348
Views
10
CrossRef citations to date
0
Altmetric
Review

Recent advances in the treatment of C. difficile using biotherapeutic agents

, , &
Pages 1597-1615 | Published online: 10 Jun 2019

References

  • Vindigni SM, Broussard EK, Surawicz CM. Alteration of the intestinal microbiome: fecal microbiota transplant and probiotics for Clostridium difficile and beyond. Expert Rev Gastroenterol Hepatol. 2013;7(7):615–628. doi:10.1586/17474124.2013.83250124070153
  • Tsutsumi LS, Owusu YB, Hurdle JG, Sun D. Progress in the discovery of treatments for C. difficile infection: a clinical and medicinal chemistry review. Curr Top Med Chem. 2014;14(1):152–175.24236721
  • Kim PK, Huh HC, Cohen HW, et al. Intracolonic vancomycin for severe Clostridium difficile colitis. Surg Infect (Larchmt). 2013;14(6):532–539. doi:10.1089/sur.2012.15823560732
  • Mulcahy-O’Grady H, Workentine ML, Challenge T. Potential of metagenomics in the clinic. Front Immunol. 2016;7:29. doi:10.3389/fimmu.2016.0002926870044
  • Khan FY, Elzouki AN. Clostridium difficile infection: a review of the literature. Asian Pac J Trop Med. 2014;7s1:S6–S13. doi:10.1016/S1995-7645(14)60197-825312190
  • McCarville JL, Caminero A, Verdu EF. Novel perspectives on therapeutic modulation of the gut microbiota. Therap Adv Gastroenterol. 2016;9(4):580–593. doi:10.1177/1756283X16637819
  • Lau CS, Chamberlain RS. Probiotics are effective at preventing Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Int J Gen Med. 2016;9:27–37. doi:10.2147/IJGM.S9828026955289
  • Di Bella S, Ascenzi P, Siarakas S, Petrosillo N, Di Masi A. Clostridium difficile Toxins A and B: insights into pathogenic properties and extraintestinal effects. Toxins. 2016;8(5):134. doi:10.3390/toxins8050134
  • Sofia MA, Rubin DT. The impact of therapeutic antibodies on the management of digestive diseases: history, current practice, and future directions. Dig Dis Sci. 2017;62(4):833–842. doi:10.1007/s10620-017-4479-028197743
  • Baines SD, Wilcox MH. Antimicrobial resistance and reduced susceptibility in Clostridium difficile: potential consequences for induction, treatment, and recurrence of C. difficile infection. Antibiotics. 2015;4(3):267–298. doi:10.3390/antibiotics403026727025625
  • Ofosu A. Clostridium difficile infection: a review of current and emerging therapies. Ann Gastroenterol. 2016;29(2):147–154. doi:10.20524/aog.2016.000627065726
  • von Müller L. Aktuelles zu Clostridium-difficile-infektionen. Dtsch Med Wochenschr. 2016;141(16):1144–1147. doi:10.1055/s-0042-10744327509341
  • Lübbert C, John E, von Müller L. Clostridium Difficile infection: guideline-based diagnosis and treatment. Dtsch Arztebl Int. 2014;111(43):723–731. doi:10.3238/arztebl.2014.072325404529
  • Dial S, Kezouh A, Dascal A, Barkun A, Suissa S. Patterns of antibiotic use and risk of hospital admission because of Clostridium difficile infection. CMAJ. 2008;179(8):767–772. doi:10.1503/cmaj.07181218838451
  • 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(2):388–396. doi:10.1093/jac/dkn16318434341
  • Tenover FC, Tickler IA, Persing DH. Antimicrobial-resistant strains of Clostridium difficile from North America. Antimicrob Agents Chemother. 2012;56(6):2929–2932. doi:10.1128/AAC.00220-1222411613
  • Fuzi M. Dissimilar fitness associated with resistance to fluoroquinolones influences clonal dynamics of various multiresistant bacteria. Front Microbiol. 2016;7:1017. doi:10.3389/fmicb.2016.0101727458434
  • Abdulgader SM, Shittu AO, Nicol MP, Kaba M. Molecular epidemiology of Methicillin-resistant Staphylococcus aureus in Africa: a systematic review. Front Microbiol. 2015;6:348. doi:10.3389/fmicb.2015.0034825983721
  • Wasels F, Kuehne SA, Cartman ST, et al. Fluoroquinolone resistance does not impose a cost on the fitness of Clostridium difficile in vitro. Antimicrob Agents Chemother. 2015;59(3):1794–1796. doi:10.1128/AAC.04503-1425534738
  • Valiente E, Cairns MD, Wren BW. The Clostridium difficile PCR ribotype 027 lineage: a pathogen on the move. Clin Microbiol Infect. 2014;20(5):396–404. doi:10.1111/1469-0691.1261924621128
  • Lee JH, Lee Y, Lee K, Riley TV, Kim H. The changes of PCR ribotype and antimicrobial resistance of Clostridium difficile in a tertiary care hospital over 10 years. J Med Microbiol. 2014;63(Pt 6):819–823. doi:10.1099/jmm.0.072082-024696516
  • Kouzegaran S, Ganjifard M, Tanha AS. Detection, ribotyping and antimicrobial resistance properties of Clostridium difficile strains isolated from the Cases of Diarrhea. Mater Sociomed. 2016;28(5):324–328. doi:10.5455/msm.2016.28.324-32827999477
  • Gupta A, Khanna S. Community-acquired Clostridium difficile infection: an increasing public health threat. Infect Drug Resist. 2014;7:63–72. doi:10.2147/IDR.S4678024669194
