Frontiers in antibiotic alternatives for Clostridioides difficile infection

Matthew Phanchana, Phurt Harnvoravongchai, Supapit Wongkuna, Tanaporn Phetruen, Wichuda Phothichaisri, Supakan Panturat, Methinee Pipatthana, Sitthivut Charoensutthivarakul, Surang Chankhamhaengdecha, Tavan Janvilisri, Matthew Phanchana, Phurt Harnvoravongchai, Supapit Wongkuna, Tanaporn Phetruen, Wichuda Phothichaisri, Supakan Panturat, Methinee Pipatthana, Sitthivut Charoensutthivarakul, Surang Chankhamhaengdecha, Tavan Janvilisri

Abstract

Clostridioides difficile (C. difficile) is a gram-positive, anaerobic spore-forming bacterium and a major cause of antibiotic-associated diarrhea. Humans are naturally resistant to C. difficile infection (CDI) owing to the protection provided by healthy gut microbiota. When the gut microbiota is disturbed, C. difficile can colonize, produce toxins, and manifest clinical symptoms, ranging from asymptomatic diarrhea and colitis to death. Despite the steady-if not rising-prevalence of CDI, it will certainly become more problematic in a world of antibiotic overuse and the post-antibiotic era. C. difficile is naturally resistant to most of the currently used antibiotics as it uses multiple resistance mechanisms. Therefore, current CDI treatment regimens are extremely limited to only a few antibiotics, which include vancomycin, fidaxomicin, and metronidazole. Therefore, one of the main challenges experienced by the scientific community is the development of alternative approaches to control and treat CDI. In this Frontier article, we collectively summarize recent advances in alternative treatment approaches for CDI. Over the past few years, several studies have reported on natural product-derived compounds, drug repurposing, high-throughput library screening, phage therapy, and fecal microbiota transplantation. We also include an update on vaccine development, pre- and pro-biotics for CDI, and toxin antidote approaches. These measures tackle CDI at every stage of disease pathology via multiple mechanisms. We also discuss the gaps and concerns in these developments. The next epidemic of CDI is not a matter of if but a matter of when. Therefore, being well-equipped with a collection of alternative therapeutics is necessary and should be prioritized.

Keywords: Alternative therapy; Bacteriophage; Clostridioides difficile; Drug resistance; Fecal microbiota; Pharmaceutical.

Conflict of interest statement

Conflict-of-interest statement: The authors declare no conflict of interest.

©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.

Figures

Figure 1
Figure 1
Alternative approaches for Clostridioides difficile infection treatment under development. Different approaches are aiming at the different pathological stages of Clostridioides difficile (C. difficile) infection. Small molecule and natural product derived have broad range activity from vegetative cell inhibition to biofilm and spore effects. Bacteriophage therapy affects mostly the vegetative stage of C. difficile. Fecal microbiota transplantation and pre- and pro-biotics aim to restore the balance of the gut microbiota mitigating the chance of C. difficile population and production of toxins. Vaccine and antitoxin antibody are targeting toxin neutralization.

References

    1. Kuiper GA, van Prehn J, Ang W, Kneepkens F, van der Schoor S, de Meij T. Clostridium difficile infections in young infants: Case presentations and literature review. IDCases. 2017;10:7–11.
    1. Tullus K, Aronsson B, Marcus S, Möllby R. Intestinal colonization with Clostridium difficile in infants up to 18 months of age. Eur J Clin Microbiol Infect Dis. 1989;8:390–393.
    1. Hooks KB, O'Malley MA. Dysbiosis and Its Discontents. mBio. 2017;8
    1. Seekatz AM, Young VB. Clostridium difficile and the microbiota. J Clin Invest. 2014;124:4182–4189.
    1. Chandrasekaran R, Lacy DB. The role of toxins in Clostridium difficile infection. FEMS Microbiol Rev. 2017;41:723–750.
    1. Kuehne SA, Collery MM, Kelly ML, Cartman ST, Cockayne A, Minton NP. Importance of toxin A, toxin B, and CDT in virulence of an epidemic Clostridium difficile strain. J Infect Dis. 2014;209:83–86.
    1. Smits WK, Lyras D, Lacy DB, Wilcox MH, Kuijper EJ. Clostridium difficile infection. Nat Rev Dis Primers. 2016;2:16020.
    1. Androga GO, Hart J, Foster NF, Charles A, Forbes D, Riley TV. Infection with Toxin A-Negative, Toxin B-Negative, Binary Toxin-Positive Clostridium difficile in a Young Patient with Ulcerative Colitis. J Clin Microbiol. 2015;53:3702–3704.
    1. Eckert C, Emirian A, Le Monnier A, Cathala L, De Montclos H, Goret J, Berger P, Petit A, De Chevigny A, Jean-Pierre H, Nebbad B, Camiade S, Meckenstock R, Lalande V, Marchandin H, Barbut F. Prevalence and pathogenicity of binary toxin-positive Clostridium difficile strains that do not produce toxins A and B. New Microbes New Infect. 2015;3:12–17.
    1. Abt MC, McKenney PT, Pamer EG. Clostridium difficile colitis: pathogenesis and host defence. Nat Rev Microbiol. 2016;14:609–620.
