A Review of Experimental and Off-Label Therapies for Clostridium difficile Infection

Infectious Diseases and Therapy

Volumn 6, Issue 1, 2017, Pages

  Fehér, Csaba ^a   Soriano, Alex ^a,b,c   Mensa, Josep ^a,b  

^a HOSPITAL CLÍNIC   (Spain)

^b INSTITUT D INVESTIGACIONS BIOMÈDIQUES AUGUST PI I SUNYER IDIBAPS   (Spain)

^c UNIVERSITY OF BARCELONA   (Spain)

Author keywords

Clinical development pipeline; Clostridium difficile infection (CDI); Controversial therapies; Experimental therapies

Indexed keywords

GLYCOPEPTIDE; RIFAMYCIN; TETRACYCLINE;

ACTIVE IMMUNOTHERAPY; BACTERICIDAL ACTIVITY; CLOSTRIDIUM DIFFICILE INFECTION; DISEASE SURVEILLANCE; HUMAN; IMMUNE RESPONSE; IMMUNOGENICITY; MORTALITY; NONHUMAN; PASSIVE IMMUNIZATION; PRIORITY JOURNAL; PROTEIN SYNTHESIS; REVIEW; SURVIVAL RATE;

EID: 85014653259     PISSN: 21938229     EISSN: 21936382     Source Type: Journal    
DOI: 10.1007/s40121-016-0140-z     Document Type: Review

References (248)

1. Debast SB, Bauer MP, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014;20(Suppl 2):1–26. doi:10.1111/1469-0691.12418.
2. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431–55. doi:10.1086/651706.
3. Cornely OA, Nathwani D, Ivanescu C, Odufowora-Sita O, Retsa P, Odeyemi IAO. Clinical efficacy of fidaxomicin compared with vancomycin and metronidazole in Clostridium difficile infections: a meta-analysis and indirect treatment comparison. J Antimicrob Chemother. 2014;69:2892–900. doi:10.1093/jac/dku261.
4. Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet. 2012;12:281–9. doi:10.1016/S0140-6736(11)61514-6.WEB-ONLY.
5. Louie TJ, Miller MA, Mullane K, Weiss K, Lentnek A, Golan Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364:422–31.
6. Ponziani FR, Scaldaferri F, Petito V, Paroni Sterbini F, Pecere S, Lopetuso LR, et al. The Role of antibiotics in gut microbiota modulation: the eubiotic effects of rifaximin. Dig Dis. 2016;34:269–78. doi:10.1159/000443361.
7. Neff GW, Jones M, Jonas M, Ravinuthala R, Novick D, Kaiser TE, et al. Lack of Clostridium difficile infection in patients treated with rifaximin for hepatic encephalopathy: a retrospective analysis. J Clin Gastroenterol. 2013;47:188–92. doi:10.1097/MCG.0b013e318276be13.
8. Zullo A, Ridola L, Hassan C. Rifaximin therapy and Clostridium difficile infection. A note of caution. J Clin Gastroenterol. 2013;47:737–8.
9. Kokkotou E, Moss AC, Michos A, Espinoza D, Cloud JW, Mustafa N, et al. Comparative efficacies of rifaximin and vancomycin for treatment of Clostridium difficile-associated diarrhea and prevention of disease recurrence in hamsters. Antimicrob Agents Chemother. 2008;52:1121–6. doi:10.1128/AAC.01143-07.
10. Basu PP, Dinani A, Rayapudi K, Pacana T, Shah NJ, Hampole H, et al. Rifaximin therapy for metronidazole-unresponsive Clostridium difficile infection: a prospective pilot trial. Therap Adv Gastroenterol. 2010;3:221–5. doi:10.1177/1756283X10372985.
11. Garey KW, Jiang Z-D, Bellard A, Dupont HL. Rifaximin in treatment of recurrent Clostridium difficile-associated diarrhea: an uncontrolled pilot study. J Clin Gastroenterol. 2009;43:91–3. doi:10.1097/MCG.0b013e31814a4e97.
12. Tannous G, Neff G, Kemmer N. Therapeutic success of rifaximin for Clostridium difficile infection refractory to metronidazole and vancomycin. Case Rep Gastroenterol. 2010;4:404–9. doi:10.1159/000320685.
13. Rubin DT, Sohi S, Glathar M, Thomas T, Yadron N, Surma BL. Rifaximin is effective for the treatment of Clostridium difficile—associated diarrhea: results of an open-label pilot study. Gastroenterol Res Pract. 2011;2011:106978. doi:10.1155/2011/106978.
14. Pardi DS, Brennan R, Spinnell M, Gareca MG, Greenberg E, Tian W, et al. The efficacy and safety of rifaximin vs. vancomycin in the treatment of mild to moderate C. difficile infection: a randomized double-blind active comparator trial. Gastroenterology 2012;142:S-599. doi:10.1016/S0016-5085(12)62296-3.
15. Marchese A, Salerno A, Pesce A, Debbia E a, Schito GC. In vitro activity of rifaximin, metronidazole and vancomycin against Clostridium difficile and the rate of selection of spontaneously resistant mutants against representative anaerobic and aerobic bacteria, including ammonia-producing species. Chemotherapy. 2000;46:253–66. doi:10.1159/000007297.
16. Jiang Z-D, DuPont HL, La Rocco M, Garey KW. In vitro susceptibility of Clostridium difficile to rifaximin and rifampin in 359 consecutive isolates at a university hospital in Houston. Texas. J Clin Pathol. 2010;63:355–8. doi:10.1136/jcp.2009.071688.
17. Liao CH, Ko WC, Lu JJ, Hsueh PR. Characterizations of clinical isolates of Clostridium difficile by toxin genotypes and by susceptibility to 12 antimicrobial agents, including fidaxomicin (OPT-80) and rifaximin: a multicenter study in Taiwan. Antimicrob Agents Chemother. 2012;56:3943–9. doi:10.1128/AAC.00191-12.
18. Carman RJ, Boone JH, Grover H, Wickham KN, Chen L. In vivo selection of rifamycin-resistant Clostridium difficile during rifaximin therapy. Antimicrob Agents Chemother. 2012;56:6019–20. doi:10.1128/AAC.00974-12.
19. Johnson S, Schriever C, Galang M, Kelly CP, Gerding DN. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis. 2007;44:846–8. doi:10.1086/511870.
20. Trubiano JA, Cheng AC, Korman TM, Roder C, Campbell A, May MLA, et al. Australasian Society of Infectious Diseases updated guidelines for the management of Clostridium difficile infection in adults and children in Australia and New Zealand. Intern Med J. 2016;46:479–93. doi:10.1111/imj.13027.
21. Johnson S, Schriever C, Patel U, Patel T, Hecht DW, Gerding DN. Rifaximin Redux: treatment of recurrent Clostridium difficile infections with Rifaximin immediately post-vancomycin treatment. Anaerobe. 2009;15:290–1. doi:10.1016/j.anaerobe.2009.08.004.
22. Garey KW, Ghantoji SS, Shah DN, Habib M, Arora V, Jiang ZD, et al. A randomized, double-blind, placebo-controlled pilot study to assess the ability of rifaximin to prevent recurrent diarrhoea in patients with Clostridium difficile infection. J Antimicrob Chemother. 2011;66:2850–5. doi:10.1093/jac/dkr377.
23. Rifaximin for Preventing Relapse of Clostridium Associated Diarrhoea (RAPID) ClinicalTrials.gov Identifier: NCT01670149. https://clinicaltrials.gov/ct2/show/NCT01670149?term=rifaximin+clostridium&rank=1. Accessed 22 Sep 2016.
24. Anton PM, O’Brien M, Kokkotou E, Eisenstein B, Michaelis A, Rothstein D, et al. Rifalazil treats and prevents relapse of Clostridium difficile-associated diarrhea in hamsters. Antimicrob Agents Chemother. 2004;48:3975–9. doi:10.1128/AAC.48.10.3975-3979.2004.
25. Miesel L, Hecht DW, Osmolski JR, Gerding D, Flattery A, Li F, et al. Kibdelomycin is a potent and selective agent against toxigenic Clostridium difficile. Antimicrob Agents Chemother. 2014;58:2387–92. doi:10.1128/AAC.00021-14.
26. Firmin D. Bringing true novelty to the anti-infective space. SMi’s 17th Annu Conf Superbugs Superdrugs, London: 2015.