  • Lambert PJ, Dyck M, Thompson LH, Hammond GW. Population-based surveillance of Clostridium difficile infection in Manitoba, Canada, by using interim surveillance definitions. Infect Control Hosp Epidemiol. 2009;30(10):945–951. doi:10.1086/60571919732008
  • Bloomfield LE, Riley TV. Epidemiology and risk factors for community-associated Clostridium difficile infection: a narrative review. Infect Dis Ther. 2016;5(3):231–251. doi:10.1007/s40121-016-0117-y27370914
  • Martinez FJ, Leffler DA, Kelly CP. Clostridium difficile outbreaks: prevention and treatment strategies. Risk Manag Healthc Policy. 2012;5:55–64. doi:10.2147/RMHP.S1305322826646
  • Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372(9):825–834. doi:10.1056/NEJMoa140891325714160
  • Ozaki E, Kato H, Kita H, et al. Clostridium difficile colonization in healthy adults: transient colonization and correlation with enterococcal colonization. J Med Microbiol. 2004;53(Pt 2):167–172. doi:10.1099/jmm.0.05376-014729940
  • Spigaglia P. Recent advances in the understanding of antibiotic resistance in Clostridium difficile infection. Ther Adv Infect Dis. 2016;3(1):23–42. doi:10.1177/204993611562289126862400
  • Chaparro-Rojas F, Mullane KM. Emerging therapies for Clostridium difficile infection - focus on fidaxomicin. Infect Drug Resist. 2013;6:41–53. doi:10.2147/IDR.S2443423843696
  • Chandrasekaran R, Lacy DB. The role of toxins in Clostridium difficile infection. FEMS Microbiol Rev. 2017;41(6):723–750. doi:10.1093/femsre/fux04829048477
  • Aktories K, Papatheodorou P, Schwan C. Binary Clostridium difficile toxin (CDT) - A virulence factor disturbing the cytoskeleton. Anaerobe. 2018. doi:10.1016/j.anaerobe.2018.03.001
  • Samarkos M, Mastrogianni E, Kampouropoulou O. The role of gut microbiota in Clostridium difficile infection. Eur J Intern Med. 2018;50:28–32. doi:10.1016/j.ejim.2018.02.00629428498
  • Crook DW, Walker AS, Kean Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis. 2012;55 Suppl 2:S93–S103. doi:10.1093/cid/cis49922752871
  • Wolfe C, Pagano P, Pillar CM, Shinabarger DL, Boulos RA. Comparison of the in vitro antibacterial activity of Ramizol, fidaxomicin, vancomycin, and metronidazole against 100 clinical isolates of Clostridium difficile by broth microdilution. Diagn Microbiol Infect Dis. 2018;92(3):250–252. doi:10.1016/j.diagmicrobio.2018.06.00230042035
  • Cornely OA, Watt M, McCrea C, Goldenberg SD, De Nigris E. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients aged >/=60 years (EXTEND): analysis of cost-effectiveness. J Antimicrob Chemother. 2018;73(9):2529–2539. doi:10.1093/jac/dky18429800295
  • Baro E, Galperine T, Denies F, et al. Cost-effectiveness analysis of five competing strategies for the management of multiple recurrent community-onset Clostridium difficile infection in France. PLoS One. 2017;12(1):e0170258. doi:10.1371/journal.pone.017025828103289
  • Jiang M, N-H L, Ip M, You JHS. Cost-effectiveness analysis of ribotype-guided fecal microbiota transplantation in Chinese patients with severe Clostridium difficile infection. PLoS One. 2018;13(7):e0201539. doi:10.1371/journal.pone.020153930048534
  • Le P, Nghiem VT, Mullen PD, Deshpande A. Cost-effectiveness of competing treatment strategies for Clostridium difficile infection: a systematic review. Infect Control Hosp Epidemiol. 2018;39(4):412–424. doi:10.1017/ice.2017.30329463339
  • Sunenshine RH, McDonald LC. Clostridium difficile-associated disease: new challenges from an established pathogen. Cleve Clin J Med. 2006;73(2):187–197.16478043
  • Dostal A, Lacroix C, Bircher L, et al. Iron modulates butyrate production by a child gut microbiota In Vitro. mBio. 2015;6:6. doi:10.1128/mBio.01453-15
  • Chilton CH, Crowther GS, Spiewak K, et al. Potential of lactoferrin to prevent antibiotic-induced Clostridium difficile infection. J Antimicrob Chemother. 2016;71(4):975–985. doi:10.1093/jac/dkv45226759363
  • Zanella Terrier MC, Simonet ML, Bichard P, Frossard JL. Recurrent Clostridium difficile infections: the importance of the intestinal microbiota. World J Gastroenterol. 2014;20(23):7416–7423. doi:10.3748/wjg.v20.i23.741624966611
  • Perez-Cobas AE, Moya A, Gosalbes MJ, Latorre A. Colonization resistance of the gut microbiota against Clostridium difficile. Antibiotics (Basel). 2015;4(3):337–357. doi:10.3390/antibiotics403033727025628
  • Wehrhahn MC, Keighley C, Kurtovic J, et al. A series of three cases of severe Clostridium difficile infection in Australia associated with a binary toxin producing clade 2 ribotype 251 strain. Anaerobe. 2018;55:117–123. doi:10.1016/j.anaerobe.2018.11.009.