    1. Poxton IR, McCoubrey J, Blair G. The pathogenicity of Clostridium difficile. Clin Microbiol Infect. 2001;7:421–427.
    1. Suetens C, Latour K, Kärki T, Ricchizzi E, Kinross P, Moro ML, Jans B, Hopkins S, Hansen S, Lyytikäinen O, Reilly J, Deptula A, Zingg W, Plachouras D, Monnet DL The Healthcare-Associated Infections Prevalence Study Group. Prevalence of healthcare-associated infections, estimated incidence and composite antimicrobial resistance index in acute care hospitals and long-term care facilities: results from two European point prevalence surveys, 2016 to 2017. Euro Surveill. 2018;23
    1. Vardakas KZ, Trigkidis KK, Boukouvala E, Falagas ME. Clostridium difficile infection following systemic antibiotic administration in randomised controlled trials: a systematic review and meta-analysis. Int J Antimicrob Agents. 2016;48:1–10.
    1. O'Grady K, Knight DR, Riley TV. Antimicrobial resistance in Clostridioides difficile. Eur J Clin Microbiol Infect Dis. 2021
    1. McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Shaklee Sammons J, Sandora TJ, Wilcox MH. 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. 2018;66:e1–e48.
    1. Baur D, Gladstone BP, Burkert F, Carrara E, Foschi F, Döbele S, Tacconelli E. 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.
    1. Negrut N, Nistor-Cseppento DC, Khan SA, Pantis C, Maghiar TA, Maghiar O, Aleya S, Rus M, Tit DM, Aleya L, Rahdar A, Bungau S. Clostridium difficile infection epidemiology over a period of 8 years—a single centre study. Sustainability. 2020;12:4439.
    1. Marra AR, Perencevich EN, Nelson RE, Samore M, Khader K, Chiang HY, Chorazy ML, Herwaldt LA, Diekema DJ, Kuxhausen MF, Blevins A, Ward MA, McDanel JS, Nair R, Balkenende E, Schweizer ML. Incidence and Outcomes Associated With Clostridium difficile Infections: A Systematic Review and Meta-analysis. JAMA Netw Open. 2020;3:e1917597.
    1. Principi N, Silvestri E, Esposito S. Advantages and Limitations of Bacteriophages for the Treatment of Bacterial Infections. Front Pharmacol. 2019;10:513.
    1. Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA, Ford K, Harris K, Gilmour KC, Soothill J, Jacobs-Sera D, Schooley RT, Hatfull GF, Spencer H. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med. 2019;25:730–733.
    1. Amidon S, Brown JE, Dave VS. Colon-targeted oral drug delivery systems: design trends and approaches. AAPS PharmSciTech. 2015;16:731–741.
    1. Jarrad AM, Karoli T, Blaskovich MA, Lyras D, Cooper MA. Clostridium difficile drug pipeline: challenges in discovery and development of new agents. J Med Chem. 2015;58:5164–5185.
    1. Petrosillo N, Granata G, Cataldo MA. Novel Antimicrobials for the Treatment of Clostridium difficile Infection. Front Med (Lausanne) 2018;5:96.
    1. Mendes RE, Rhomberg PR, Locher HH, Jones RN. Activity of cadazolid against Gram-positive clinical isolates, including linezolid-resistant subsets with defined resistance mechanisms. ICACC; 2013; North Liberty, IA, USA. Available from: .
    1. Chilton CH, Crowther GS, Baines SD, Todhunter SL, Freeman J, Locher HH, Athanasiou A, Wilcox MH. In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection. J Antimicrob Chemother. 2014;69:697–705.
    1. Odingo J, Bailey MA, Files M, Early JV, Alling T, Dennison D, Bowman J, Dalai S, Kumar N, Cramer J, Masquelin T, Hipskind PA, Parish T. In Vitro Evaluation of Novel Nitazoxanide Derivatives against Mycobacterium tuberculosis. ACS Omega. 2017;2:5873–5890.
    1. Hoffman PS, Sisson G, Croxen MA, Welch K, Harman WD, Cremades N, Morash MG. Antiparasitic drug nitazoxanide inhibits the pyruvate oxidoreductases of Helicobacter pylori, selected anaerobic bacteria and parasites, and Campylobacter jejuni. Antimicrob Agents Chemother. 2007;51:868–876.
    1. de Carvalho LP, Darby CM, Rhee KY, Nathan C. Nitazoxanide Disrupts Membrane Potential and Intrabacterial pH Homeostasis of Mycobacterium tuberculosis. ACS Med Chem Lett. 2011;2:849–854.
    1. Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014;110:94–103.
    1. Stachulski AV, Taujanskas J, Pate SL, Rajoli RKR, Aljayyoussi G, Pennington SH, Ward SA, Hong WD, Biagini GA, Owen A, Nixon GL, Leung SC, O'Neill PM. Therapeutic Potential of Nitazoxanide: An Appropriate Choice for Repurposing versus SARS-CoV-2? ACS Infect Dis. 2021;7:1317–1331.
    1. Musher DM, Logan N, Bressler AM, Johnson DP, Rossignol JF. Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double-blind study. Clin Infect Dis. 2009;48:e41–e46.
    1. Rafiullah F, Kanwal S, Majeed UM, Korsten MA, Cheema FH, Luthra M, Sohail MR. Successful use of nitazoxanide in the treatment of recurrent Clostridium difficile infection. BMJ Case Rep. 2011;2011
    1. Brook I, Wexler HM, Goldstein EJ. Antianaerobic antimicrobials: spectrum and susceptibility testing. Clin Microbiol Rev. 2013;26:526–546.