27. Ravic M, Firmin D, Sahgal O, van der Berg F, Suckling C, Hunter I. A single-centre, double-blind, placebo-controlled study in healthy men to assess the safety and tolerability of single and repeated ascending doses of MGB-BP-3, a new class of antibacterial agent. Boston: ASM Microbe Meet; 2016.
28. Programmes Overview. http://www.mgb-biopharma.com/programs-overview-2/. Accessed 12 Oct 2016.
29. ClinicalTrials.org. https://clinicaltrials.gov/ct2/results?term=ops-2071+phase+1&Search=Search. Accessed 4 Oct 2016.
30. Otsuka Group–Pipeline Information 2016. https://www.otsuka.com/en/rd/pharmaceuticals/pipeline/pdf.php?financial=442. Accessed 9 Sep 2016.
31. Nathwani D. Tigecycline: clinical evidence and formulary positioning. Int J Antimicrob Agents. 2005;25:185–92. doi:10.1016/j.ijantimicag.2004.11.006.
32. Aldape MJ, Heeney DD, Bryant AE, Stevens DL. Tigecycline suppresses toxin A and B production and sporulation in Clostridium difficile. J Antimicrob Chemother. 2015;70:153–9. doi:10.1093/jac/dku325.
33. Garneau JR, Valiquette L, Fortier L-C. Prevention of Clostridium difficile spore formation by sub-inhibitory concentrations of tigecycline and piperacillin/tazobactam. BMC Infect Dis. 2014;14:29. doi:10.1186/1471-2334-14-29.
34. Bassis CM, Theriot CM, Young VB. Alteration of the Murine gastrointestinal microbiota by tigecycline leads to increased susceptibility to Clostridium difficile infection. Antimicrob Agents Chemother. 2014;58:2767–74. doi:10.1128/AAC.02262-13.
35. Kim HB, Zhang Q, Sun X, Beamer G, Wang Y, Tzipori S. Beneficial effect of oral tigecycline treatment on Clostridium difficile infection in gnotobiotic piglets. Antimicrob Agents Chemother. 2014;58:7560–4. doi:10.1128/AAC.03447-14.
36. Kundrapu S, Hurless K, Sunkesula VCK, Tomas M, Donskey CJ. Tigecycline exhibits inhibitory activity against Clostridium difficile in the intestinal tract of hospitalised patients. Int J Antimicrob Agents. 2015;45:424–6. doi:10.1016/j.ijantimicag.2014.11.016.
37. Fantin F, Manica A, Soldani F, Bissoli L, Zivelonghi A, Zamboni M. Use of tigecycline in elderly patients for Clostridium difficile infection. Geriatr Gerontol Int. 2015;15:230–1. doi:10.1111/ggi.12336.
38. Herpers BL, Vlaminckx B, Burkhardt O, Blom H, Biemond-Moeniralam HS, Hornef M, et al. Intravenous tigecycline as adjunctive or alternative therapy for severe refractory Clostridium difficile infection. Clin Infect Dis. 2009;48:1732–5. doi:10.1086/599224.
39. Larson KC, Belliveau PP, Spooner LM. Tigecycline for the treatment of severe Clostridium difficile infection. Ann Pharmacother. 2011;45:1005–10. doi:10.1345/aph.1Q080.
40. Navalkele BD, Lerner SA. Intravenous tigecycline facilitates cure of severe Clostridium difficile infection (CDI) after failure of standard therapy: a case report and literature review of tigecycline use in CDI. Open Forum Infect Dis 2016;3:ofw094. doi:10.1093/ofid/ofw094.
41. Tanaka SK, Steenbergen J, Villano S. Discovery, pharmacology, and clinical profile of omadacycline, a novel aminomethylcycline antibiotic. Bioorg Med Chem. 2016. doi:10.1016/j.bmc.2016.07.029.
42. Kim O, Leahy RG, Traczewsky M, Macone A, Steenbergen J, Tanaka SK. Activity and efficacy of Omadacycline against Clostridium difficile. Amsterdam: Eur Congr Clin Microbiol Infect Dis; 2016.
43. Nakamura S, Nakashio S, Mikawa M, Yamakawa K, Okumura S, Nishida S. Antimicrobial susceptibility of Clostridium difficile from different sources. Microbiol Immunol. 1982;26:25–30.
44. Wenisch C, Parschalk B, Hasenhündl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis. 1996;22:813–8. doi:10.1093/clinids/22.5.813.
45. Wullt M, Odenholt I. A double-blind randomized controlled trial of fusidic acid and metronidazole for treatment of an initial episode of Clostridium difficile-associated diarrhoea. J Antimicrob Chemother. 2004;54:211–6. doi:10.1093/jac/dkh278.
46. Norén T, Wullt M, Åkerlund T, Bäck E, Odenholt I, Burman LG. Frequent emergence of resistance in Clostridium difficile during treatment of C. difficile-associated diarrhea with fusidic acid. Antimicrob Agents Chemother. 2006;50:3028–32. doi:10.1128/AAC.00019-06.
47. Citron DM, Tyrrell KL, Merriam CV, Goldstein EJC. Comparative in vitro activities of LFF571 against Clostridium difficile and 630 other intestinal strains of aerobic and anaerobic bacteria. Antimicrob Agents Chemother. 2012;56:2493–503. doi:10.1128/AAC.06305-11.
48. Sachdeva M, Leeds JA. Subinhibitory concentrations of LFF571 reduce toxin production by clostridium difficile. Antimicrob Agents Chemother. 2015;59:1252–7. doi:10.1128/AAC.04436-14.
49. Leeds JA, Sachdeva M, Mullin S, Barnes SW, Ruzin A. In vitro selection, via serial passage, of Clostridium difficile mutants with reduced susceptibility to fidaxomicin or vancomycin. J Antimicrob Chemother. 2014;69:41–4. doi:10.1093/jac/dkt302.
50. Trzasko A, Leeds JA, Praestgaard J, LaMarche MJ, McKenney D. Efficacy of LFF571 in a hamster model of Clostridium difficile infection. Antimicrob Agents Chemother. 2012;56:4459–62. doi:10.1128/AAC.06355-11.
51. Mullane K, Lee C, Bressler A, Buitrago M, Weiss K, Dabovic K, et al. Multicenter, randomized clinical trial to compare the safety and efficacy of LFF571 and vancomycin for Clostridium difficile infections. Antimicrob Agents Chemother. 2015;59:1435–40. doi:10.1128/AAC.04251-14.
52. Citron DM, Warren YA, Tyrrell KL, Merriam V, Goldstein EJC. Comparative in vitro activity of REP3123 against Clostridium difficile and other anaerobic intestinal bacteria. J Antimicrob Chemother. 2009;63:972–6. doi:10.1093/jac/dkp037.
53. Critchley IA, Green LS, Young CL, Bullard JM, Evans RJ, Price M, et al. Spectrum of activity and mode of action of REP3123, a new antibiotic to treat Clostridium difficile infections. J Antimicrob Chemother. 2009;63:954–63. doi:10.1093/jac/dkp041.
54. Ochsner UA, Bell SJ, O’Leary AL, Hoang T, Stone KC, Young CL, et al. Inhibitory effect of REP3123 on toxin and spore formation in Clostridium difficile, and in vivo efficacy in a hamster gastrointestinal infection model. J Antimicrob Chemother. 2009;63:964–71. doi:10.1093/jac/dkp042.
55. Clinical stage program targeting Clostridium difficile Infection, a devastating GI-tract infection with suboptimal therapies http://www.crestonepharma.com/index.php/cdi. Accessed 23 Sep 2016.
56. Mathur T, Kumar M, Barman TK, Kumar GR, Kalia V, Singhal S, et al. Activity of RBx 11760, a novel biaryl oxazolidinone, against Clostridium difficile. J Antimicrob Chemother. 2011;66:1087–95. doi:10.1093/jac/dkr033.
57. Kumar M, Mathur T, Barman TK, Ramkumar G, Bhati A, Shukla G, et al. In Vitro and In Vivo activities of the novel ketolide RBx 14255 against Clostridium difficile. Antimicrob Agents Chemother. 2012;56:5986–9. doi:10.1128/AAC.00015-12.
58. Sully EK, Geller BL. Antisense antimicrobial therapeutics. Curr Opin Microbiol. 2016;33:47–55. doi:10.1016/j.mib.2016.05.017.
59. Hegarty JP, Krzeminski J, Sharma AK, Guzman-villanueva D, Weissig V, Sr. DBS. Bolaamphiphile-based nanocomplex delivery of phosphorothioate gapmer antisense oligonucleotides as a treatment for Clostridium difficile. Int J Nanomedicine. 2016;11:3607–19.
60. Dubreuil L, Houcke I, Mouton Y, Rossignol JF. In vitro evaluation of activities of nitazoxanide and tizoxanide against anaerobes and aerobic organisms. Antimicrob Agents Chemother. 1996;40:2266–70.
61. Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014;110:94–103. doi:10.1016/j.antiviral.2014.07.014.
62. Freeman J, Baines SD, Todhunter SL, Huscroft GS, Wilcox MH. Nitazoxanide is active against Clostridium difficile strains with reduced susceptibility to metronidazole. J Antimicrob Chemother. 2011;66:1407–8. doi:10.1093/jac/dkr077.
63. McVay CS, Rolfe RD. In vitro and in vivo activities of nitazoxanide against Clostridium difficile. Antimicrob Agents Chemother. 2000;44:2254–8. doi:10.1128/AAC.44.9.2254-2258.2000.
64. Musher DM, Logan N, Hamill RJ, Dupont HL, Lentnek A, Gupta A, et al. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis. 2006;43:421–7. doi:10.1086/506351.
65. 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:e41–6. doi:10.1086/596552.
66. Pipeline and Publications. http://www.romark.com/research/products-in-development. Accessed 14 Nov 2016.
67. Warren CA, Van Opstal E, Ballard TE, Kennedy A, Wang X, Riggins M, et al. Amixicile, a novel inhibitor of pyruvate: ferredoxin oxidoreductase, shows efficacy against Clostridium difficile in a mouse infection model. Antimicrob Agents Chemother. 2012;56:4103–11. doi:10.1128/AAC.00360-12.
68. Hoffman PS, Bruce AM, Olekhnovich I, Warren CA, Burgess SL, Hontecillas R, et al. Preclinical studies of amixicile, a systemic therapeutic developed for treatment of Clostridium difficile infections that also shows efficacy against Helicobacter pylori. Antimicrob Agents Chemother. 2014;58:4703–12. doi:10.1128/AAC.03112-14.
69. Popovic N, Korac M, Nesic Z, Milosevic B, Urosevic A, Jevtovic D, et al. Oral teicoplanin for successful treatment of severe refractory Clostridium difficile infection. J Infect Dev Ctries. 2015;9:1062–7. doi:10.3855/jidc.6335.
70. Pantosti A, Luzzi IDA, Cardines R, Gianfrilli P. Comparison of the In vitro activities of teicoplanin and vancomycin against Clostridium difficile and their interactions with cholestyramine. Antimicrob Agents Chemother. 1985;28:847–8.
71. Wongwanich S, Kusum M, Phan-Urai R. Antibacterial activity of teicoplanin against Clostridium difficile. Southeast Asian J Trop Med Public Health. 1996;27:606–9.
72. de Lalla F, Privitera G, Rinaldi E, Ortisi G, Santoro D, Rizzardini G. Treatment of Clostridium difficile-associated disease with teicoplanin. Antimicrob Agents Chemother. 1989;33:1125–7.
73. de Lalla F, Nicolin R, Rinaldi E, Scarpellini P, Rigoli R, Manfrin V, et al. Prospective study of oral teicoplanin versus oral vancomycin for therapy of pseudomembranous colitis and Clostridium difficile-associated diarrhea. Antimicrob Agents Chemother. 1992;36:2192–6. doi:10.1128/AAC.36.10.2192.
74. Nelson R, Kelsey P, Leeman H, Meardon N, Patel H, Paul K, et al. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults (Review). Cochrane Database Syst Rev 2011;7:CD004610.
75. Biavasco F, Manso E, Varaldo PE. In vitro activities of ramoplanin and four glycopeptide antibiotics against clinical isolates of Clostridium difficile. Antimicrob Agents Chemother. 1991;35:195–7. doi:10.1128/AAC.35.1.195.
76. Peláez T, Alcallá L, Alonso R, Martín-López A, García-Arias V, Marín M, et al. In vitro activity of ramoplanin against Clostridium difficile, including strains with reduced susceptibility to vancomycin or with resistance to metronidazole. Antimicrob Agents Chemother. 2005;49:1157–9. doi:10.1128/AAC.49.3.1157-1159.2005.
77. Freeman J, Baines SD, Jabes D, Wilcox MH. Comparison of the efficacy of ramoplanin and vancomycin in both in vitro and in vivo models of clindamycin-induced Clostridium difficile infection. J Antimicrob Chemother. 2005;56:717–25. doi:10.1093/jac/dki321.
78. Kraus CN, Lyerly MW, Carman RJ. Ambush of Clostridium difficile spores by Ramoplanin: activity in an in vitro model. Antimicrob Agents Chemother. 2015;59:2525–30. doi:10.1128/AAC.04853-14.
79. Pullman J, Prieto J, Leach T. Ramoplanin vs vancomycin in the treatment of Clostridium difficile diarrhea: A phase II study. 44th Intersci Conf Antimicrob Agents Chemother, Washington, D.C.: 2014.
80. NTI-851 (Ramoplanin™) http://www.nanotherapeutics.com/ramoplanin/. Accessed 27 Sep 2016.
81. O’Connor R, Baines SD, Freeman J, Wilcox MH. In vitro susceptibility of genotypically distinct and clonal Clostridium difficile strains to oritavancin. J Antimicrob Chemother. 2008;62:762–5. doi:10.1093/jac/dkn276.
82. Baines SD, O’Connor R, Saxton K, Freeman J, Wilcox MH. Comparison of oritavancin versus vancomycin as treatments for clindamycin-induced Clostridium difficile PCR ribotype 027 infection in a human gut model. J Antimicrob Chemother. 2008;62:1078–85. doi:10.1093/jac/dkn358.
83. Chilton CH, Freeman J, Crowther GS, Todhunter SL, Wilcox MH. Effectiveness of a short (4 day) course of oritavancin in the treatment of simulated Clostridium difficile infection using a human gut model. J Antimicrob Chemother. 2012;67:2434–7. doi:10.1093/jac/dks243.
84. Freeman J, Marquis M, Crowther GS, Todhunter SL, Fawley WN, Chilton CH, et al. Oritavancin does not induce Clostridium difficile germination and toxin production in hamsters or a human gut model. J Antimicrob Chemother. 2012;67:2919–26. doi:10.1093/jac/dks309.
85. Chilton CH, Freeman J, Baines SD, Crowther GS, Nicholson S, Wilcox MH. Evaluation of the effect of oritavancin on Clostridium difficile spore germination, outgrowth and recovery. J Antimicrob Chemother. 2013;68:2078–82. doi:10.1093/jac/dkt160.
86. Yan H, Qi D, Cheng X, Song Z, Li W, He B. Antibiotic activities and affinities for bacterial cell wall analogue of N-demethylvancomycin and its derivatives. J Antibiot (Tokyo). 1998;51:750–6.
87. Zhang SJ, Yang Q, Xu L, Chang J, Sun X. Synthesis and antibacterial activity against Clostridium difficile of novel demethylvancomycin derivatives. Bioorganic Med Chem Lett. 2012;22:4942–5. doi:10.1016/j.bmcl.2012.06.039.
88. Mathur H, O’Connor PM, Hill C, Cotter PD, Ross RP. Analysis of anti-Clostridium difficile activity of thuricin CD, vancomycin, metronidazole, ramoplanin, and actagardine, both singly and in paired combinations. Antimicrob Agents Chemother. 2013;57:2882–6. doi:10.1128/AAC.00261-13.
89. Boakes S, Ayala T, Herman M, Appleyard AN, Dawson MJ, Cortés J. Generation of an actagardine A variant library through saturation mutagenesis. Appl Microbiol Biotechnol. 2012;95:1509–17. doi:10.1007/s00253-012-4041-0.
90. Crowther GS, Baines SD, Todhunter SL, Freeman J, Chilton CH, Wilcox MH. Evaluation of NVB302 versus vancomycin activity in an in vitro human gut model of Clostridium difficile infection. J Antimicrob Chemother. 2013;68:168–76. doi:10.1093/jac/dks359.
91. Assessment of the safety and distribution of NVB302 in healthy volunteers. http://www.isrctn.com/ISRCTN40071144. Accessed 27 Sep 2016.