  • King AM, Mackin KE, Lyras D. Emergence of toxin A-negative, toxin B-positive Clostridium difficile strains: epidemiological and clinical considerations. Future Microbiol. 2015;10(1):1–4. doi:10.2217/fmb.14.11525598331
  • Chaves-Olarte E, Freer E, Parra A, Guzman-Verri C, Moreno E, Thelestam M. R-Ras glucosylation and transient RhoA activation determine the cytopathic effect produced by toxin B variants from toxin A-negative strains of Clostridium difficile. J Biol Chem. 2003;278(10):7956–7963. doi:10.1074/jbc.M20924420012496290
  • Stewart DB, Berg A, Hegarty J. Predicting recurrence of C. difficile colitis using bacterial virulence factors: binary toxin is the key. J Gastrointest Surg. 2013;17(1):118–124;discussion p.124–115. doi:10.1007/s11605-012-2056-6
  • Hutton ML, Mackin KE, Chakravorty A, Lyras D. Small animal models for the study of Clostridium difficile disease pathogenesis. FEMS Microbiol Lett. 2014;352(2):140–149. doi:10.1111/1574-6968.1236724372713
  • Cowardin CA, Buonomo EL, Saleh MM, et al. The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. Nat Microbiol. 2016;1(8):16108. doi:10.1038/nmicrobiol.2016.10827573114
  • Darkoh C, DuPont HL, Norris SJ, Kaplan HB. Toxin synthesis by Clostridium difficile is regulated through quorum signaling. MBio. 2015;6(2):e02569. doi:10.1128/mBio.02569-1425714717
  • Lyon SA, Hutton ML, Rood JI, Cheung JK, Lyras D. CdtR regulates TcdA and TcdB production in Clostridium difficile. PLoS Pathog. 2016;12(7):e1005758. doi:10.1371/journal.ppat.100575827414650
  • Culligan EP, Hill C, Sleator RD. Probiotics and gastrointestinal disease: successes, problems and future prospects. Gut Pathog. 2009;1(1):19. doi:10.1186/1757-4749-1-1919930635
  • Wong A, Ngu DYS, Dan LA, Ooi A, Lim RLH. Detection of antibiotic resistance in probiotics of dietary supplements. Nutr J. 2015;14(1):95. doi:10.1186/s12937-015-0084-226370532
  • Zheng M, Zhang R, Tian X, Zhou X, Pan X, Wong A. Assessing the risk of probiotic dietary supplements in the context of antibiotic resistance. Front Microbiol. 2017;8:908–908. doi:10.3389/fmicb.2017.0090828579981
  • Maziade PJ, Pereira P, Goldstein EJ. A decade of experience in primary prevention of Clostridium difficile infection at a community hospital using the probiotic combination Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2 (Bio-K+). Clin Infect Dis. 2015;60 Suppl 2:S144–147. doi:10.1093/cid/civ17825922400
  • More MI, Vandenplas Y. Saccharomyces boulardii CNCM I-745 improves intestinal enzyme function: a trophic effects review. Clin Med Insights Gastroenterol. 2018;11:1179552217752679. doi:10.1177/117955221775267929449779
  • Surawicz CM, McFarland LV, Greenberg RN, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis. 2000;31(4):1012–1017. doi:10.1086/31813011049785
  • Pozzoni P, Riva A, Bellatorre AG, et al. Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in adult hospitalized patients: a single-center, randomized, double-blind, placebo-controlled trial. Am J Gastroenterol. 2012;107(6):922–931. doi:10.1038/ajg.2012.5622472744
  • Wullt M, Hagslatt ML, Odenholt I. Lactobacillus plantarum 299v for the treatment of recurrent Clostridium difficile-associated diarrhoea: a double-blind, placebo-controlled trial. Scand J Infect Dis. 2003;35(6–7):365–367. doi:10.1080/0036554031001098512953945
  • Gueimonde M, Sanchez B, GdLR-G C, Margolles A. Antibiotic resistance in probiotic bacteria. Front Microbiol. 2013;4:202. doi:10.3389/fmicb.2013.0007723882264
  • Cameron D, Hock QS, Kadim M, et al. Probiotics for gastrointestinal disorders: proposed recommendations for children of the Asia-Pacific region. World J Gastroenterol. 2017;23(45):7952–7964. doi:10.3748/wjg.v23.i45.795229259371
  • Julliard W, De Wolfe TJ, Fechner JH, Safdar N, Agni R, Mezrich JD. Amelioration of Clostridium difficile infection in mice by dietary supplementation with indole-3-carbinol. Ann Surg. 2017;265(6):1183–1191. doi:10.1097/SLA.000000000000183027280500
  • Hryckowian AJ, Pruss KM, Sonnenburg JL. The emerging metabolic view of Clostridium difficile pathogenesis. Curr Opin Microbiol. 2017;35:42–47. doi:10.1016/j.mib.2016.11.00627997854
  • Dolan KT, Chang EB. Diet, gut microbes, and the pathogenesis of inflammatory bowel diseases. Mol Nutr Food Res. 2017;61(1). doi:10.1002/mnfr.201600129
  • Kelly CP, Kyne L. The host immune response to Clostridium difficile. J Med Microbiol. 2011;60(Pt 8):1070–1079. doi:10.1099/jmm.0.030015-021415200
  • Solomon K. The host immune response to Clostridium difficile infection. Ther Adv Infect Dis. 2013;1(1):19–35. doi:10.1177/204993611247217325165542
  • Mathur H, Rea MC, Cotter PD, Ross RP, Hill C. The potential for emerging therapeutic options for Clostridium difficile infection. Gut Microbes. 2014;5(6):696–710. doi:10.4161/19490976.2014.98376825564777
  • Simon M, Chervin S, Brown S, et al. Polyclonal Antibody Therapies for Clostridium difficile Infection. Antibodies. 2014;3:272–288. doi:10.3390/antib3040272
  • Hurez V, Kazatchkine MD, Vassilev T, et al. Pooled normal human polyspecific IgM contains neutralizing anti-idiotypes to IgG autoantibodies of autoimmune patients and protects from experimental autoimmune disease. Blood. 1997;90(10):4004–4013.9354669