    1. Vickers R, Robinson N, Best E, Echols R, Tillotson G, Wilcox M. A randomised phase 1 study to investigate safety, pharmacokinetics and impact on gut microbiota following single and multiple oral doses in healthy male subjects of SMT19969, a novel agent for Clostridium difficile infections. BMC Infect Dis. 2015;15:91.
    1. Qian X, Yanagi K, Kane AV, Alden N, Lei M, Snydman DR, Vickers RJ, Lee K, Thorpe CM. Ridinilazole, a narrow spectrum antibiotic for treatment of Clostridioides difficile infection, enhances preservation of microbiota-dependent bile acids. Am J Physiol Gastrointest Liver Physiol. 2020;319:G227–G237.
    1. Bassères E, Endres BT, Khaleduzzaman M, Miraftabi F, Alam MJ, Vickers RJ, Garey KW. Impact on toxin production and cell morphology in Clostridium difficile by ridinilazole (SMT19969), a novel treatment for C. difficile infection. J Antimicrob Chemother. 2016;71:1245–1251.
    1. Vickers RJ, Tillotson GS, Nathan R, Hazan S, Pullman J, Lucasti C, Deck K, Yacyshyn B, Maliakkal B, Pesant Y, Tejura B, Roblin D, Gerding DN, Wilcox MH CoDIFy study group. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Lancet Infect Dis. 2017;17:735–744.
    1. Swinney DC, Anthony J. How were new medicines discovered? Nat Rev Drug Discov. 2011;10:507–519.
    1. Volochnyuk DM, Ryabukhin SV, Moroz YS, Savych O, Chuprina A, Horvath D, Zabolotna Y, Varnek A, Judd DB. Evolution of commercially available compounds for HTS. Drug Discov Today. 2019;24:390–402.
    1. AbdelKhalek A, Mohammad H, Mayhoub AS, Seleem MN. Screening for potent and selective anticlostridial leads among FDA-approved drugs. J Antibiot (Tokyo) 2020;73:392–409.
    1. AbdelKhalek A, Seleem MN. Repurposing the Veterinary Antiprotozoal Drug Ronidazole for the Treatment of Clostridioides difficile Infection. Int J Antimicrob Agents. 2020;56:106188.
    1. Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D, Pirmohamed M. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18:41–58.
    1. Pal R, Seleem MN. Screening of Natural Products and Approved Oncology Drug Libraries for Activity against Clostridioides difficile. Sci Rep. 2020;10:5966.
    1. Fillbrunn A, Dietz C, Pfeuffer J, Rahn R, Landrum GA, Berthold MR. KNIME for reproducible cross-domain analysis of life science data. J Biotechnol. 2017;261:149–156.
    1. Beisken S, Meinl T, Wiswedel B, de Figueiredo LF, Berthold M, Steinbeck C. KNIME-CDK: Workflow-driven cheminformatics. BMC Bioinformatics. 2013;14:257.
    1. Mazanetz MP, Marmon RJ, Reisser CB, Morao I. Drug discovery applications for KNIME: an open source data mining platform. Curr Top Med Chem. 2012;12:1965–1979.
    1. Kong KF, Schneper L, Mathee K. Beta-lactam antibiotics: from antibiosis to resistance and bacteriology. APMIS. 2010;118:1–36.
    1. Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev. 1999;12:40–79.
    1. de la Torre BG, Albericio F. The Pharmaceutical Industry in 2019. An Analysis of FDA Drug Approvals from the Perspective of Molecules. Molecules. 2020;25
    1. Palombo EA. Phytochemicals from traditional medicinal plants used in the treatment of diarrhoea: modes of action and effects on intestinal function. Phytother Res. 2006;20:717–724.
    1. Patridge E, Gareiss P, Kinch MS, Hoyer D. An analysis of FDA-approved drugs: natural products and their derivatives. Drug Discov Today. 2016;21:204–207.
    1. Roshan N, Riley TV, Hammer KA. Antimicrobial activity of natural products against Clostridium difficile in vitro. J Appl Microbiol. 2017;123:92–103.
    1. Perumalsamy H, Jung MY, Hong SM, Ahn YJ. Growth-Inhibiting and morphostructural effects of constituents identified in Asarum heterotropoides root on human intestinal bacteria. BMC Complement Altern Med. 2013;13:245.
    1. Fraternale D, Flamini G, Ricci D. Essential oil composition and antimicrobial activity of Angelica archangelica L. (Apiaceae) roots. J Med Food. 2014;17:1043–1047.
    1. Cermak P, Olsovska J, Mikyska A, Dusek M, Kadleckova Z, Vanicek J, Nyc O, Sigler K, Bostikova V, Bostik P. Strong antimicrobial activity of xanthohumol and other derivatives from hops (Humulus lupulus L.) on gut anaerobic bacteria. APMIS. 2017;125:1033–1038.
    1. Canning C, Sun S, Ji X, Gupta S, Zhou K. Antibacterial and cytotoxic activity of isoprenylated coumarin mammea A/AA isolated from Mammea africana. J Ethnopharmacol. 2013;147:259–262.