92. Moore JH, van Opstal E, Kolling GL, Shin JH, Bogatcheva E, Nikonenko B, et al. Treatment of Clostridium difficile infection using SQ641, a capuramycin analogue, increases post-treatment survival and improves clinical measures of disease in a murine model. J Antimicrob Chemother. 2016;71:1300–6. doi:10.1007/s13398-014-0173-7.2.
93. Alam MZ, Wu X, Mascio C, Chesnel L, Hurdle JG. Mode of action and bactericidal properties of surotomycin against growing and nongrowing clostridium difficile. Antimicrob Agents Chemother. 2015;59:5165–70. doi:10.1128/AAC.01087-15.
94. Snydman DR, Jacobus NV, McDermott LA. Activity of a novel cyclic lipopeptide, CB-183,315, against resistant Clostridium difficile and other gram-positive aerobic and anaerobic intestinal pathogens. Antimicrob Agents Chemother. 2012;56:3448–52. doi:10.1128/AAC.06257-11.
95. Citron DM, Tyrrell KL, Merriam CV, Goldstein EJC. In vitro activities of CB-183,315, vancomycin, and metronidazole against 556 strains of Clostridium difficile, 445 other intestinal anaerobes, and 56 Enterobacteriaceae species. Antimicrob Agents Chemother. 2012;56:1613–5. doi:10.1128/AAC.05655-11.
96. Citron DM, Tyrrell KL, Dale SE, Chesnel L, Goldstein EJC. Impact of Surotomycin on the Gut Microbiota of healthy volunteers in a phase 1 Clinical Trial. Antimicrob Agents Chemother 2016;2382:AAC.02531-15. doi:10.1128/AAC.02531-15.
97. Deshpande A, Hurless K, Cadnum JL, Chesnel L, Gao L, Chan L, et al. Effect of surotomycin, a novel cyclic lipopepide antibiotic, on intestinal colonization with vancomycin-resistant enterococci and Klebsiella pneumoniae in mice. Antimicrob Agents Chemother. 2016;60:3333–9. doi:10.1128/AAC.02904-15.
98. Mascio CTM, Chesnel L, Thorne G, Silverman JA. Surotomycin demonstrates low in vitro frequency of resistance and rapid bactericidal activity in Clostridium difficile, Enterococcus faecalis, and Enterococcus faecium. Antimicrob Agents Chemother. 2014;58:3976–82. doi:10.1128/AAC.00124-14.
99. Adams HM, Li X, Mascio C, Chesnel L, Palmer KL. Mutations associated with reduced surotomycin susceptibility in Clostridium difficile and Enterococcus species. Antimicrob Agents Chemother. 2015;59:4139–47. doi:10.1128/AAC.00526-15.
100. Lee CH, Patino H, Stevens C, Rege S, Chesnel L, Louie T, et al. Surotomycin versus vancomycin for Clostridium difficile infection: Phase 2, randomized, controlled, double-blind, non-inferiority, multicentre trial. J Antimicrob Chemother. 2016;71:2964–71. doi:10.1093/jac/dkw246.
101. Study of CB-183,315 in Patients With Clostridium difficile Associated Diarrhea. https://clinicaltrials.gov/ct2/results?term=surotomycin+phase+3&Search=Search. Accessed 27 Sep 2016.
102. Boix V, Pesant Y, Fedorak R, Mullane K, Stoutenburgh U, Jin M, et al. Primary clinical outcomes from a Phase 3, randomized, double-blind, active-controlled study of surotomycin in patients with Clostridium difficile associated diarrhea. Amsterdam: Eur Congr Clin Microbiol Infect Dis; 2016.
103. Merck Pipeline. http://www.merck.com/research/pipeline/home.html. Accessed 13 Oct 2016.
104. Rea MC, Sit CS, Clayton E, O’Connor PM, Whittal RM, Zheng J, et al. Thuricin CD, a posttranslationally modified bacteriocin with a narrow spectrum of activity against Clostridium difficile. Proc Natl Acad Sci USA. 2010;107:9352–7. doi:10.1073/pnas.0913554107.
105. Rea MC, Dobson A, O’Sullivan O, Crispie F, Fouhy F, Cotter PD, et al. Effect of broad- and narrow-spectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon. Proc Natl Acad Sci USA. 2011;108:4639–44. doi:10.1073/pnas.1001224107.
106. Mathur H, Rea MC, Cotter PD, Hill C, Ross RP. The efficacy of thuricin CD, tigecycline, vancomycin, teicoplanin, rifampicin and nitazoxanide, independently and in paired combinations against Clostridium difficile biofilms and planktonic cells. Gut Pathog. 2016;8:20. doi:10.1186/s13099-016-0102-8.
107. Sangster W, Hegarty JP, Stewart DB. Phage tail-like particles kill Clostridium difficile and represent an alternative to conventional antibiotics. Surg (United States). 2015;157:96–103. doi:10.1016/j.surg.2014.06.015.
108. Gebhart D, Lok S, Clare S, Tomas M, Stares M, Scholl D, et al. A modified R-type bacteriocin specifically targeting Clostridium difficile prevents colonization of mice without affecting gut microbiota diversity. MBio. 2015;6:1–13. doi:10.1128/mBio.02368-14.Editor.
109. AvidBiotics, Bacterial Diseases. http://avidbiotics.com/technology/avidocin-proteins/bacterial-diseases/. Accessed 29 Sep 2016.
110. Wang Q, Euler CW, Delaune A, Fischetti VA. Using a novel lysin to help control Clostridium difficile infections. Antimicrob Agents Chemother 2015;59:AAC.01357-15. doi:10.1128/AAC.01357-15.
111. Locher HH, Caspers P, Bruyère T, Schroeder S, Pfaff P, Knezevic A, et al. Investigations of the Mode of Action and Resistance Development of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections. Antimicrob Agents Chemother. 2014;58:901–8. doi:10.1128/AAC.01831-13.
112. Gerding DN, Hecht DW, Louie T, Nord CE, Talbot GH, Cornely OA, et al. Susceptibility of Clostridium difficile isolates from a Phase 2 clinical trial of cadazolid and vancomycin in C. difficile infection. J Antimicrob Chemother 2015:dkv300. doi:10.1093/jac/dkv300.
113. Chilton CH, Crowther GS, Baines SD, Todhunter SL, Freeman J, Locher HH, et al. 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. doi:10.1093/jac/dkt411.
114. Seiler P, Enderlin-Paput M, Pfaff P, Weiss M, Ritz D, Clozel M, et al. Cadazolid does not promote intestinal colonization of vancomycin-resistant enterococci in mice. Antimicrob Agents Chemother. 2016;60:628–31. doi:10.1128/AAC.01923-15.
115. Louie T, Nord CE, Talbot GH, Wilcox M, Gerding DN, Buitrago M, et al. A Multicenter, Double-blind, randomized, phase 2 study evaluating the novel antibiotic, cadazolid, in patients with Clostridium difficile infection. Antimicrob Agents Chemother 2015;59:AAC.00504-15. doi:10.1128/AAC.00504-15.
116. ClinicalTrial.gov. https://clinicaltrials.gov/ct2/results?term=cadazolid&recr=Open. Accessed 2 Oct 2016.
117. Rashid MU, Dalhoff A, Weintraub A, Nord CE. Invitro activity of MCB3681 against Clostridium difficile strains. Anaerobe. 2014;28:216–9. doi:10.1016/j.anaerobe.2014.07.001.
118. Dalhoff A, Rashid M-U, Kapsner T, Panagiotidis G, Weintraub A, Nord CE. Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle. Clin Microbiol Infect 2015;21:767.e1-767.e4. doi:10.1016/j.cmi.2015.05.025.
119. Morphochem. http://www.morphochem.de/. Accessed 29 Sep 2016.
120. Butler MM, LaMarr WA, Foster KA, Barnes MH, Skow DJ, Lyden PT, et al. Antibacterial activity and mechanism of action of a novel anilinouracil-fluoroquinolone hybrid compound. Antimicrob Agents Chemother. 2007;51:119–27. doi:10.1128/AAC.01311-05.
121. Butler MM, Shinabarger DL, Citron DM, Kelly CP, Dvoskin S, Wright GE, et al. MBX-500, a hybrid antibiotic with in vitro and in vivo efficacy against toxigenic Clostridium difficile. Antimicrob Agents Chemother. 2012;56:4786–92. doi:10.1128/AAC.00508-12.