  • Humphreys DP, Wilcox MH. Antibodies for treatment of Clostridium difficile infection. Clin Vaccine Immunol. 2014;21(7):913–923. doi:10.1128/CVI.00116-1424789799
  • Torres JF, Lyerly DM, Hill JE, Monath TP. Evaluation of formalin-inactivated Clostridium difficile vaccines administered by parenteral and mucosal routes of immunization in hamsters. Infect Immun. 1995;63(12):4619–4627.7591115
  • Greenberg RN, Marbury TC, Foglia G, Warny M. Phase I dose finding studies of an adjuvanted Clostridium difficile toxoid vaccine. Vaccine. 2012;30(13):2245–2249. doi:10.1016/j.vaccine.2012.01.06522306375
  • Feher C, Mensa J. A comparison of current guidelines of five international societies on Clostridium difficile infection management. Infect Dis Ther. 2016;5(3):207–230. doi:10.1007/s40121-016-0122-127470257
  • Feher C, Soriano A, Mensa J. A review of experimental and off-label therapies for Clostridium difficile infection. Infect Dis Ther. 2017;6(1):1–35. doi:10.1007/s40121-016-0140-z27910000
  • Broecker F, Hanske J, Martin CE, et al. Multivalent display of minimal Clostridium difficile glycan epitopes mimics antigenic properties of larger glycans. Nat Commun. 2016;7:11224. doi:10.1038/ncomms1122427091615
  • Kirk JA, Banerji O, Fagan RP. Characteristics of the Clostridium difficile cell envelope and its importance in therapeutics. Microb Biotechnol. 2017;10(1):76–90. doi:10.1111/1751-7915.1237227311697
  • Hussack G, Tanha J. An update on antibody-based immunotherapies for Clostridium difficile infection. Clin Exp Gastroenterol. 2016;9:209–224. doi:10.2147/CEG.S8401727536153
  • Sun X, Hirota SA. The roles of host and pathogen factors and the innate immune response in the pathogenesis of Clostridium difficile infection. Mol Immunol. 2015;63(2):193–202. doi:10.1016/j.molimm.2014.09.00525242213
  • Karczewski J, Zorman J, Wang S, et al. Development of a recombinant toxin fragment vaccine for Clostridium difficile infection. Vaccine. 2014;32(24):2812–2818. doi:10.1016/j.vaccine.2014.02.02624662701
  • Spencer J, Leuzzi R, Buckley A, et al. Vaccination against Clostridium difficile using toxin fragments: observations and analysis in animal models. Gut Microbes. 2014;5(2):225–232. doi:10.4161/gmic.2771224637800
  • Leuzzi R, Spencer J, Buckley A, et al. Protective efficacy induced by recombinant Clostridium difficile toxin fragments. Infect Immun. 2013;81(8):2851–2860. doi:10.1128/IAI.01341-1223716610
  • Wang H, Sun X, Zhang Y, et al. A chimeric toxin vaccine protects against primary and recurrent Clostridium difficile infection. Infect Immun. 2012;80(8):2678–2688. doi:10.1128/IAI.00215-1222615245
  • Wang YK, Yan YX, Kim HB, et al. A chimeric protein comprising the glucosyltransferase and cysteine proteinase domains of toxin B and the receptor binding domain of toxin A induces protective immunity against Clostridium difficile infection in mice and hamsters. Hum Vaccin Immunother. 2015;11(9):2215–2222. doi:10.1080/21645515.2015.105235226036797
  • Secore S, Wang S, Doughtry J, et al. Development of a novel vaccine containing binary toxin for the prevention of Clostridium difficile disease with enhanced efficacy against NAP1 strains. PLoS One. 2017;12(1):e0170640. doi:10.1371/journal.pone.017064028125650
  • Leuzzi R, Adamo R, Scarselli M. Vaccines against Clostridium difficile. Hum Vaccin Immunother. 2014;10(6):1466–1477. doi:10.4161/hv.2842824637887
  • Yang Z, Ramsey J, Hamza T, et al. Mechanisms of protection against Clostridium difficile infection by the monoclonal antitoxin antibodies actoxumab and bezlotoxumab. Infect Immun. 2015;83(2):822–831. doi:10.1128/IAI.02897-1425486992
  • Anosova NG, Cole LE, Li L, et al. A combination of three fully human toxin A- and toxin B-specific monoclonal antibodies protects against challenge with highly virulent epidemic strains of Clostridium difficile in the hamster model. Clin Vaccine Immunol. 2015;22(7):711–725. doi:10.1128/CVI.00763-1425924765
  • Morrison C. Antibacterial antibodies gain traction. Nat Rev Drug Discov. 2015;14(11):737–738. doi:10.1038/nrd477026514853
  • Qiu H, Cassan R, Johnstone D, et al. Novel Clostridium difficile anti-toxin (TcdA and TcdB) humanized monoclonal antibodies demonstrate In Vitro neutralization across a broad spectrum of clinical strains and In Vivo potency in a hamster spore challenge model. PLoS One. 2016;11(6):e0157970. doi:10.1371/journal.pone.015797027336843
  • Davies NL, Compson JE, Mackenzie B, et al. A mixture of functionally oligoclonal humanized monoclonal antibodies that neutralize Clostridium difficile TcdA and TcdB with high levels of in vitro potency shows in vivo protection in a hamster infection model. Clin Vaccine Immunol. 2013;20(3):377–390. doi:10.1128/CVI.00625-1223324518
  • Marozsan AJ, Ma D, Nagashima KA, et al. Protection against Clostridium difficile infection with broadly neutralizing antitoxin monoclonal antibodies. J Infect Dis. 2012;206(5):706–713. doi:10.1093/infdis/jis41622732923
  • Hernandez LD, Kroh HK, Hsieh E, et al. Epitopes and mechanism of action of the Clostridium difficile toxin A-neutralizing antibody actoxumab. J Mol Biol. 2017;429(7):1030–1044. doi:10.1016/j.jmb.2017.02.01028232034