    1. Mody D, Athamneh AIM, Seleem MN. Curcumin: A natural derivative with antibacterial activity against Clostridium difficile. J Glob Antimicrob Resist. 2020;21:154–161.
    1. Finegold SM, Summanen PH, Corbett K, Downes J, Henning SM, Li Z. Pomegranate extract exhibits in vitro activity against Clostridium difficile. Nutrition. 2014;30:1210–1212.
    1. de Nova PJG, Carvajal A, Prieto M, Rubio P. In vitro Susceptibility and Evaluation of Techniques for Understanding the Mode of Action of a Promising Non-antibiotic Citrus Fruit Extract Against Several Pathogens. Front Microbiol. 2019;10:884.
    1. Gadhi CA, Weber M, Mory F, Benharref A, Lion C, Jana M, Lozniewski A. Antibacterial activity of Aristolochia paucinervis Pomel. J Ethnopharmacol. 1999;67:87–92.
    1. Roshan N, Riley TV, Knight DR, Steer JH, Hammer KA. Natural products show diverse mechanisms of action against Clostridium difficile. J Appl Microbiol. 2019;126:468–479.
    1. Harnvoravongchai P, Chankhamhaengdecha S, Ounjai P, Singhakaew S, Boonthaworn K, Janvilisri T. Antimicrobial Effect of Asiatic Acid Against Clostridium difficile Is Associated With Disruption of Membrane Permeability. Front Microbiol. 2018;9:2125.
    1. Shilling M, Matt L, Rubin E, Visitacion MP, Haller NA, Grey SF, Woolverton CJ. Antimicrobial effects of virgin coconut oil and its medium-chain fatty acids on Clostridium difficile. J Med Food. 2013;16:1079–1085.
    1. Blaskovich MAT, Kavanagh AM, Elliott AG, Zhang B, Ramu S, Amado M, Lowe GJ, Hinton AO, Pham DMT, Zuegg J, Beare N, Quach D, Sharp MD, Pogliano J, Rogers AP, Lyras D, Tan L, West NP, Crawford DW, Peterson ML, Callahan M, Thurn M. The antimicrobial potential of cannabidiol. Commun Biol. 2021;4:7.
    1. Gigli S, Seguella L, Pesce M, Bruzzese E, D'Alessandro A, Cuomo R, Steardo L, Sarnelli G, Esposito G. Cannabidiol restores intestinal barrier dysfunction and inhibits the apoptotic process induced by Clostridium difficile toxin A in Caco-2 cells. United European Gastroenterol J. 2017;5:1108–1115.
    1. Adejumo AC, Bukong TN. Cannabis use and risk of Clostridioides difficile infection: Analysis of 59,824 hospitalizations. Anaerobe. 2020;61:102095.
    1. Roshan N, Riley TV, Hammer KA. Effects of natural products on several stages of the spore cycle of Clostridium difficile in vitro. J Appl Microbiol. 2018;125:710–723.
    1. Mooyottu S, Flock G, Venkitanarayanan K. Carvacrol reduces Clostridium difficile sporulation and spore outgrowth in vitro. J Med Microbiol. 2017;66:1229–1234.
    1. Yu L, Palafox-Rosas R, Luna B, She RC. The Bactericidal Activity and Spore Inhibition Effect of Manuka Honey against Clostridioides Difficile. Antibiotics (Basel) 2020;9
    1. Pellissery AJ, Vinayamohan PG, Venkitanarayanan K. In vitro antivirulence activity of baicalin against Clostridioides difficile. J Med Microbiol. 2020;69:631–639.
    1. Roshan N, Riley TV, Knight DR, Hammer KA. Effect of natural products on the production and activity of Clostridium difficile toxins in vitro. Sci Rep. 2018;8:15735.
    1. Wultańska D, Piotrowski M, Pituch H. The effect of berberine chloride and/or its combination with vancomycin on the growth, biofilm formation, and motility of Clostridioides difficile. Eur J Clin Microbiol Infect Dis. 2020;39:1391–1399.
    1. Giles SL, Laheij RJF. Successful treatment of persistent Clostridium difficile infection with manuka honey. Int J Antimicrob Agents. 2017;49:522–523.
    1. Orth P, Xiao L, Hernandez LD, Reichert P, Sheth PR, Beaumont M, Yang X, Murgolo N, Ermakov G, DiNunzio E, Racine F, Karczewski J, Secore S, Ingram RN, Mayhood T, Strickland C, Therien AG. Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem. 2014;289:18008–18021.
    1. Yang Z, Ramsey J, Hamza T, Zhang Y, Li S, Yfantis HG, Lee D, Hernandez LD, Seghezzi W, Furneisen JM, Davis NM, Therien AG, Feng H. Mechanisms of protection against Clostridium difficile infection by the monoclonal antitoxin antibodies actoxumab and bezlotoxumab. Infect Immun. 2015;83:822–831.
    1. Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, Cornely OA, Rahav G, Bouza E, Lee C, Jenkin G, Jensen W, Kim YS, Yoshida J, Gabryelski L, Pedley A, Eves K, Tipping R, Guris D, Kartsonis N, Dorr MB MODIFY I and MODIFY II Investigators. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017;376:305–317.
    1. Maiti PK, inventor Immunimed Inc , assignee. Use of polyclonal antibodies against Clostridium Difficile for treatment of inflammatory bowel disease. US patent US20180362618A1. 2017. Available from: .
