hepatol. 2016;13:206–16.
Knetsch CW, Connor TR, Mutreja A, van Dorp SM, Sanders IM, Browne HP, 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.
Keessen EC, Harmanus C, Dohmen W, Kuijper EJ, Lipman LJ. Clostridium difficile infection associated with pig farms. Emerg Infect Dis. 2013;19:1032–4.
Schneeberg A, Neubauer H, Schmoock G, Baier S, Harlizius J, Nienhoff H, et al. Clostridium difficile genotypes in piglet populations in Germany. J Clin Microbiol. 2013;51:3796–803.
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;14:325–7.
Orden C, Neila C, Blanco JL, Alvarez-Perez S, Harmanus C, Kuijper EJ, et al. Recreational sandboxes for children and dogs can be a source of epidemic ribotypes of Clostridium difficile. Zoonoses Public Health. 2017;65:88–95.
Rodriguez C, Taminiau B, Van Broeck J, Delmee M, Daube G. Clostridium difficile in food and animals: a comprehensive review. Adv Exp Med Biol. 2016;932:65–92.
Kotila SM, Pitkanen T, Brazier J, Eerola E, Jalava J, Kuusi M, et al. Clostridium difficile contamination of public tap water distribution system during a waterborne outbreak in Finland. Scand J Public Health. 2013;41:541–5.
Bhalla A, Pultz NJ, Gries DM, Ray AJ, Eckstein EC, Aron DC, et al. Acquisition of nosocomial pathogens on hands after contact with environmental surfaces near hospitalized patients. Infect Control Hosp Epidemiol. 2004;25:164–7.
Sorg JA, Sonenshein AL. Bile salts and glycine as cogerminants for Clostridium difficile spores. J Bacteriol. 2008;190:2505–12.
Sorg JA, Sonenshein AL. Chenodeoxycholate is an inhibitor of Clostridium difficile spore germination. J Bacteriol. 2009;191:1115–7.
Theriot CM, Bowman AA, Young VB. 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. 2016;1.
Theriot CM, Koenigsknecht MJ, Carlson PE Jr, Hatton GE, Nelson AM, Li B, et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun. 2014;5:3114.
Hensgens MP, Goorhuis A, Dekkers OM, Kuijper EJ. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother. 2012;67:742–8.
Borriello SP, Barclay FE. An in-vitro model of colonisation resistance to Clostridium difficile infection. J Med Microbiol. 1986;21:299–309.
Abujamel T, Cadnum JL, Jury LA, Sunkesula VC, Kundrapu S, Jump RL, 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.
Isaac S, Scher JU, Djukovic A, Jimenez N, Littman DR, Abramson SB, et al. Short- and long-term effects of oral vancomycin on the human intestinal microbiota. J Antimicrob Chemother. 2017;72:128–36.
Vrieze A, Out C, Fuentes S, Jonker L, Reuling I, Kootte RS, et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol. 2014;60:824–31.
• Jump RL, Polinkovsky A, Hurless K, Sitzlar B, Eckart K, Tomas M, et al. Metabolomics analysis identifies intestinal microbiota-derived biomarkers of colonization resistance in clindamycin-treated mice. PLoS One. 2014;9:e101267. Compounds in fecal specimens were identified as potential useful biomarkers indicating intact or disrupted colonization resistance.
• 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 Urinary metabolites were identified as biomarkers indicating intact or disrupted colonization resistance.
van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–15.
Gupta S, Allen-Vercoe E, Petrof EO. Fecal microbiota transplantation: in perspective. Ther Adv Gastroenterol. 2016;9:229–39.
Stiefel U, Harmoinen J, Koski P, Kaariainen S, Wickstrand N, Lindevall K, et al. Orally administered recombinant metallo-beta-lactamase preserves colonization resistance of piperacillin-tazobactam-treated mice. Antimicrob Agents Chemother. 2005;49:5190–1.
• Kokai-Kun JF, Roberts T, Coughlin O, Sicard E, Rufiange M, Fedorak R, et al. The oral beta-lactamase SYN-004 (ribaxamase) degrades ceftriaxone excreted into the intestine in phase 2a clinical studies. 61 Phase 2a clinical study of ribaxamase, an oral beta-lactamase excreted into the small intestine. In vivo mechanism of action was confirmed.
Kokai-Kun JF, Roberts T, Coughlin O, Whalen H, Le C, Da Costa C, et al. SYN-004 (ribaxamase) prevents new onset Clostridium difficile infection by protecting the integrity gut microbiome in a phase 2b study. Open Forum Infect Dis. 2017;4(Supplement 1):S12.
Barlam TF, Cosgrove SE, Abbo LM, MacDougall C, Schuetz AN, Septimus EJ, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62:e51–77.
Baur D, Gladstone BP, Burkert F, Carrara E, Foschi F, Dobele S, et al. Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis. Lancet Infect Dis. 2017;17:990–1001.
• Donskey CJ. Colonization and its importance for the emergence of clinical resistance. In: Rice LB, editor. Antimicrobial stewardship, principles and practice. Wallingford: CAB International; 2017. p. 87–98. Comprehensive review on the topic of colonization resistance.
Adams DA, Riggs MM, Donskey CJ. Effect of fluoroquinolone treatment on growth of and toxin production by epidemic and nonepidemic clostridium difficile strains in the cecal contents of mice. Antimicrob Agents Chemother. 2007;51:2674–8.
• Dingle KE, Didelot X, Quan TP, Eyre DW, Stoesser N, Golubchik T, et al. Effects of control interventions on Clostridium difficile infection in England: an observational study. Lancet Infect Dis. 2017;17:411–21. Observational study which showed restriction in fluoroquinolone prescribing appeared to explain the decrease in incidence of C. difficile infections in the United Kingdom.
Pear SM, Williamson TH, Bettin KM, Gerding DN, Galgiani JN. Decrease in nosocomial Clostridium difficile-associated diarrhea by restricting clindamycin use. Ann Intern Med. 1994;120:272–7.
Rao A, Jump RL, Pultz NJ, Pultz MJ, Donskey CJ. In vitro killing of nosocomial pathogens by acid and acidified nitrite. Antimicrob Agents Chemother. 2006;50:3901–4.
Tariq R, Singh S, Gupta A, Pardi DS, Khanna S. Association of gastric acid suppression with recurrent Clostridium difficile infection: a systematic review and meta-analysis. JAMA Intern Med. 2017;177:784–91.
Vesper BJ, Jawdi A, Altman KW, Haines GK 3rd, Tao L, Radosevich JA. The effect of proton pump inhibitors on the human microbiota. Curr Drug Metab. 2009;10:84–9.
Kandel CE, Gill S, McCready J, Matelski J, Powis JE. Reducing co-administration of proton pump inhibitors and antibiotics using a computerized order entry alert and prospective audit and feedback. BMC Infect Dis. 2016;16:355.
Conflict of Interest
Curtis J. Donskey has received grants from Pfizer, Merck, Gojo Industries, Clorox, and Ecolab and is on the advisory board of Synthetic biologics.
Silvia Munoz-Price and Rossana Rosa declare that they have no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human subjects performed by any of the authors.
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
This article is part of the Topical Collection on Healthcare Associated Infections
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Rosa, R., Donskey, C.J. & Munoz-Price, L.S. The Intersection Between Colonization Resistance, Antimicrobial Stewardship, and Clostridium difficile. Curr Infect Dis Rep 20, 27 (2018). https://doi.org/10.1007/s11908-018-0631-z
- Colonization resistance
- Clostridium difficile
- Antimicrobial stewardship