  • Milani C, Ticinesi A, Gerritsen J, et al. Gut microbiota composition and Clostridium difficile infection in hospitalized elderly individuals: a metagenomic study. Sci Rep. 2016;6:25945. doi:10.1038/srep2594527166072
  • Martinez I, Lattimer JM, Hubach KL, et al. Gut microbiome composition is linked to whole grain-induced immunological improvements. ISME J. 2013;7(2):269–280. doi:10.1038/ismej.2012.10423038174
  • Dzunkova M, D’Auria G, Xu H, et al. The monoclonal antitoxin antibodies (Actoxumab-Bezlotoxumab) treatment facilitates normalization of the gut microbiota of mice with Clostridium difficile infection. Front Cell Infect Microbiol. 2016;6:119. doi:10.3389/fcimb.2016.0011927757389
  • Ritter AS, Petri WA Jr. New developments in chemotherapeutic options for Clostridium difficile colitis. Curr Opin Infect Dis. 2013;26(5):461–470. doi:10.1097/QCO.0b013e328363456e23982237
  • Hussack G, Arbabi-Ghahroudi M, Mackenzie CR, Tanha J. Isolation and characterization of Clostridium difficile toxin-specific single-domain antibodies. Methods Mol Biol. 2012;911:211–239.22886255
  • Hussack G, Arbabi-Ghahroudi M, van Faassen H, et al. Neutralization of Clostridium difficile toxin A with single-domain antibodies targeting the cell receptor binding domain. J Biol Chem. 2011;286(11):8961–8976. doi:10.1074/jbc.M110.19875421216961
  • Andersen KK, Strokappe NM, Hultberg A, et al. Neutralization of Clostridium difficile toxin B mediated by engineered Lactobacilli that produce single-domain antibodies. Infect Immun. 2016;84(2):395–406. doi:10.1128/IAI.00870-1526573738
  • Shkoporov AN, Khokhlova EV, Savochkin KA, Kafarskaia LI, Efimov BA. Production of biologically active scFv and VHH antibody fragments in Bifidobacterium longum. FEMS Microbiol Lett. 2015;362(12):fnv083. doi:10.1093/femsle/fnv08325994292
  • Unger M, Eichhoff AM, Schumacher L, et al. Selection of nanobodies that block the enzymatic and cytotoxic activities of the binary Clostridium difficile toxin CDT. Sci Rep. 2015;5:7850. doi:10.1038/srep0785025597743
  • Hong HA, Hitri K, Hosseini S, et al. Mucosal antibodies to the C terminus of toxin A prevent colonization of Clostridium difficile. Infect Immun. 2017;85(4):e01060-16. doi:10.1128/IAI.01060-16.
  • Sulea T, Hussack G, Ryan S, Tanha J, Purisima EO. Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody. Sci Rep. 2018;8(1):2260. doi:10.1038/s41598-018-20599-429396522
  • Lyerly DM, Phelps CJ, Toth J, Wilkins TD. Characterization of toxins A and B of Clostridium difficile with monoclonal antibodies. Infect Immun. 1986;54(1):70–76.2428753
  • Roberts A, McGlashan J, Al-Abdulla I, et al. Development and evaluation of an ovine antibody-based platform for treatment of Clostridium difficile infection. Infect Immun. 2012;80(2):875–882. doi:10.1128/IAI.05684-1122144483
  • van Dissel JT, de Groot N, Hensgens CM, et al. Bovine antibody-enriched whey to aid in the prevention of a relapse of Clostridium difficile-associated diarrhoea: preclinical and preliminary clinical data. J Med Microbiol. 2005;54(Pt 2):197–205. doi:10.1099/jmm.0.45773-015673517
  • Numan SC, Veldkamp P, Kuijper EJ, van Den Berg RJ, van Dissel JT. Clostridium difficile-associated diarrhoea: bovine anti-Clostridium difficile whey protein to help aid the prevention of relapses. Gut. 2007;56(6):888–889. doi:10.1136/gut.2006.11901617519495
  • Mattila E, Anttila VJ, Broas M, et al. A randomized, double-blind study comparing Clostridium difficile immune whey and metronidazole for recurrent Clostridium difficile-associated diarrhoea: efficacy and safety data of a prematurely interrupted trial. Scand J Infect Dis. 2008;40(9):702–708. doi:10.1080/0036554080196496019086244
  • Hutton ML, Cunningham BA, Mackin KE, et al. Bovine antibodies targeting primary and recurrent Clostridium difficile disease are a potent antibiotic alternative. Sci Rep. 2017;7(1):3665. doi:10.1038/s41598-017-03982-528623367
  • O’Brien JB, McCabe MS, Athie-Morales V, McDonald GS, Ni Eidhin DB, Kelleher DP. Passive immunisation of hamsters against Clostridium difficile infection using antibodies to surface layer proteins. FEMS Microbiol Lett. 2005;246(2):199–205. doi:10.1016/j.femsle.2005.04.00515899406
  • Ghose C, Eugenis I, Sun X, et al. Immunogenicity and protective efficacy of recombinant Clostridium difficile flagellar protein FliC. Emerg Microbes Infect. 2016;5:e8. doi:10.1038/emi.2016.826839147
  • Bojanova DP, Bordenstein SR. Fecal transplants: what is being transferred? PLoS Biol. 2016;14(7):e1002503. doi:10.1371/journal.pbio.100250327404502
  • Clatworthy AE, Pierson E, Hung DT. Targeting virulence: a new paradigm for antimicrobial therapy. Nat Chem Biol. 2007;3(9):541–548. doi:10.1038/nchembio.2007.2417710100
  • Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108(4):478–498; quiz 499. doi:10.1038/ajg.2013.4
  • van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407–415. doi:10.1056/NEJMoa120503723323867
  • Pecere S, Sabatelli M, Fantoni M, Ianiro G, Gasbarrini A, Cammarota G. Letter: faecal microbiota transplantation in combination with fidaxomicin to treat severe complicated recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015;42(8):1030. doi:10.1111/apt.1336226374258
  • Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis. 2011;53(10):994–1002. doi:10.1093/cid/cir63222002980
  • Bang BW, Park JS, Kim HK, et al. Fecal microbiota transplantation for refractory and recurrent Clostridium difficile infection: a case series of nine patients. Korean J Gastroenterol. 2017;69(4):226–231. doi:10.4166/kjg.2017.69.4.22628449424
  • Kelly CR, Khoruts A, Staley C, et al. Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: a randomized trial. Ann Intern Med. 2016;165(9):609–616. doi:10.7326/M16-027127547925
  • Carlucci C, Petrof EO, Allen-Vercoe E. Fecal microbiota-based therapeutics for recurrent Clostridium difficile infection, ulcerative colitis and obesity. EBioMedicine. 2016;13:37–45. doi:10.1016/j.ebiom.2016.09.02927720396
  • Anand R, Song Y, Garg S, et al. Effect of aging on the composition of fecal microbiota in donors for FMT and its impact on clinical outcomes. Dig Dis Sci. 2017;62(4):1002–1008. doi:10.1007/s10620-017-4449-628181098
  • Lagier JC, Delord M, Million M, et al. Dramatic reduction in Clostridium difficile ribotype 027-associated mortality with early fecal transplantation by the nasogastric route: a preliminary report. Eur J Clin Microbiol Infect Dis. 2015;34(8):1597–1601. doi:10.1007/s10096-015-2394-x25947205
  • Tanaka T, Kato H, Fujimoto T. Successful fecal microbiota transplantation as an initial therapy for Clostridium difficile infection on an outpatient basis. Intern Med. 2016;55(8):999–1000. doi:10.2169/internalmedicine.55.570127086820
  • Kang DW, Adams JB, Gregory AC, et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017;5(1):10. doi:10.1186/s40168-016-0225-728122648
  • Giau VV, Wu SY, Jamerlan A, An SSA, Kim SY, Hulme J. Gut microbiota and their neuroinflammatory implications in Alzheimer’s disease. Nutrients. 2018;10(11):1765. doi:10.3390/nu10111765.
  • Baumler AJ, Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature. 2016;535(7610):85–93. doi:10.1038/nature1884927383983
  • Staley C, Kelly CR, Brandt LJ, Khoruts A, Sadowsky MJ. Complete microbiota engraftment is not essential for recovery from recurrent Clostridium difficile infection following fecal microbiota transplantation. mBio. 2016;7(6). doi:10.1128/mBio.01965-16
  • Julliard W, Fechner JH, Owens L, et al. Modeling the effect of the aryl hydrocarbon receptor on transplant immunity. Transplant Direct. 2017;3(5):e157. doi:10.1097/TXD.000000000000066628573192
  • Suez J, Zmora N, Zilberman-Schapira G, et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell. 2018;174(6):1406–1423.e1416. doi:10.1016/j.cell.2018.08.04730193113
  • Lamendella R, Wright JR, Hackman J, et al. Antibiotic treatments for Clostridium difficile infection are associated with distinct bacterial and fungal community structures. mSphere. 2018;3(1). doi:10.1128/mSphere.00572-17
  • Khoruts A, Rank KM, Newman KM, et al. Inflammatory bowel disease affects the outcome of fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol. 2016;14(10):1433–1438. doi:10.1016/j.cgh.2016.02.01826905904
  • Lamas B, Richard ML, Leducq V, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016;22(6):598–605. doi:10.1038/nm.410227158904
  • Anderson JL, Edney RJ, Whelan K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther. 2012;36(6):503–516. doi:10.1111/j.1365-2036.2012.05220.x22827693
  • Moayyedi P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. 2015;149(1):102–109.e106. doi:10.1053/j.gastro.2015.04.00125857665
  • Abedon ST. Phage therapy: eco-physiological pharmacology. Scientifica. 2014;2014:581639. doi:10.1155/2014/72617925031881
  • Sybesma W, Zbinden R, Chanishvili N, et al. Bacteriophages as potential treatment for urinary tract infections. Front Microbiol. 2016;7:465. doi:10.3389/fmicb.2016.0046527148173
  • Khawaldeh A, Morales S, Dillon B, et al. Bacteriophage therapy for refractory Pseudomonas aeruginosa urinary tract infection. J Med Microbiol. 2011;60(Pt 11):1697–1700. doi:10.1099/jmm.0.029744-021737541
  • Melo LDR, Veiga P, Cerca N, et al. Development of a phage cocktail to control proteus mirabilis catheter-associated urinary tract infections. Front Microbiol. 2016;7:1024. doi:10.3389/fmicb.2016.0102427446059
  • Merabishvili M, Vervaet C, Pirnay JP, et al. Stability of Staphylococcus aureus phage ISP after freeze-drying (lyophilization). PLoS One. 2013;8(7):e68797. doi:10.1371/journal.pone.006879723844241
  • Hargreaves KR, Clokie MR. Clostridium difficile phages: still difficult? Front Microbiol. 2014;5:184. doi:10.3389/fmicb.2014.0054724808893
  • Sullivan MJ, Petty NK, Beatson SA. Easyfig: a genome comparison visualizer. Bioinformatics. 2011;27(7):1009–1010. doi:10.1093/bioinformatics/btr03921278367
  • Rashid S, Barylski J, Hargreaves K, Millard A, Vinner G, Clokie M. Two novel myoviruses from the north of Iraq reveal insights into Clostridium difficile phage diversity and biology. Viruses. 2016;8(11):310. doi:10.3390/v8110310
  • Meessen-Pinard M, Sekulovic O, Fortier LC. Evidence of in vivo prophage induction during Clostridium difficile infection. Appl Environ Microbiol. 2012;78(21):7662–7670. doi:10.1128/AEM.02275-1222923402