    1. Sponseller JK, Steele JA, Schmidt DJ, Kim HB, Beamer G, Sun X, Tzipori S. Hyperimmune bovine colostrum as a novel therapy to combat Clostridium difficile infection. J Infect Dis. 2015;211:1334–1341.
    1. Heidebrecht HJ, Weiss WJ, Pulse M, Lange A, Gisch K, Kliem H, Mann S, Pfaffl MW, Kulozik U, von Eichel-Streiber C. Treatment and Prevention of Recurrent Clostridium difficile Infection with Functionalized Bovine Antibody-Enriched Whey in a Hamster Primary Infection Model. Toxins (Basel) 2019;11
    1. Sholeh M, Krutova M, Forouzesh M, Mironov S, Sadeghifard N, Molaeipour L, Maleki A, Kouhsari E. Antimicrobial resistance in Clostridioides (Clostridium) difficile derived from humans: a systematic review and meta-analysis. Antimicrob Resist Infect Control. 2020;9:158.
    1. Reeves AE, Theriot CM, Bergin IL, Huffnagle GB, Schloss PD, Young VB. The interplay between microbiome dynamics and pathogen dynamics in a murine model of Clostridium difficile Infection. Gut Microbes. 2011;2:145–158.
    1. Gupta S, Allen-Vercoe E, Petrof EO. Fecal microbiota transplantation: in perspective. Therap Adv Gastroenterol. 2016;9:229–239.
    1. Sbahi H, Di Palma JA. Faecal microbiota transplantation: applications and limitations in treating gastrointestinal disorders. BMJ Open Gastroenterol. 2016;3:e000087.
    1. Mullish BH, Quraishi MN, Segal JP, McCune VL, Baxter M, Marsden GL, Moore DJ, Colville A, Bhala N, Iqbal TH, Settle C, Kontkowski G, Hart AL, Hawkey PM, Goldenberg SD, Williams HRT. The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines. Gut. 2018;67:1920–1941.
    1. Khoruts A, Staley C, Sadowsky MJ. Faecal microbiota transplantation for Clostridioides difficile: mechanisms and pharmacology. Nat Rev Gastroenterol Hepatol. 2021;18:67–80.
    1. Segal JP, Mullish BH, Quraishi MN, Iqbal T, Marchesi JR, Sokol H. Mechanisms underpinning the efficacy of faecal microbiota transplantation in treating gastrointestinal disease. Therap Adv Gastroenterol. 2020;13:1756284820946904.
    1. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–415.
    1. Kim KO, Gluck M. Fecal Microbiota Transplantation: An Update on Clinical Practice. Clin Endosc. 2019;52:137–143.
    1. Cammarota G, Masucci L, Ianiro G, Bibbò S, Dinoi G, Costamagna G, Sanguinetti M, Gasbarrini A. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015;41:835–843.
    1. Hui W, Li T, Liu W, Zhou C, Gao F. Fecal microbiota transplantation for treatment of recurrent C. difficile infection: An updated randomized controlled trial meta-analysis. PLoS One. 2019;14:e0210016.
    1. Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, Chang HJ, Coward S, Goodman KJ, Xu H, Madsen K, Mason A, Wong GK, Jovel J, Patterson J, Louie T. Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA. 2017;318:1985–1993.
    1. Hamilton MJ, Weingarden AR, Unno T, Khoruts A, Sadowsky MJ. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes. 2013;4:125–135.
    1. Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, Weese JS, Collins S, Moayyedi P, Crowther M, Ropeleski MJ, Jayaratne P, Higgins D, Li Y, Rau NV, Kim PT. Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA. 2016;315:142–149.
    1. Jiang ZD, Ajami NJ, Petrosino JF, Jun G, Hanis CL, Shah M, Hochman L, Ankoma-Sey V, DuPont AW, Wong MC, Alexander A, Ke S, DuPont HL. Randomised clinical trial: faecal microbiota transplantation for recurrent Clostridum difficile infection - fresh, or frozen, or lyophilised microbiota from a small pool of healthy donors delivered by colonoscopy. Aliment Pharmacol Ther. 2017;45:899–908.
    1. Agrawal M, Aroniadis OC, Brandt LJ, Kelly C, Freeman S, Surawicz C, Broussard E, Stollman N, Giovanelli A, Smith B, Yen E, Trivedi A, Hubble L, Kao D, Borody T, Finlayson S, Ray A, Smith R. The Long-term Efficacy and Safety of Fecal Microbiota Transplant for Recurrent, Severe, and Complicated Clostridium difficile Infection in 146 Elderly Individuals. J Clin Gastroenterol. 2016;50:403–407.
    1. Fischer M, Sipe B, Cheng YW, Phelps E, Rogers N, Sagi S, Bohm M, Xu H, Kassam Z. Fecal microbiota transplant in severe and severe-complicated Clostridium difficile: A promising treatment approach. Gut Microbes. 2017;8:289–302.
    1. DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, Sater MRA, Huntley MH, Turbett S, Chung RT, Chen YB, Hohmann EL. Drug-Resistant E. coli Bacteremia Transmitted by Fecal Microbiota Transplant. N Engl J Med. 2019;381:2043–2050.
    1. Wilcox MH, McGovern BH, Hecht GA. The Efficacy and Safety of Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection: Current Understanding and Gap Analysis. Open Forum Infect Dis. 2020;7:ofaa114.