122. Steele J, Zhang Q, Beamer G, Butler M, Bowlin T, Tzipori S. MBX-500 Is effective for treatment of Clostridium difficile infection in gnotobiotic piglets. Antimicrob Agents Chemother. 2013;57:4039–41. doi:10.1128/AAC.00304-13.
123. Iscla I, Wray R, Blount P, Larkins-ford J, Conery AL, Ausubel FM, et al. A new antibiotic with potent activity targets MscL. J Antibiot (Tokyo). 2015;68:1–10. doi:10.1038/ja.2015.4.
124. James E, Viola H, Hool L, Eggers PK, Raston CL, Boulos RA. A novel antimicrobial agent reduces oxidative stress in cells. RSC Adv. 2013;3:7277. doi:10.1039/c3ra40658j.
125. Rao S, Prestidge CA, Miesel L, Sweeney D, Shinabarger DL, Boulos RA. Preclinical development of Ramizol, an antibiotic belonging to a new class, for the treatment of Clostridium difficile colitis. J Antibiot (Tokyo). 2016;. doi:10.1038/ja.2016.45.
126. ®: A new treatment for Clostridium difficile associated disease. http://bouloscooper.com/wp-content/uploads/2014/10/Ramizol-A-new-treatment-for-Clostridium-difficile-asociated-disease.pdf. Accessed 29 Sep 2016.
127. Salzman NH. Microbiota-immune system interaction: an uneasy alliance. Curr Opin Microbiol. 2011;14:99–105. doi:10.1016/j.mib.2010.09.018.Microbiota-Immune.
128. Giesemann T, Guttenberg G, Aktories K. Human alpha-defensins inhibit Clostridium difficile toxin B. Gastroenterology. 2008;134:2049–58. doi:10.1053/j.gastro.2008.03.008.
129. Furci L, Baldan R, Bianchini V, Trovato A, Ossi C, Cichero P, et al. New role for human alpha-defensin 5 in the fight against hypervirulent Clostridium difficile strains. Infect Immun. 2015;83:986–95. doi:10.1128/IAI.02955-14.
130. Shilling M, Matt L, Rubin E, Visitacion MP, Haller NA, Grey SF, et al. Antimicrobial effects of virgin coconut oil and its medium-chain fatty acids on Clostridium difficile. J Med Food. 2013;16:1079–85. doi:10.1089/jmf.2012.0303.
131. Kabara JJ, Swieczkowski DM, Conley AJ, Truant JP. Fatty acids and derivatives as antimicrobial agents. Antimicrob Agents Chemother. 1972;2:23–8. doi:10.1128/AAC.2.1.23.
132. Weiss W, Pulse M, Vickers R. In vivo assessment of SMT19969 in a hamster model of Clostridium difficile infection. Antimicrob Agents Chemother. 2014;58:5714–8. doi:10.1128/AAC.02903-14.
133. Freeman J, Vernon J, Vickers R, Wilcox MH. Susceptibility of Clostridium difficile isolates of varying antimicrobial resistance phenotypes to SMT19969 and 11 comparators. Antimicrob Agents Chemother. 2015;60:689–92. doi:10.1128/AAC.02000-15.
134. Baines SD, Crowther GS, Freeman J, Todhunter S, Vickers R, Wilcox MH. SMT19969 as a treatment for Clostridium difficile infection: an assessment of antimicrobial activity using conventional susceptibility testing and an in vitro gut model. J Antimicrob Chemother. 2015;70:182–9. doi:10.1093/jac/dku324.
135. Bassères E, Endres BT, Khaleduzzaman M, Miraftabi F, Alam MJ, Vickers RJ, et al. Impact on toxin production and cell morphology in Clostridium difficile by ridinilazole (SMT19969), a novel treatment for C. difficile infection. J Antimicrob Chemother. 2016;71:1245–51. doi:10.1093/jac/dkv498.
136. Sattar A, Thommes P, Payne L, Warn P, Vickers RJ. SMT19969 for Clostridium difficile infection (CDI): in vivo efficacy compared with fidaxomicin and vancomycin in the hamster model of CDI. J Antimicrob Chemother. 2015;70:1757–62. doi:10.1093/jac/dkv005.
137. Vickers R, Tillotson G, Nathan R, Hazam S, Lucasti C, Pullman J, et al. Ridinilazole for Clostridium difficile infections: safety and efficacy compared with vancomycin from the CoDIFy Phase 2 Trial. Amsterdam: Eur Congr Clin Microbiol Infect Dis; 2016.
138. C. difficile Infection. http://www.summitplc.com/programmes/c-difficile-infections/. Accessed 29 Sep 2016.
139. Lv Z, Peng G, Liu W, Xu H, Su J. Berberine blocks the relapse of Clostridium difficile infection in C57BL/6 mice after vancomycin standard treatment. Antimicrob Agents Chemother 2015;59:AAC.04794-14. doi:10.1128/AAC.04794-14.
140. Wang S, Setlow B, Setlow P, Li Y. Uptake and levels of the antibiotic berberine in individual dormant and germinating Clostridium difficile and Bacillus cereus spores as measured by laser tweezers Raman spectroscopy. J Antimicrob Chemother. 2016;71:1540–6. doi:10.1093/jac/dkv504.
141. Teraguchi S, Shin K, Ozawa K, Nakamura S, Fukuwatari Y, Tsuyuki S, et al. Bacteriostatic effect of orally administered bovine lactoferrin on proliferation of Clostridium species in the gut of mice fed bovine milk. Appl Environ Microbiol. 1995;61:501–6.
142. Boone JH, Dipersio JR, Tan MJ, Salstrom SJ, Wickham KN, Carman RJ, et al. Elevated lactoferrin is associated with moderate to severe Clostridium difficile disease, stool toxin, and 027 infection. Eur J Clin Microbiol Infect Dis. 2013;32:1517–23. doi:10.1007/s10096-013-1905-x.
143. Chilton CH, Crowther GS, Śpiewak K, Brindell M, Singh G, Wilcox MH, et al. Potential of lactoferrin to prevent antibiotic-induced Clostridium difficile infection. J Antimicrob Chemother. 2016;71:975–85. doi:10.1093/jac/dkv452.
144. Bovine Lactoferrin and Antibiotic-associated Diarrhoea. (BLAAD). https://clinicaltrials.gov/ct2/show/NCT02626104?term=lactoferrin+clostridium&rank=3. Accessed 1 Oct 2016.
145. De Sordi L, Butt MA, Pye H, Kohoutova D, Mosse CA, Yahioglu G, et al. Development of photodynamic antimicrobial chemotherapy (PACT) for Clostridium difficile. PLoS One. 2015;10:1–17. doi:10.1371/journal.pone.0135039.
146. Taylor NS, Bartlett JG. Binding of Clostridium difficile cytotoxin and vancomycin by anion-exchange resins. J Infect Dis. 1980;141:92–7.
147. Kunimoto D, Thomson AB. Recurrent Clostridium difficile-associated colitis responding to cholestyramine. Digestion. 1986;33:225–8.
148. Moncino MD, Falletta JM. Multiple relapses of Clostridium difficile-associated diarrhea in a cancer patient. Successful control with long-term cholestyramine therapy. Am J Pediatr Hematol Oncol. 1992;14:361–4.
149. Puri BK, Hakkarainen-Smith JS, Monro JA. The potential use of cholestyramine to reduce the risk of developing Clostridium difficile-associated diarrhoea in patients receiving long-term intravenous ceftriaxone. Med Hypotheses. 2015;84:78–80. doi:10.1016/j.mehy.2014.11.020.
150. Kurtz CB, Cannon EP, Brezzani A, Pitruzzello M, Dinardo C, Rinard E, et al. GT160-246, a toxin binding polymer for treatment of Clostridium difficile colitis. Antimicrob Agents Chemother. 2001;45:2340–7. doi:10.1128/AAC.45.8.2340-2347.2001.
151. Louie TJ, Peppe J, Watt CK, Johnson D, Mohammed R, Dow G, et al. Tolevamer, a novel nonantibiotic polymer, compared with vancomycin in the treatment of mild to moderately severe Clostridium difficile-associated diarrhea. Clin Infect Dis. 2006;43:411–20. doi:10.1086/506349.
152. Baines SD, Freeman J, Wilcox MH. Tolevamer is not efficacious in the neutralization of cytotoxin in a human gut model of Clostridium difficile infection. Antimicrob Agents Chemother. 2009;53:2202–4. doi:10.1128/AAC.01085-08.
153. Johnson S, Louie TJ, Gerding DN, Cornely O a., Chasan-Taber S, Fitts D, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis 2014;59:345–54. doi:10.1093/cid/ciu313.
154. Weiss K. Toxin-binding treatment for Clostridium difficile: a review including reports of studies with tolevamer. Int J Antimicrob Agents. 2009;33:4–7. doi:10.1016/j.ijantimicag.2008.07.011.
155. Dadu R, Hu MI, Cleeland C, Busaidy NL, Habra M, Waguespack SG, et al. Efficacy of the natural clay, calcium aluminosilicate anti-diarrheal, in reducing medullary thyroid cancer-related diarrhea and its effects on quality of life: a pilot study. Thyroid. 2015;25:1085–90. doi:10.1089/thy.2015.0166.
156. Kee BK, Morris JS, Slack RS, Crocenzi T, Wong L, Esparaz B, et al. A phase II, randomized, double blind trial of calcium aluminosilicate clay versus placebo for the prevention of diarrhea in patients with metastatic colorectal cancer treated with irinotecan. Support Care Cancer. 2015;23:661–70. doi:10.1007/s00520-014-2402-1.
157. Sturino JM, Pokusaeva K, Carpenter R. Effective sequestration of Clostridium difficile protein toxins by calcium aluminosilicate. Antimicrob Agents Chemother. 2015;59:7178–83. doi:10.1128/AAC.05050-14.
158. Proof-of-Concept, Calcium Aluminosilicate Anti-Diarrheal (CASAD) for Treatment of Clostridium difficile Infection. https://clinicaltrials.gov/ct2/show/NCT01570634?term=casad&rank=2. Accessed 29 Sep 2016.
159. Ivarsson ME, Durantie E, Hueberli C, Huwiler S, Lu J, Verdu EF, et al. Therapeutic potential of small molecule triggers of pre-emptive Clostridium difficile Toxin B auto-proteolysis. 5th Int Clostridium difficile Symp, Bled, Slovenia: 2015.
160. Inositec AG. http://inositec.com/. Accessed 17 Oct 2016.
161. Lyerly DM, Bostwick EF, Binion SB, Wilkins TD. Passive immunization of hamsters against disease caused by clostridium dijficile by use of bovine immunoglobulin G concentrate. Immunology. 1991;59:2215–8.
162. Kelly CP, Pothoulakis C, Vavva F, Castagliuolo I, Bostwick EF, Keane JCO, et al. Anti- Clostridium difficile bovine immunoglobulin concentrate inhibits cytotoxicity and enterotoxicity of C. difficile toxins. Antimicrob Agents Chemother. 1996;40:373–9.
163. Sponseller JK, Steele JA, Schmidt DJ, Kim HB, Beamer G, Sun X, et al. Hyperimmune bovine colostrum as a novel therapy to combat Clostridium difficile infection. J Infect Dis. 2015;211:1334–41. doi:10.1093/infdis/jiu605.
164. Young KWH, Munro IC, Taylor SL, Veldkamp P, van Dissel JT. The safety of whey protein concentrate derived from the milk of cows immunized against Clostridium difficile. Regul Toxicol Pharmacol. 2007;47:317–26. doi:10.1016/j.yrtph.2006.12.001.
165. Mattila E, Anttila V-J, Broas M, Marttila H, Poukka P, Kuusisto K, 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;40:702–8. doi:10.1080/00365540801964960.
166. Abougergi MS, Kwon JH. Intravenous immunoglobulin for the treatment of Clostridium difficile infection: a review. Dig Dis Sci. 2011;56:19–26. doi:10.1007/s10620-010-1411-2.
167. IVIG Versus Placebo for the Treatment of Patients With Severe C-Diff. https://clinicaltrials.gov/ct2/show/NCT00177970?term=ivig+clostridium&rank=1. Accessed 30 Sep 2016.
168. Juang P, Skledar SJ, Zgheib NK, Paterson DL, Vergis EN, Shannon WD, et al. Clinical outcomes of intravenous immune globulin in severe clostridium difficile-associated diarrhea. Am J Infect Control. 2007;35:131–7. doi:10.1016/j.ajic.2006.06.007.
169. Shahani L, Koirala J. Use of intravenous immunoglobulin in severe Clostridium difficile -associated diarrhea. Hosp Pract. 2015;43:154–7. doi:10.1080/21548331.2015.1071636.
170. Babcock GJ, Broering TJ, Hernandez HJ, Mandell RB, Donahue K, Boatright N, et al. Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters. Infect Immun. 2006;74:6339–47. doi:10.1128/IAI.00982-06.
171. Lowy I, Molrine D, Leav BA, Blair B, Baxter R, Gerding DN, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins Israel. N Engl J Med. 2010;362:197–205. doi:10.1056/NEJMoa1201637.
172. Gerding DN, Kelly C, Rahav G, Lee C, Dubberke E, Kumar P, et al. Efficacy of Bezlotoxumab, the Monoclonal Antibody Targeting C. difficile Toxin B, for Prevention of C. difficile Infection (CDI) Recurrence in Patients at High Risk of Recurrence or CDI-Related Adverse Outomes. Eur Congr Clin Microbiol Infect Dis, Amsterdam: 2016.
173. FDA Approves Merck’s ZINPLAVA™ (bezlotoxumab) to Reduce Recurrence of Clostridium difficile Infection (CDI) in Adult Patients Receiving Antibacterial Drug Treatment for CDI Who Are at High Risk of CDI Recurrence. http://www.mercknewsroom.com/news-release/corporate-news/fda-approves-mercks-zinplava-bezlotoxumab-reduce-recurrence-clostridium. Accessed 14 Nov 2016.
174. Roberts A, Mcglashan J, Ibrahim AA, Ling R, Denton H, Green S, et al. Development and evaluation of an ovine antibody-based platform for treatment of Clostridium difficile infection. Infect Immun. 2012;80:875–82. doi:10.1128/IAI.05684-11.
175. Product Pipeline. http://micropharm.co.uk/products/product_pipeline/. Accessed 30 Sep 2016.
176. Davies NL, Compson JE, MacKenzie B, O’Dowd VL, Oxbrow AKF, Heads JT, 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;20:377–90. doi:10.1128/CVI.00625-12.
177. Qiu H, Cassan R, Johnstone D, Han X, Joyee AG, McQuoid M, 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:e0157970. doi:10.1371/journal.pone.0157970.
178. Anosova NG, Cole LE, Li L, Zhang J, Brown AM, Mundle S, 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;22:711–25. doi:10.1128/CVI.00763-14.
179. Yang Z, Schmidt D, Liu W, Li S, Shi L, Sheng J, et al. A novel multivalent, single-domain antibody targeting TcdA and TcdB prevents fulminant Clostridium difficile infection in mice. J Infect Dis. 2014;210:964–72. doi:10.1093/infdis/jiu196.
180. Schmidt DJ, Beamer G, Tremblay JM, Steele JA, Kim HB, Wang Y, et al. A tetraspecific VHH-based neutralizing antibody modifies disease outcome in three animal models of Clostridium difficile infection. Clin Vaccine Immunol. 2016;23:774–84. doi:10.1128/CVI.00730-15.
181. Hussack G, Tanha J. An update on antibody-based immunotherapies for Clostridium difficile infection. Clin Exp Gastroenterol. 2016;9:209–24. doi:10.2147/CEG.S84017.
182. Anosova NG, Brown AM, Li L, Liu N, Cole LE, Zhang J, et al. Systemic antibody responses induced by a two-component Clostridium difficile toxoid vaccine protect against C. difficile-associated disease in hamsters. J Med Microbiol. 2013;62:1394–404. doi:10.1099/jmm.0.056796-0.
183. Greenberg RN, Marbury TC, Foglia G, Warny M. Phase I dose finding studies of an adjuvanted Clostridium difficile toxoid vaccine. Vaccine. 2012;30:2245–9. doi:10.1016/j.vaccine.2012.01.065.
184. de Bruyn G, Saleh J, Workman D, Pollak R, Elinoff V, Fraser NJ, et al. Defining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: a randomized Phase 2 clinical trial. Vaccine. 2016;34:2170–8. doi:10.1016/j.vaccine.2016.03.028.
185. Study of a Candidate Clostridium difficile Toxoid Vaccine (Cdiffense) in Subjects at Risk for C. Difficile infection. https://clinicaltrials.gov/ct2/show/NCT01887912?term=cdiffense&rank=1. Accessed 29 Sep 2016.