  • Nale JY, Spencer J, Hargreaves KR, et al. Bacteriophage combinations significantly reduce Clostridium difficile growth in vitro and proliferation in vivo. Antimicrob Agents Chemother. 2016;60(2):968–981. doi:10.1128/AAC.01774-1526643348
  • Goh S, Ong PF, Song KP, Riley TV, Chang BJ. The complete genome sequence of Clostridium difficile phage phiC2 and comparisons to phiCD119 and inducible prophages of CD630. Microbiology. 2007;153(Pt 3):676–685. doi:10.1099/mic.0.2006/002436-017322187
  • Sebaihia M, Wren BW, Mullany P, et al. The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome. Nat Genet. 2006;38(7):779–786. doi:10.1038/ng183016804543
  • Zhang Q, Widmer G, Tzipori S. A pig model of the human gastrointestinal tract. Gut Microbes. 2013;4(3):193–200. doi:10.4161/gmic.2386723549377
  • Zackular JP, Moore JL, Jordan AT, et al. Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection. Nat Med. 2016;22(11):1330–1334. doi:10.1038/nm.417427668938
  • Seekatz AM, Young VB. Clostridium difficile and the microbiota. J Clin Invest. 2014;124(10):4182–4189. doi:10.1172/JCI7233625036699
  • Merril CR, Scholl D, Adhya SL. The prospect for bacteriophage therapy in Western medicine. Nat Rev Drug Discov. 2003;2(6):489–497. doi:10.1038/nrd111112776223
  • Meader E, Mayer MJ, Gasson MJ, Steverding D, Carding SR, Narbad A. Bacteriophage treatment significantly reduces viable Clostridium difficile and prevents toxin production in an in vitro model system. Anaerobe. 2010;16(6):549–554. doi:10.1016/j.anaerobe.2010.08.00620816997
  • 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. doi:10.1016/j.anaerobe.2013.05.00123685029
  • Govind R, Fralick JA, Rolfe RD. In vivo lysogenization of a Clostridium difficile bacteriophage ΦCD119. Anaerobe. 2011;17(3):125–129. doi:10.1016/j.anaerobe.2011.05.01221664468
  • Sekulovic O, Garneau JR, Neron A, Fortier LC. Characterization of temperate phages infecting Clostridium difficile isolates of human and animal origins. Appl Environ Microbiol. 2014;80(8):2555–2563. doi:10.1128/AEM.00237-1424532062
  • Goh S, Hussain H, Chang BJ, Emmett W, Riley TV, Mullany P. Phage ϕC2 mediates transduction of Tn6215, encoding erythromycin resistance, between Clostridium difficile strains. mBio. 2013;4(6). doi:10.1128/mBio.00840-13
  • Nale JY, Chutia M, Carr P, Hickenbotham PT, Clokie MR. ‘Get in Early’; Biofilm and Wax Moth (Galleria mellonella) models reveal new insights into the therapeutic potential of Clostridium difficile bacteriophages. Front Microbiol. 2016;7:1383. doi:10.3389/fmicb.2016.0138327630633
  • Sekulovic O, Meessen-Pinard M, Fortier LC. Prophage-stimulated toxin production in Clostridium difficile NAP1/027 lysogens. J Bacteriol. 2011;193(11):2726–2734. doi:10.1128/JB.00787-1021441508
  • Nagy E, Foldes J. Inactivation of metronidazole by Enterococcus faecalis. J Antimicrob Chemother. 1991;27(1):63–70. doi:10.1093/jac/27.1.63
  • Anonye BO. Commentary: bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome. Front Cell Infect Microbiol. 2018;8:104. doi:10.3389/fcimb.2018.0002629670863
  • Fortier LC. Bacteriophages contribute to shaping clostridioides (Clostridium) difficile species. Front Microbiol. 2018;9:2033. doi:10.3389/fmicb.2018.0203330233520
  • Abaev I, Foster-Frey J, Korobova O, et al. Staphylococcal phage 2638A endolysin is lytic for Staphylococcus aureus and harbors an inter-lytic-domain secondary translational start site. Appl Microbiol Biotechnol. 2013;97(8):3449–3456. doi:10.1007/s00253-012-4252-422777279
  • Gaeng S, Scherer S, Neve H, Loessner MJ. Gene cloning and expression and secretion of Listeria monocytogenes bacteriophage-lytic enzymes in Lactococcus lactis. Appl Environ Microbiol. 2000;66(7):2951–2958. doi:10.1128/aem.66.7.2951-2958.200010877791
  • Schuch R, Nelson D, Fischetti VA. A bacteriolytic agent that detects and kills Bacillus anthracis. Nature. 2002;418(6900):884–889.12192412
  • Bai J, Kim YT, Ryu S, Lee JH. Biocontrol and rapid detection of food-borne pathogens using bacteriophages and endolysins. Front Microbiol. 2016;7:474. doi:10.3389/fmicb.2016.0047427092128
  • Eyre DW, Walker AS, Griffiths D, et al. Clostridium difficile mixed infection and reinfection. J Clin Microbiol. 2012;50(1):142–144. doi:10.1128/JCM.05177-1122075589
  • He M, Miyajima F, Roberts P, et al. Emergence and global spread of epidemic healthcare-associated Clostridium difficile. Nat Genet. 2013;45(1):109–113. doi:10.1038/ng.247823222960
  • Ajuebor J, McAuliffe O, O’Mahony J, Ross RP, Hill C, Coffey A. Bacteriophage endolysins and their applications. Sci Prog. 2016;99(2):183–199. doi:10.3184/003685016X1462791363770528742472
  • Thanissery R, Zeng D, Doyle RG, Theriot CM. A small molecule-screening pipeline to evaluate the therapeutic potential of 2-aminoimidazole molecules against Clostridium difficile. Front Microbiol. 2018;9:1206. doi:10.3389/fmicb.2018.0120629928268
  • Letourneau JJ, Stroke IL, Hilbert DW, et al. Synthesis and SAR studies of novel benzodiazepinedione-based inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB). Bioorg Med Chem Lett. 2018;28(23-24):3601–3605. doi: 10.1016/j.bmcl.2018.10.047.