    1. Kwak S, Choi J, Hink T, Reske KA, Blount K, Jones C, Bost MH, Sun X, Burnham CD, Dubberke ER, Dantas G CDC Prevention Epicenter Program. Impact of investigational microbiota therapeutic RBX2660 on the gut microbiome and resistome revealed by a placebo-controlled clinical trial. Microbiome. 2020;8:125.
    1. Ford C, Litcofsky K, McGovern B, Pardi D, Nathan R, Hansen V, Brennan R, Pullman J, Bernardo P, Tomlinson A, Horgan K, Bryant J, Walsh E, Rodriguez M, Rogalin H, Wang E, Henn M. 1503. Engraftment of investigational microbiome drug, SER-262, in subjects receiving vancomycin is associated with reduced rates of recurrence after primary Clostridium infection (CDI) Open Forum Infect Dis. 2019;6:S547–S548.
    1. McGovern BH, Ford CB, Henn MR, Pardi DS, Khanna S, Hohmann EL, O'Brien EJ, Desjardins CA, Bernardo P, Wortman JR, Lombardo MJ, Litcofsky KD, Winkler JA, McChalicher CWJ, Li SS, Tomlinson AD, Nandakumar M, Cook DN, Pomerantz RJ, Auninš JG, Trucksis M. SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial. Clin Infect Dis. 2021;72:2132–2140.
    1. Quera R, Espinoza R, Estay C, Rivera D. Bacteremia as an adverse event of fecal microbiota transplantation in a patient with Crohn's disease and recurrent Clostridium difficile infection. J Crohns Colitis. 2014;8:252–253.
    1. Vendrik KEW, Terveer EM, Kuijper EJ, Nooij S, Boeije-Koppenol E, Sanders IMJG, van Lingen E, Verspaget HW, Berssenbrugge EKL, Keller JJ, van Prehn J Netherlands Donor Faeces Bank Study Group. Periodic screening of donor faeces with a quarantine period to prevent transmission of multidrug-resistant organisms during faecal microbiota transplantation: a retrospective cohort study. Lancet Infect Dis. 2021;21:711–721.
    1. US Food and Drug Administration. Safety alert regarding use of fecal microbiota for transplantation and additional safety protections pertaining to SARS-CoV-2 and COVID-19. 2020. Available from: .
    1. Joint FAO/WHO. Guidelines for the evaluation of probiotics in food. 2002. Available from: .
    1. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, Morelli L, Canani RB, Flint HJ, Salminen S, Calder PC, Sanders ME. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11:506–514.
    1. Hudson LE, Anderson SE, Corbett AH, Lamb TJ. Gleaning Insights from Fecal Microbiota Transplantation and Probiotic Studies for the Rational Design of Combination Microbial Therapies. Clin Microbiol Rev. 2017;30:191–231.
    1. Mills JP, Rao K, Young VB. Probiotics for prevention of Clostridium difficile infection. Curr Opin Gastroenterol. 2018;34:3–10.
    1. McFarland LV, Surawicz CM, Greenberg RN, Fekety R, Elmer GW, Moyer KA, Melcher SA, Bowen KE, Cox JL, Noorani Z. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA. 1994;271:1913–1918.
    1. Gorbach SL, Chang TW, Goldin B. Successful treatment of relapsing Clostridium difficile colitis with Lactobacillus GG. Lancet. 1987;2:1519.
    1. Pace F, Pace M, Quartarone G. Probiotics in digestive diseases: focus on Lactobacillus GG. Minerva Gastroenterol Dietol. 2015;61:273–292.
    1. Cameron D, Hock QS, Kadim M, Mohan N, Ryoo E, Sandhu B, Yamashiro Y, Jie C, Hoekstra H, Guarino A. Probiotics for gastrointestinal disorders: Proposed recommendations for children of the Asia-Pacific region. World J Gastroenterol. 2017;23:7952–7964.
    1. Valdés-Varela L, Gueimonde M, Ruas-Madiedo P. Probiotics for Prevention and Treatment of Clostridium difficile Infection. Adv Exp Med Biol. 2018;1050:161–176.
    1. McFarland LV, Ship N, Auclair J, Millette M. Primary prevention of Clostridium difficile infections with a specific probiotic combining Lactobacillus acidophilus, L. casei, and L. rhamnosus strains: assessing the evidence. J Hosp Infect. 2018;99:443–452.
    1. Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, Bulpitt CJ. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;335:80.
    1. Gao XW, Mubasher M, Fang CY, Reifer C, Miller LE. Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients. Am J Gastroenterol. 2010;105:1636–1641.
    1. Barker AK, Duster M, Valentine S, Hess T, Archbald-Pannone L, Guerrant R, Safdar N. A randomized controlled trial of probiotics for Clostridium difficile infection in adults (PICO) J Antimicrob Chemother. 2017;72:3177–3180.
    1. Zmora N, Zilberman-Schapira G, Suez J, Mor U, Dori-Bachash M, Bashiardes S, Kotler E, Zur M, Regev-Lehavi D, Brik RB, Federici S, Cohen Y, Linevsky R, Rothschild D, Moor AE, Ben-Moshe S, Harmelin A, Itzkovitz S, Maharshak N, Shibolet O, Shapiro H, Pevsner-Fischer M, Sharon I, Halpern Z, Segal E, Elinav E. Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features. Cell. 2018;174:1388–1405.e21.