186. Sheldon E, Kitchin N, Peng Y, Eiden J, Gruber W, Johnson E, et al. A phase 1, placebo-controlled, randomized study of the safety, tolerability, and immunogenicity of a Clostridium difficile vaccine administered with or without aluminum hydroxide in healthy adults. Vaccine. 2016;34:2082–91. doi:10.1016/j.vaccine.2016.03.010.
187. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=pfizer+clostridium+%22phase+2%22&Search=Search. Accessed 30 Sep 2016.
188. Bézay N, Ayad A, Dubischar K, Firbas C, Hochreiter R, Kiermayr S, et al. Safety, immunogenicity and dose response of VLA84, a new vaccine candidate against Clostridium difficile, in healthy volunteers. Vaccine. 2016;34:2585–92. doi:10.1016/j.vaccine.2016.03.098.
189. Valneva’s Clostridium difficile vaccine candidate—VLA84. http://www.valneva.com/en/rd/vla84. Accessed 29 Sep 2016.
190. Gardiner DF, Rosenberg T, Zaharatos J, Franco D, Ho DD. A DNA vaccine targeting the receptor-binding domain of Clostridium difficile toxin A. Vaccine. 2009;27:3598–604. doi:10.1126/scisignal.2001449.Engineering.
191. Jin K, Wang S, Zhang C, Xiao Y, Lu S, Huang Z. Protective antibody responses against Clostridium difficile elicited by a DNA vaccine expressing the enzymatic domain of toxin B. Hum Vaccines Immunother. 2013;9:63–73. doi:10.4161/hv.22434.
192. Baliban SM, Michael A, Shammassian B, Mudakha S, Khan AS, Cocklin S, et al. An optimized, synthetic DNA vaccine encoding the toxin A and toxin B receptor binding domains of Clostridium difficile induces protective antibody responses in vivo. Infect Immun. 2014;82:4080–91. doi:10.1128/IAI.01950-14.
193. Ní Eidhin DB, O’Brien JB, McCabe MS, Athié-Morales V, Kelleher DP. Active immunization of hamsters against Clostridium difficile infection using surface-layer protein. FEMS Immunol Med Microbiol. 2008;52:207–18. doi:10.1111/j.1574-695X.2007.00363.x.
194. Bruxelle J-F, Mizrahi A, Hoys S, Collignon A, Janoir C, Péchiné S. Immunogenic properties of the surface layer precursor of Clostridium difficile and vaccination assays in animal models. Anaerobe. 2015;37:78–84. doi:10.1016/j.anaerobe.2015.10.010.
195. Péchiné S, Denève C, Le Monnier A, Hoys S, Janoir C, Collignon A. Immunization of hamsters against Clostridium difficile infection using the Cwp84 protease as an antigen. FEMS Immunol Med Microbiol. 2011;63:73–81. doi:10.1111/j.1574-695X.2011.00832.x.
196. Sandolo C, Péchiné S, Le Monnier A, Hoys S, Janoir C, Coviello T, et al. Encapsulation of Cwp84 into pectin beads for oral vaccination against Clostridium difficile. Eur J Pharm Biopharm. 2011;79:566–73. doi:10.1016/j.ejpb.2011.05.011.
197. Péchiné S, Janoir C, Boureau H, Gleizes A, Tsapis N, Hoys S, et al. Diminished intestinal colonization by Clostridium difficile and immune response in mice after mucosal immunization with surface proteins of Clostridium difficile. Vaccine. 2007;25:3946–54. doi:10.1016/j.vaccine.2007.02.055.
198. Ghose C, Eugenis I, Sun X, Edwards AN, McBride SM, Pride DT, et al. Immunogenicity and protective efficacy of recombinant Clostridium difficile flagellar protein FliC. Emerg Microbes Infect. 2016;5:e8. doi:10.1016/j.anaerobe.2015.12.001.
199. Bertolo L, Boncheff AG, Ma Z, Chen YH, Wakeford T, Friendship RM, et al. Clostridium difficile carbohydrates: glucan in spores, PSII common antigen in cells, immunogenicity of PSII in swine and synthesis of a dual C. difficile-ETEC conjugate vaccine. Carbohydr Res. 2012;354:79–85. doi:10.1016/j.carres.2012.03.032.
200. Martin CE, Broecker F, Oberli MA, Komor J, Mattner J, Anish C, et al. Immunological evaluation of a synthetic Clostridium difficile oligosaccharide conjugate vaccine candidate and identification of a minimal epitope. J Am Chem Soc. 2013;135:9713–22. doi:10.1021/ja401410y.
201. Oberli MA, Hecht ML, Bindschädler P, Adibekian A, Adam T, Seeberger PH. A possible oligosaccharide-conjugate vaccine candidate for Clostridium difficile is antigenic and immunogenic. Chem Biol. 2011;18:580–8. doi:10.1016/j.chembiol.2011.03.009.
202. Broecker F, Martin CE, Wegner E, Mattner J, Baek JY, Pereira CL, et al. Synthetic lipoteichoic acid glycans are potential vaccine candidates to protect from Clostridium difficile infections. Cell Chem Biol. 2016;23:1014–22. doi:10.1016/j.chembiol.2016.07.009.
203. Spencer J, Leuzzi R, Buckley A, Irvine J, Candlish D, Scarselli M, et al. Vaccination against Clostridium difficile using toxin fragments. Gut Microbes. 2014;5:225–32.
204. Leuzzi R, Adamo R, Scarselli M. Vaccines against clostridium difficile. Hum Vaccines Immunother. 2014;10:1466–77.
205. Seekatz AM, Rao K, Santhosh K, Young VB. Dynamics of the fecal microbiome in patients with recurrent and nonrecurrent Clostridium difficile infection. Genome Med. 2016;8:47. doi:10.1186/s13073-016-0298-8.
206. Kelly CR, Khoruts A, Staley C, Sadowsky MJ, Abd M, Alani M, et al. Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: a randomized trial. Ann Intern Med. 2016;. doi:10.7326/M16-0271.
207. Cammarota G, Masucci L, Ianiro G, Bibbò S, Dinoi G, Costamagna G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015;41:835–43. doi:10.1111/apt.13144.
208. Stool Transplant in Pediatric Patients With Recurring C. Difficile Infection. https://clinicaltrials.gov/ct2/show/NCT01972334?term=NCT01972334&rank=1. Accessed 29 Sep 2016.
209. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=stool+transplant+clostridium&recr=Open. Accessed 1 Oct 2016.
210. Youngster I, Sauk J, Pindar C, Wilson RG, Kaplan JL, Smith MB, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014;58:1515–22. doi:10.1093/cid/ciu135.
211. Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, et al. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile infection. JAMA. 2016;315:142. doi:10.1001/jama.2015.18098.
212. Zipursky JS, Sidorsky TI, Freedman CA, Sidorsky MN, Kirkland KB. Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. Clin Infect Dis. 2012;55:1652–8. doi:10.1093/cid/cis809.
213. Zipursky JS, Sidorsky TI, Freedman CA, Sidorsky MN, Kirkland KB. Physician attitudes toward the use of fecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection. Clin Infect Dis. 2014;28:319–24. doi:10.1093/cid/cis809.
214. Moossavi S, Salimzadeh H, Katoonizadeh A, Mojarrad A, Merat D, Ansari R, et al. Physicians’ knowledge and attitude towards fecal microbiota transplant in Iran. Middle East J Dig Dis. 2015;7:155–60.
215. Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, Capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014;312:1772–8. doi:10.1001/jama.2014.13875.
216. Tian H, Ding C, Gong J, Wei Y, McFarland LV, Li N. Freeze-dried, capsulized fecal microbiota transplantation for relapsing Clostridium difficile infection. J Clin Gastroenterol. 2015;49:537–8.
217. Hecker MT, Obrenovich ME, Cadnum JL, Jenson A, Jain AK, Ho E, et al. Fecal microbiota transplantation by freeze-dried oral capsules for reurrent Clostridium diffiicile infection. Open Forum Infect Dis. 2016;3:1–2. doi:10.1093/ofid/ofw091.
218. Orenstein R, Dubberke E, Hardi R, Ray A, Mullane K, Pardi DS, et al. Safety and durability of RBX2660 (microbiota suspension) for recurrent Clostridium difficile infection: results of the PUNCH CD study. Clin Infect Dis. 2015;2660:1–6. doi:10.1093/cid/civ938.
219. RBX2660 Clinical Trials. http://www.rebiotix.com/clinical-trials/rbx2660-clinical-trials/. Accessed 1 Oct 2016.
220. Khanna S, Pardi DS, Kelly CR, Kraft CS, Dhere T, Henn MR, et al. A novel microbiome therapeutic increases gut microbial diversity and prevents recurrent Clostridium difficile infection. J Infect Dis. 2016;214:173–81. doi:10.1093/infdis/jiv766.
221. SER-109 versus placebo to prevent recurrent Clostridium difficile infection (RCDI) (ECOSPOR). https://clinicaltrials.gov/ct2/show/study/NCT02437487?term=seres&rank=4. Accessed 2 Sep 2016.
222. SER-262 (SER-262-001 STUDY). http://www.serestherapeutics.com/ser-262-ser-262-001-study. Accessed 1 Oct 2016.
223. SER-262 versus placebo in adults with primary Clostridium difficile infection to prevent recurrence. https://clinicaltrials.gov/ct2/show/NCT02830542?term=SER-262&rank=1. Accessed 1 Oct 2016.
224. Petrof EO, Gloor GB, Vanner SJ, Weese SJ, Carter D, Daigneault MC, et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: “RePOOPulating” the gut. Microbiome. 2013;1:3. doi:10.1186/2049-2618-1-3.
225. MET-1 Clinical Pilot Study for Recurrent C. Difficile. https://clinicaltrials.gov/ct2/show/NCT02865616?term=met-1&rank=1. Accessed 2 Oct 2016.
226. Nagaro KJ, Phillips ST, Cheknis AK, Sambol SP, Zukowski WE, Johnson S, et al. Nontoxigenic Clostridium difficile protects hamsters against challenge with historic and epidemic strains of toxigenic BI/NAP1/027 C. difficile. Antimicrob Agents Chemother. 2013;57:5266–70. doi:10.1128/AAC.00580-13.
227. Gerding DN, Meyer T, Lee C, Cohen SH, Murthy UK, Poirier A, et al. Administration of spores of nontoxigenic Clostridium difficile Strain M3 for prevention of recurrent C difficile infection. JAMA. 2015;313:1719. doi:10.1001/jama.2015.3725.
228. Zhang K, Zhao S, Wang Y, Zhu X, Shen H, Chen Y, et al. The non-toxigenic Clostridium difficile CD37 protects mice against infection with a BI/NAP1/027 type of C. difficile strain. Anaerobe 2015;36:49–52. doi:10.1016/j.anaerobe.2015.09.009.
229. Winston JA, Theriot CM. Impact of microbial derived secondary bile acids on colonization resistance against Clostridium difficile in the gastrointestinal tract. Anaerobe. 2016;41:44–50. doi:10.1016/j.anaerobe.2016.05.003.
230. 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 2015;1:e00045–15. doi:10.1128/mSphere.00045-15.Editor.
231. Weingarden AR, Chen C, Zhang N, Graiziger CT, Dosa PI, Steer CJ, et al. Ursodeoxycholic acid inhibits Clostridium difficile spore germination and vegetative growth, and prevents the recurrence of ileal pouchitis associated with the infection. J Clin Gastroenterol. 2016;50:624–30. doi:10.1097/MCG.0000000000000427.
232. Howerton A, Ramirez N, Abel-Santos E. Mapping interactions between germinants and Clostridium difficile spores. J Bacteriol. 2011;193:274–82. doi:10.1128/JB.00980-10.
233. Howerton A, Patra M, Abel-Santos E. A new strategy for the prevention of Clostridium difficile infection. J Infect Dis. 2013;207:1498–504. doi:10.1093/infdis/jit068.
234. de Gunzburg J, Ducher A, Modess C, Wegner D, Oswald S, Dressman J, et al. Targeted adsorption of molecules in the colon with the novel adsorbent-based Medicinal Product, DAV132: a proof of concept study in healthy subjects. J Clin Pharmacol. 2015;55:10–6. doi:10.1002/jcph.359.
235. de Gunzburg J, Ghozlane A, Ducher A, Duval X, Ruppé E, Pulse M, et al. DAV132, an Adsorbent-Based Product, Protects the Gut Microbiome and Prevents Clostridium difficile Infections during Moxifloxacin Treatments. IDWeek, San Diego: 2015.
236. Miossec C, Sayah- Janne S, Augustin V, Chachaty E, Weiss W, Pulse M, et al. DAV131, an oral adsorbent-based product, fully protects hamsters against mociflocavin-induced Clostridium difficile lethal infection. Denver: Intersci Conf Antimicrob Agents Chemother; 2013.
237. Safety and Efficacy Study of Different DAV132 Dose Regimens in Healthy Volunteers. https://clinicaltrials.gov/ct2/show/NCT02917200?term=dav132&rank=2. Accessed 3 Oct 2016.
238. DAV132—Preventing occurence and recurrence of Clostridium difficile infection. http://www.davolterra.com/content/dav132-preventing-occurence-and-recurrence-clostridium-difficile-infection. Accessed 3 Oct 2016.
239. Stiefel U, Nerandzic MM, Koski P, Donskey CJ. Orally administered beta-lactamase enzymes represent a novel strategy to prevent colonization by Clostridium difficile. J Antimicrob Chemother. 2008;62:1105–8. doi:10.1093/jac/dkn298.
240. Kokai-Kun JF, Bristol JA, Setser J, Schlosser M. Nonclinical safety assessment of SYN-004: an Oral β-lactamase for the protection of the gut microbiome from disruption by biliary-excreted, intravenously administered antibiotics. Int J Toxicol. 2016;35:309–16. doi:10.1177/1091581815623236.
241. Roberts T, Kokai-Kun JF, Coughlin O, Lopez BV, Whalen H, Bristol JA, et al. Tolerability and pharmacokinetics of SYN-004, an orally administered β-lactamase for the prevention of Clostridium difficile-associated disease and antibiotic-associated diarrhea, in two phase 1 studies. Clin Drug Investig. 2016;36:725–34. doi:10.1007/s40261-016-0420-0.
242. Stiefel U, Nerandzic MM, Pultz MJ, Donskeya CJ. Gastrointestinal colonization with a cephalosporinase-producing Bacteroides species preserves colonization resistance against vancomycin-resistant Enterococcus and Clostridium difficile in cephalosporin-treated mice. Antimicrob Agents Chemother. 2014;58:4535–42. doi:10.1128/AAC.02782-14.
243. Carneiro BA, Fujii J, Brito GAC, Alcantara C, Oriá RB, Lima AAM, et al. Caspase and bid involvement in Clostridium difficile toxin A-induced apoptosis and modulation of toxin A effects by glutamine and alanyl-glutamine in vivo and in vitro. Infect Immun. 2006;74:81–7. doi:10.1128/IAI.74.1.81-87.2006.
244. Rodrigues RS, Oliveira RAC, Li Y, Zaja-Milatovic S, Costa LB, Braga Neto MB, et al. Intestinal epithelial restitution after TcdB challenge and recovery from Clostridium difficile infection in mice with alanyl-glutamine treatment. J Infect Dis. 2013;207:1505–15. doi:10.1093/infdis/jit041.
245. Efficacy study of alanyl-glutamine supplementation for the treatment of C. difficile infection. https://clinicaltrials.gov/ct2/show/NCT02053350?term=alanyl-glutamine&rank=2. Accessed 3 Oct 2016.
246. Li Y, Figler RA, Kolling G, Bracken TC, Rieger J, Stevenson RW, et al. Adenosine A2A receptor activation reduces recurrence and mortality from Clostridium difficile infection in mice following vancomycin treatment. BMC Infect Dis. 2012;12:342. doi:10.1186/1471-2334-12-342.
247. Cavalcante IC, Castro MV, Barreto ARF, Sullivan GW, Vale M, Almeida PRC, et al. Effect of novel A2A adenosine receptor agonist ATL 313 on Clostridium difficile toxin A-induced murine ileal enteritis. Infect Immun. 2006;74:2606–12. doi:10.1128/IAI.74.5.2606-2612.2006.
248. Warren CA, Calabrese GM, Li Y, Pawlowski SW, Figler RA, Rieger J, et al. Effects of adenosine A2A receptor activation and alanyl-glutamine in Clostridium difficile toxin-induced ileitis in rabbits and cecitis in mice. BMC Infect Dis. 2012;12:13. doi:10.1186/1471-2334-12-13.