  • Letourneau JJ, Stroke IL, Hilbert DW, et al. Identification and initial optimization of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB). Bioorg Med Chem Lett. 2018;28(4):756–761. doi:10.1016/j.bmcl.2018.01.00529331267
  • Mayer MJ, Narbad A, Gasson MJ. Molecular characterization of a Clostridium difficile bacteriophage and its cloned biologically active endolysin. J Bacteriol. 2008;190(20):6734–6740. doi:10.1128/JB.00686-0818708505
  • Beilhartz GL, Tam J, Zhang Z, Melnyk RA. Comment on “A small-molecule antivirulence agent for treating Clostridium difficile infection”. Sci Transl Med. 2016;8(370):370tc372. doi:10.1126/scitranslmed.aaf0746
  • Xie Y, Tan Y, Zheng Y, Du X, Liu Q. Ebselen ameliorates beta-amyloid pathology, tau pathology, and cognitive impairment in triple-transgenic Alzheimer’s disease mice. J Biol Inorg Chem. 2017;22(6):851–865. doi:10.1007/s00775-017-1463-228502066
  • Ivarsson ME, Durantie E, Huberli C, et al. Small-molecule allosteric triggers of Clostridium difficile toxin B auto-proteolysis as a therapeutic strategy. Cell Chem Biol. 2018;26(1):17–26.e13.
  • Egan K, Field D, Ross RP, Cotter PD, Hill C. In silico prediction and exploration of potential bacteriocin gene clusters within the bacterial genus geobacillus. Front Microbiol. 2018;9:2116. doi:10.3389/fmicb.2018.0211630298056
  • Le Lay C, Dridi L, Bergeron MG, Ouellette M, Fliss IL. Nisin is an effective inhibitor of Clostridium difficile vegetative cells and spore germination. J Med Microbiol. 2016;65(2):169–175. doi:10.1099/jmm.0.00020226555543
  • Khosa S, Lagedroste M, Smits SH. Protein defense systems against the lantibiotic nisin: function of the immunity protein nisi and the resistance protein NSR. Front Microbiol. 2016;7:504. doi:10.3389/fmicb.2016.0050427148193
  • Chai C, Lee KS, Imm GS, Kim YS, Oh SW. Inactivation of Clostridium difficile spore outgrowth by synergistic effects of nisin and lysozyme. Can J Microbiol. 2017;63(7):638–643. doi:10.1139/cjm-2016-055028346844
  • Rea MC, O’Sullivan O, Shanahan F, et al. Clostridium difficile carriage in elderly subjects and associated changes in the intestinal microbiota. J Clin Microbiol. 2012;50(3):867–875. doi:10.1128/JCM.05176-1122162545
  • Mathur H, Field D, Rea MC, Cotter PD, Hill C, Ross RP. Bacteriocin-antimicrobial synergy: a medical and food perspective. Front Microbiol. 2017;8:1205. doi:10.3389/fmicb.2017.0120528706513
  • Hanchi H, Hammami R, Gingras H, et al. Inhibition of MRSA and of Clostridium difficile by durancin 61A: synergy with bacteriocins and antibiotics. Future Microbiol. 2017;12:205–212. doi:10.2217/fmb-2016-011328262046
  • Rea MC, Sit CS, Clayton E, et al. Thuricin CD, a posttranslationally modified bacteriocin with a narrow spectrum of activity against Clostridium difficile. Proc Natl Acad Sci. 2010;107(20):9352–9357. doi:10.1073/pnas.091355410720435915
  • Li C, Teng P, Peng Z, Sang P, Sun X, Cai J. Bis-cyclic guanidines as a novel class of compounds potent against Clostridium difficile. ChemMedChem. 2018;13(14):1414–1420. doi:10.1002/cmdc.20180024029768720
  • Petrosillo N, Granata G, Cataldo MA. Novel antimicrobials for the treatment of Clostridium difficile infection. Front Med. 2018;5:96. doi:10.3389/fmed.2018.00096
  • Tyrrell KL, Citron DM, Merriam CV, Leoncio E, Goldstein EJC. In vitro activity of DS-2969b and comparator antimicrobial agents against Clostridioides (Clostridium) difficile, methicillin-resistant Staphylococcus aureus, and other anaerobic bacteria. Anaerobe. 2018;54:39–41. doi:10.1016/j.anaerobe.2018.04.01030096588
  • Van Giau V, An SSA, Hulme J. Recent advances in the treatment of pathogenic infections using antibiotics and nano-drug delivery vehicles. Drug Des Devel Ther. 2019;13:327–343. doi:10.2147/DDDT.S190577
  • Millan B, Park H, Hotte N, et al. Fecal microbial transplants reduce antibiotic-resistant genes in patients with recurrent Clostridium difficile infection. Clin Infect Dis. 2016;62(12):1479–1486. doi:10.1093/cid/ciw18527025836