    1. Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D, Costea PI, Godneva A, Kalka IN, Bar N, Shilo S, Lador D, Vila AV, Zmora N, Pevsner-Fischer M, Israeli D, Kosower N, Malka G, Wolf BC, Avnit-Sagi T, Lotan-Pompan M, Weinberger A, Halpern Z, Carmi S, Fu J, Wijmenga C, Zhernakova A, Elinav E, Segal E. Environment dominates over host genetics in shaping human gut microbiota. Nature. 2018;555:210–215.
    1. So D, Whelan K, Rossi M, Morrison M, Holtmann G, Kelly JT, Shanahan ER, Staudacher HM, Campbell KL. Dietary fiber intervention on gut microbiota composition in healthy adults: a systematic review and meta-analysis. Am J Clin Nutr. 2018;107:965–983.
    1. Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, Scott K, Stanton C, Swanson KS, Cani PD, Verbeke K, Reid G. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol. 2017;14:491–502.
    1. Rätsep M, Kõljalg S, Sepp E, Smidt I, Truusalu K, Songisepp E, Stsepetova J, Naaber P, Mikelsaar RH, Mikelsaar M. A combination of the probiotic and prebiotic product can prevent the germination of Clostridium difficile spores and infection. Anaerobe. 2017;47:94–103.
    1. Sell TL, Schaberg DR, Fekety FR. Bacteriophage and bacteriocin typing scheme for Clostridium difficile. J Clin Microbiol. 1983;17:1148–1152.
    1. Fortier LC, Moineau S. Morphological and genetic diversity of temperate phages in Clostridium difficile. Appl Environ Microbiol. 2007;73:7358–7366.
    1. Mayer MJ, Narbad A, Gasson MJ. Molecular characterization of a Clostridium difficile bacteriophage and its cloned biologically active endolysin. J Bacteriol. 2008;190:6734–6740.
    1. Fortier LC. Bacteriophages Contribute to Shaping Clostridioides (Clostridium) difficile Species. Front Microbiol. 2018;9:2033.
    1. Li T, Zhang Y, Dong K, Kuo CJ, Li C, Zhu YQ, Qin J, Li QT, Chang YF, Guo X, Zhu Y. Isolation and Characterization of the Novel Phage JD032 and Global Transcriptomic Response during JD032 Infection of Clostridioides difficile Ribotype 078. mSystems. 2020;5
    1. Drulis-Kawa Z, Majkowska-Skrobek G, Maciejewska B. Bacteriophages and phage-derived proteins--application approaches. Curr Med Chem. 2015;22:1757–1773.
    1. Gebhart D, Lok S, Clare S, Tomas M, Stares M, Scholl D, Donskey CJ, Lawley TD, Govoni GR. A modified R-type bacteriocin specifically targeting Clostridium difficile prevents colonization of mice without affecting gut microbiota diversity. mBio. 2015;6
    1. Mayer MJ, Garefalaki V, Spoerl R, Narbad A, Meijers R. Structure-based modification of a Clostridium difficile-targeting endolysin affects activity and host range. J Bacteriol. 2011;193:5477–5486.
    1. Wang Q, Euler CW, Delaune A, Fischetti VA. Using a Novel Lysin To Help Control Clostridium difficile Infections. Antimicrob Agents Chemother. 2015;59:7447–7457.
    1. Meader E, Mayer MJ, Steverding D, Carding SR, Narbad A. Evaluation of bacteriophage therapy to control Clostridium difficile and toxin production in an in vitro human colon model system. Anaerobe. 2013;22:25–30.
    1. Loc-Carrillo C, Abedon ST. Pros and cons of phage therapy. Bacteriophage. 2011;1:111–114.
    1. Nale JY, Spencer J, Hargreaves KR, Buckley AM, Trzepiński P, Douce GR, Clokie MR. Bacteriophage Combinations Significantly Reduce Clostridium difficile Growth In Vitro and Proliferation In Vivo. Antimicrob Agents Chemother. 2016;60:968–981.
    1. Selle K, Fletcher JR, Tuson H, Schmitt DS, McMillan L, Vridhambal GS, Rivera AJ, Montgomery SA, Fortier LC, Barrangou R, Theriot CM, Ousterout DG. In Vivo Targeting of Clostridioides difficile Using Phage-Delivered CRISPR-Cas3 Antimicrobials. mBio. 2020;11
    1. Nale JY, Redgwell TA, Millard A, Clokie MRJ. Efficacy of an Optimised Bacteriophage Cocktail to Clear Clostridium difficile in a Batch Fermentation Model. Antibiotics (Basel) 2018;7
    1. Shan J, Ramachandran A, Thanki AM, Vukusic FBI, Barylski J, Clokie MRJ. Bacteriophages are more virulent to bacteria with human cells than they are in bacterial culture; insights from HT-29 cells. Sci Rep. 2018;8:5091.
    1. Caflisch KM, Suh GA, Patel R. Biological challenges of phage therapy and proposed solutions: a literature review. Expert Rev Anti Infect Ther. 2019;17:1011–1041.
    1. Hall JF, Berger D. Outcome of colectomy for Clostridium difficile colitis: a plea for early surgical management. Am J Surg. 2008;196:384–388.
    1. Neal MD, Alverdy JC, Hall DE, Simmons RL, Zuckerbraun BS. Diverting loop ileostomy and colonic lavage: an alternative to total abdominal colectomy for the treatment of severe, complicated Clostridium difficile associated disease. Ann Surg. 2011;254:423–7; discussion 427.
    1. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97:1769–1775.
    1. Popovich KJ, Calfee DP, Patel PK, Lassiter S, Rolle AJ, Hung L, Saint S, Chopra V. The Centers for Disease Control and Prevention STRIVE Initiative: Construction of a National Program to Reduce Health Care-Associated Infections at the Local Level. Ann Intern Med. 2019;171:S2–S6.
    1. Anosova NG, Brown AM, Li L, Liu N, Cole LE, Zhang J, Mehta H, Kleanthous H. Systemic antibody responses induced by a two-component Clostridium difficile toxoid vaccine protect against C. difficile-associated disease in hamsters. J Med Microbiol. 2013;62:1394–1404.
    1. Sehgal K, Khanna S. Immune response against Clostridioides difficile and translation to therapy. Therap Adv Gastroenterol. 2021;14:17562848211014817.
    1. Lyerly DM, Johnson JL, Frey SM, Wilkins TD. Vaccination against lethal Clostridium difficile enterocolitis with a nontoxic recombinant peptide of toxin A. Curr Microbiol . 1990;21:29–32.
    1. Ward SJ, Douce G, Dougan G, Wren BW. Local and systemic neutralizing antibody responses induced by intranasal immunization with the nontoxic binding domain of toxin A from Clostridium difficile. Infect Immun. 1999;67:5124–5132.
    1. Ghose C, Verhagen JM, Chen X, Yu J, Huang Y, Chenesseau O, Kelly CP, Ho DD. Toll-like receptor 5-dependent immunogenicity and protective efficacy of a recombinant fusion protein vaccine containing the nontoxic domains of Clostridium difficile toxins A and B and Salmonella enterica serovar typhimurium flagellin in a mouse model of Clostridium difficile disease. Infect Immun. 2013;81:2190–2196.
    1. Péchiné S, Janoir C, Collignon A. Variability of Clostridium difficile surface proteins and specific serum antibody response in patients with Clostridium difficile-associated disease. J Clin Microbiol. 2005;43:5018–5025.
    1. Wright A, Drudy D, Kyne L, Brown K, Fairweather NF. Immunoreactive cell wall proteins of Clostridium difficile identified by human sera. J Med Microbiol. 2008;57:750–756.
    1. Adamo R, Romano MR, Berti F, Leuzzi R, Tontini M, Danieli E, Cappelletti E, Cakici OS, Swennen E, Pinto V, Brogioni B, Proietti D, Galeotti CL, Lay L, Monteiro MA, Scarselli M, Costantino P. Phosphorylation of the synthetic hexasaccharide repeating unit is essential for the induction of antibodies to Clostridium difficile PSII cell wall polysaccharide. ACS Chem Biol. 2012;7:1420–1428.
    1. Monteiro MA, Ma Z, Bertolo L, Jiao Y, Arroyo L, Hodgins D, Mallozzi M, Vedantam G, Sagermann M, Sundsmo J, Chow H. Carbohydrate-based Clostridium difficile vaccines. Expert Rev Vaccines. 2013;12:421–431.
    1. Legenza LM, Barnett SG, Rose WE. Vaccines in development for the primary prevention of Clostridium difficile infection. J Am Pharm Assoc (2003) 2017;57:547–549.
    1. Leuzzi R, Adamo R, Scarselli M. Vaccines against Clostridium difficile. Hum Vaccin Immunother. 2014;10:1466–1477.
    1. Riley TV, Lyras D, Douce GR. Status of vaccine research and development for Clostridium difficile. Vaccine. 2019;37:7300–7306.
    1. Bézay N, Ayad A, Dubischar K, Firbas C, Hochreiter R, Kiermayr S, Kiss I, Pinl F, Jilma B, Westritschnig K. Safety, immunogenicity and dose response of VLA84, a new vaccine candidate against Clostridium difficile, in healthy volunteers. Vaccine. 2016;34:2585–2592.
    1. Tian JH, Glenn G, Flyer D, Zhou B, Liu Y, Sullivan E, Wu H, Cummings JF, Elllingsworth L, Smith G. Clostridium difficile chimeric toxin receptor binding domain vaccine induced protection against different strains in active and passive challenge models. Vaccine. 2017;35:4079–4087.
    1. Donald RGK, Flint M, Kalyan N, Johnson E, Witko SE, Kotash C, Zhao P, Megati S, Yurgelonis I, Lee PK, Matsuka YV, Severina E, Deatly A, Sidhu M, Jansen KU, Minton NP, Anderson AS. A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile. Microbiology (Reading) 2013;159:1254–1266.
    1. Vidunas E, Mathews A, Weaver M, Cai P, Koh EH, Patel-Brown S, Yuan H, Zheng ZR, Carriere M, Johnson JE, Lotvin J, Moran J. Production and Characterization of Chemically Inactivated Genetically Engineered Clostridium difficile Toxoids. J Pharm Sci. 2016;105:2032–2041.
    1. United Nations, Department of Economic and Social Affairs, Population Division. World population aging 2019: Highlight. 2019. Available from: .

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner