Clostridium difficile Drug Pipeline: Challenges in Discovery and Development of New Agents

Journal of Medicinal Chemistry

Volumn 58, Issue 13, 2015, Pages 5164-5185

  Jarrad, Angie M ^a   Karoli, Tomislav ^a,c   Blaskovich, Mark A T ^a   Lyras, Dena ^b   Cooper, Matthew A ^a  

^a UNIVERSITY OF QUEENSLAND   (Australia)

^b MONASH UNIVERSITY   (Australia)

^c Progen Pharmaceuticals Limited   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; DNA TOPOISOMERASE; FIDAXOMICIN; GLYCOPEPTIDE; GYRASE INHIBITOR; INDOLE DERIVATIVE; MACROLIDE; METRONIDAZOLE; NATURAL PRODUCT; PEPTIDE DERIVATIVE; QUINOLONE DERIVATIVE; RIFAXIMIN; TETRAMIC ACID DERIVATIVE; TETRONIC ACID DERIVATIVE; VANCOMYCIN; ANTIINFECTIVE AGENT;

ANTIBIOTIC RESISTANCE; ANTIBIOTIC THERAPY; BIOLOGICAL THERAPY; CLINICAL TRIAL (TOPIC); CLOSTRIDIUM DIFFICILE INFECTION; DRUG SCREENING; DRUG TARGETING; HUMAN; IN VIVO STUDY; META ANALYSIS (TOPIC); NONHUMAN; PEPTOCLOSTRIDIUM DIFFICILE; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SYSTEMATIC REVIEW (TOPIC); DRUG DEVELOPMENT; DRUG EFFECTS; ENTEROCOLITIS, PSEUDOMEMBRANOUS; MICROBIOLOGY;

ANTI-BACTERIAL AGENTS; CLOSTRIDIUM DIFFICILE; DRUG DISCOVERY; ENTEROCOLITIS, PSEUDOMEMBRANOUS; HUMANS;

EID: 84934942717     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm5016846     Document Type: Review

References (176)

1. Antibiotic Resistance Threats in the United States, 2013. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention: Atlanta, GA, 2013; pp 1-114.
2. Carter, G. P.; Rood, J. I.; Lyras, D. The Role of Toxin A and Toxin B in the Virulence of Clostridium difficile Trends Microbiol. 2012, 20, 21-29
3. Gerding, D. N.; Johnson, S.; Rupnik, M.; Aktories, K. Clostridium difficile Binary Toxin CDT: Mechanism, Epidemiology, and Potential Clinical Importance Gut Microbes 2014, 5, 6-18
4. Edmonds, S. L.; Zapka, C.; Kasper, D.; Gerber, R.; McCormack, R.; Macinga, D.; Johnson, S.; Sambol, S.; Fricker, C.; Arbogast, J.; Gerding, D. N. Effectiveness of Hand Hygiene for Removal of Clostridium difficile Spores From Hands Infect. Control Hosp. Epidemiol. 2013, 34, 302-305
5. Sunkesula, V. C. K.; Kundrapu, S.; Jury, L. A.; Deshpande, A.; Sethi, A. K.; Donskey, C. J. Potential for Transmission of Spores by Patients Awaiting Laboratory Testing To Confirm Suspected Clostridium difficile Infection Infect. Control Hosp. Epidemiol. 2013, 34, 306-308
6. Warny, M.; Pepin, J.; Fang, A.; Killgore, G.; Thompson, A.; Brazier, J.; Frost, E.; McDonald, L. C. Toxin Production by an Emerging Strain of Clostridium difficile Associated with Outbreaks of Severe Disease in North America and Europe Lancet 2005, 366, 1079-1084
7. He, M.; Miyajima, F.; Roberts, P.; Ellison, L.; Pickard, D. J.; Martin, M. J.; Connor, T. R.; Harris, S. R.; Fairley, D.; Bamford, K. B.; D'Arc, S.; Brazier, J.; Brown, D.; Coia, J. E.; Douce, G.; Gerding, D.; Kim, H. J.; Koh, T. H.; Kato, H.; Senoh, M.; Louie, T.; Michell, S.; Butt, E.; Peacock, S. J.; Brown, N. M.; Riley, T.; Songer, G.; Wilcox, M.; Pirmohamed, M.; Kuijper, E.; Hawkey, P.; Wren, B. W.; Dougan, G.; Parkhill, J.; Lawley, T. D. Emergence and Global Spread of Epidemic Healthcare-Associated Clostridium difficile Nat. Genet. 2012, 45, 109-113
8. McDonald, L. C.; Killgore, G. E.; Thompson, A.; Owens, R. C., Jr.; Kazakova, S. V.; Sambol, S. P.; Johnson, S.; Gerding, D. N. An Epidemic, Toxin Gene-Variant Strain of Clostridium difficile N. Engl. J. Med. 2005, 353, 2433-2441
9. Loo, V. G.; Poirier, L.; Miller, M. A.; Oughton, M.; Libman, M. D.; Michaud, S.; Bourgault, A.-M.; Nguyen, T.; Frenette, C.; Kelly, M. A Predominantly Clonal Multi-Institutional Outbreak of Clostridium difficile -Associated Diarrhea with High Morbidity and Mortality N. Engl. J. Med. 2005, 353, 2442-2449
10. Khanna, S.; Pardi, D. S.; Aronson, S. L.; Kammer, P. P.; Baddour, L. M. Outcomes in Community-Acquired Clostridium difficile Infection Aliment. Pharmacol. Ther. 2012, 35, 613-618
11. Levine, D. P. Vancomycin: a History Clin. Infect. Dis. 2006, 42, S5-S12
12. Baines, E. J. Metronidazole: Its Past, Present and Future J. Antimicrob. Chemother. 1978, 4, 97-111
13. Vardakas, K. Z.; Polyzos, K. A.; Patouni, K.; Rafailidis, P. I.; Samonis, G.; Falagas, M. E. Treatment Failure and Recurrence of Clostridium difficile Infection Following Treatment with Vancomycin or Metronidazole: A Systematic Review of the Evidence Int. J. Antimicrob. Agents 2012, 40, 1-8
14. Venugopal, A. A.; Johnson, S. Current State of Clostridium difficile Treatment Options Clinical Infectious Diseases 2012, 55 (Suppl. 2) S71-S76
15. Cornely, O. A.; Miller, M. A.; Louie, T. J.; Crook, D. W.; Gorbach, S. L. Treatment of First Recurrence of Clostridium difficile Infection: Fidaxomicin Versus Vancomycin Clin. Infect. Dis. 2012, 55 (Suppl. 2) S154-S161
16. Louie, T. J.; Cannon, K.; Byrne, B.; Emery, J.; Ward, L.; Eyben, M.; Krulicki, W. Fidaxomicin Preserves the Intestinal Microbiome during and after Treatment of Clostridium difficile Infection (CDI) and Reduces Both Toxin Reexpression and Recurrence of CDI Clin. Infect. Dis. 2012, 55 (Suppl. 2) S132-S142
17. Finegold, S. M.; Molitoris, D.; Vaisanen, M. L.; Song, Y.; Liu, C.; Bolanos, M. In Vitro Activities of OPT-80 and Comparator Drugs against Intestinal Bacteria Antimicrob. Agents Chemother. 2004, 48, 4898-4902
18. Babakhani, F.; Bouillaut, L.; Gomez, A.; Sears, P.; Nguyen, L.; Sonenshein, A. L. Fidaxomicin Inhibits Spore Production in Clostridium difficile Clin. Infect. Dis. 2012, 55 (Suppl. 2) S162-S169
19. Müller, M. Mode of Action of Metronidazole on Anaerobic Bacteria and Protozoa Surgery 1983, 93, 165-171
20. Edwards, D. I. Nitroimidazole Drugs-Action and Resistance Mechanisms. II. Mechanisms of Resistance J. Antimicrob. Chemother. 1993, 31, 201-210
21. Bolton, R. P.; Culshaw, M. A. Faecal Metronidazole Concentrations during Oral and Intravenous Therapy for Antibiotic Associated Colitis Due to Clostridium difficile Gut 1986, 27, 1169-1172
22. Pepin, J.; Alary, M. E.; Valiquette, L.; Raiche, E.; Ruel, J.; Fulop, K.; Godin, D.; Bourassa, C. Increasing Risk of Relapse after Treatment of Clostridium difficile Colitis in Quebec, Canada Clin. Infect. Dis. 2005, 40, 1591-1597
23. Loll, P. J.; Axelsen, P. H. The Structural Biology of Molecular Recognition by Vancomycin Annu. Rev. Biophys. Biomol. Struct. 2000, 29, 265-289
24. Beauregard, D. A.; Williams, D. H.; Gwynn, M. N.; Knowles, D. J. Dimerization and Membrane Anchors in Extracellular Targeting of Vancomycin Group Antibiotics Antimicrob. Agents Chemother. 1995, 39, 781-785
25. Finegold, S. M.; Molitoris, D.; Vaisanen, M. L. Study of the in Vitro Activities of Rifaximin and Comparator Agents against 536 Anaerobic Intestinal Bacteria from the Perspective of Potential Utility in Pathology Involving Bowel Flora Antimicrob. Agents Chemother. 2008, 53, 281-286
26. Jiang, Z. D.; Ke, S.; Palazzini, E.; Riopel, L.; Dupont, H. In Vitro Activity and Fecal Concentration of Rifaximin after Oral Administration Antimicrob. Agents Chemother. 2000, 44, 2205-2206
27. New Drug To Fight Hospital Superbug Infection. http://www.specialisedtherapeutics.com.au/index.php?q=new-drug-to-fight-hospital-superbug-infection.html (accessed Mar 20, 2013).
28. Crook, D. W.; Walker, A. S.; Kean, Y.; Weiss, K.; Cornely, O. A.; Miller, M. A.; Esposito, R.; Louie, T. J.; Stoesser, N. E.; Young, B. C.; Angus, B. J.; Gorbach, S. L.; Peto, T. E. A.; Study 003/004 Teams. Fidaxomicin Versus Vancomycin for Clostridium difficile Infection: Meta-Analysis of Pivotal Randomized Controlled Trials Clin. Infect. Dis. 2012, 55, S93-S103
29. Erb, W.; Zhu, J. From Natural Product to Marketed Drug: the Tiacumicin Odyssey Nat. Prod. Rep. 2013, 30, 161-174
30. Lynch, T.; Chong, P.; Zhang, J.; Hizon, R.; Du, T.; Graham, M. R.; Beniac, D. R.; Booth, T. F.; Kibsey, P.; Miller, M.; Gravel, D.; Mulvey, M. R. Canadian Nosocomial Infectious Surveillance Program (CNISP). Characterization of a Stable, Metronidazole-Resistant Clostridium difficile Clinical Isolate PLoS One 2013, 8, e53757
31. Snydman, D. R.; Jacobus, N. V.; McDermott, L. A. 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, 3448-3452
32. Freeman, J.; Bauer, M. P.; Baines, S. D.; Corver, J.; Fawley, W. N.; Goorhuis, B.; Kuijper, E. J.; Wilcox, M. H. The Changing Epidemiology of Clostridium difficile Infections Clin. Microbiol. Rev. 2010, 23, 529-549
33. Huang, H.; Weintraub, A.; Fang, H.; Nord, C. E. Antimicrobial Resistance in Clostridium difficile Int. J. Antimicrob. Agents 2009, 34, 516-522
34. Peláez, T.; Cercenado, E.; Alcalá, L.; Marín, M.; Martín-López, A.; Martínez-Alarcón, J.; Catalán, P.; Sánchez-Somolinos, M.; Bouza, E. Metronidazole Resistance in Clostridium difficile Is Heterogeneous J. Clin. Microbiol. 2008, 46, 3028-3032
35. Goldstein, E. J. C.; Citron, D. M.; Sears, P.; Babakhani, F.; Sambol, S. P.; Gerding, D. N. Comparative Susceptibilities to Fidaxomicin (OPT-80) of Isolates Collected at Baseline, Recurrence, and Failure from Patients in Two Phase III Trials of Fidaxomicin against Clostridium difficile Infection Antimicrob. Agents Chemother. 2011, 55, 5194-5199
36. Grant, E. M. Fidaxomicin: New Therapy for Clostridium difficile -Associated Diarrhea Formulary 2011, 46, 297-308
37. O'Connor, J. R.; Galang, M. A.; Sambol, S. P.; Hecht, D. W.; Vedantam, G.; Gerding, D. N.; Johnson, S. Rifampin and Rifaximin Resistance in Clinical Isolates of Clostridium difficile Antimicrob. Agents Chemother. 2008, 52, 2813-2817
38. Johnson, S.; Homann, S. R.; Bettin, K. M.; Quick, J. N.; Clabots, C. R.; Peterson, L. R.; Gerding, D. N. Treatment of Asymptomatic Clostridium difficile Carriers (Fecal Excretors) with Vancomycin or Metronidazole. A Randomized, Placebo-Controlled Trial Ann. Intern. Med. 1992, 117, 297-302
39. Sears, P.; Crook, D. W.; Louie, T. J.; Miller, M. A.; Weiss, K. Fidaxomicin Attains High Fecal Concentrations with Minimal Plasma Concentrations Following Oral Administration in Patients with Clostridium difficile Infection Clin. Infect. Dis. 2012, 55 (Suppl. 2) S116-S120
40. Kelly, C. P. Fecal Microbiota Transplantation-An Old Therapy Comes of Age N. Engl. J. Med. 2013, 368, 474-475
41. Van Nood, E.; Vrieze, A.; Nieuwdorp, M.; Fuentes, S.; Zoetendal, E. G.; de Vos, W. M.; Visser, C. E.; Kuijper, E. J.; Bartelsman, J. F. W. M.; Tijssen, J. G. P.; Speelman, P.; Dijkgraaf, M. G. W.; Keller, J. J. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile N. Engl. J. Med. 2013, 368, 407-415
42. Gough, E.; Shaikh, H.; Manges, A. R. Systematic Review of Intestinal Microbiota Transplantation (Fecal Bacteriotherapy) for Recurrent Clostridium difficile Infection Clin. Infect. Dis. 2011, 53, 994-1002
43. Zipursky, J. S.; Sidorsky, T. I.; Freedman, C. A.; Sidorsky, M. N.; Kirkland, K. B. Patient Attitudes toward the Use of Fecal Microbiota Transplantation in the Treatment of Recurrent Clostridium difficile Infection Clin. Infect. Dis. 2012, 55, 1652-1658
44. Kahn, S. A.; Gorawara Bhat, R.; Rubin, D. T. Fecal Bacteriotherapy for Ulcerative Colitis: Patients Are Ready, Are We? Inflammatory Bowel Dis. 2011, 18, 676-684
45. Hong, G. Dongjin Dynasty. Zhou Hou Bei Ji Fang; Tianjin Science & Technology Press: Tianjin, China, 2000.
46. Zhang, F.; Luo, W.; Shi, Y.; Fan, Z.; Ji, G. Should We Standardize the 1,700-Year-Old Fecal Microbiota Transplantation? Am. J. Gastroenterol. 2012, 107, 1755-1755
47. Leake, I. Clostridium difficile Infection: Real or Fake-Faecal Matter Does the Trick for Recurrent CDI Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 129
48. Hamilton, M. J.; Weingarden, A. R.; Sadowsky, M. J.; Khoruts, A. Standardized Frozen Preparation for Transplantation of Fecal Microbiota for Recurrent Clostridium difficile Infection Am. J. Gastroenterol. 2012, 107, 761-767
49. Youngster, I.; Russell, G. H.; Pindar, C.; Ziv-Baran, T.; Sauk, J.; Hohmann, E. L. Oral, Capsulized, Frozen Fecal Microbiota Transplantation for Relapsing Clostridium difficile Infection JAMA, J. Am. Med. Assoc. 2014, 312, 1772-1778
50. Lawley, T. D.; Clare, S.; Walker, A. W.; Stares, M. D.; Connor, T. R.; Raisen, C.; Goulding, D.; Rad, R.; Schreiber, F.; Brandt, C. Targeted Restoration of the Intestinal Microbiota with a Simple, Defined Bacteriotherapy Resolves Relapsing Clostridium difficile Disease in Mice PLoS Pathog. 2012, 8, e1002995
51. Bakken, J. S.; Borody, T.; Brandt, L. J.; Brill, J. V.; Demarco, D. C.; Franzos, M. A.; Kelly, C.; Khoruts, A.; Louie, T.; Martinelli, L. P.; Moore, T. A.; Russell, G.; Surawicz, C. Treating Clostridium difficile Infection with Fecal Microbiota Transplantation Clin. Gastroenterol. Hepatol. 2011, 9, 1044-1049
52. Kapel, N.; Thomas, M.; Corcos, O.; Mayeur, C.; Barbot-Trystram, L.; Bouhnik, Y.; Joly, F. Practical Implementation of Faecal Transplantation Clin. Microbiol. Infect. 2014, 20, 1098-1105
53. The Power of Poo: DIY Instructions. http://thepowerofpoo.blogspot.com.au/p/diy-instructions.html?m=1 (accessed Aug 18, 2013).
54. American Gastroenterological Association. AGA Confirms IND Is Required for Fecal Microbiota Transplantation http://www.gastro.org/advocacy-regulation/regulatory-issues/fecal-microbiota-transplant/aga-confirms-ind-is-required-for-fecal-microbiota-transplantation (accessed Oct 29, 2014).
55. Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation To Treat Clostridium difficile Infection Not Responsive to Standard Therapies. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm361379.htm (accessed Aug 17, 2013).
56. Ratner, M. Fecal Transplantation Poses Dilemma for FDA Nat. Biotechnol. 2014, 32, 401-402
57. Smith, M. B.; Kelly, C.; Alm, E. J. Policy: How To Regulate Faecal Transplants Nature 2014, 506, 290-291
58. Tsutsumi, L. S.; Owusu, Y. B.; Hurdle, J. G.; Sun, D. Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 2014, 14, 152-175
59. Phase I Trial of a Single Dose of CRS3123. Identifier NCT01551004. http://clinicaltrials.gov/show/NCT01551004 (accessed Mar 21, 2013).
60. Novacta Biosystems Limited completes phase I study of NVB302 against C. difficile infection in healthy volunteers. http://www.novactabio.com/news.php (accessed Mar 18, 2014).
61. A Study of SMT19969 Compared with Vancomycin for the Treatment of Clostridium difficile -Associated Diarrhoea (CDAD). Identifier NCT02092935. http://clinicaltrials.gov/show/NCT02092935 (accessed Jan 18, 2015).
62. LaMarche, M. J.; Leeds, J. A.; Amaral, A.; Brewer, J. T.; Bushell, S. M.; Deng, G.; Dewhurst, J. M.; Ding, J.; Dzink-Fox, J.; Gamber, G.; Jain, A.; Lee, K.; Lee, L.; Lister, T.; McKenney, D.; Mullin, S.; Osborne, C.; Palestrant, D.; Patane, M. A.; Rann, E. M.; Sachdeva, M.; Shao, J.; Tiamfook, S.; Trzasko, A.; Whitehead, L.; Yifru, A.; Yu, D.; Yan, W.; Zhu, Q. Discovery of LFF571: An Investigational Agent for Clostridium difficile Infection J. Med. Chem. 2012, 55, 2376-2387
63. Safety and Efficacy of Multiple Daily Dosing of Oral LFF571 in Patients with Moderate Clostridium difficile Infections. Identifier NCT01232595. http://www.clinicaltrials.gov/ct2/show/NCT01232595?term=clostridium+difficile&rank=14 (accessed Mar 20, 2013).
64. Phase 3 Study with Cadazolid in CDAD. Identifier NCT01987895. https://clinicaltrials.gov/ct2/show/NCT01987895?term=cadazolid&rank=2 (accessed May 21, 2014).
65. Business Wire. Nanotherapeutics Acquires Two Late Stage Clinical Programs for Alzheimer's Treatment and CDA Disease. http://www.businesswire.com/news/home/20091216005124/en/Nanotherapeutics-Acquires-Late-Stage-Clinical-Programs-Alzheimer%E2%80%99s#.UyetsVzoXjI (accessed Mar 18, 2014).
66. Nanotherapeutics. NTI-851 (Ramoplanin). http://www.nanotherapeutics.com/ramoplanin/ (accessed Oct 29, 2014).
67. McLoughlin, F. CB-315 Fact Sheet, 2013; pp 1-3.
68. Mascio, C. T. M.; Mortin, L. I.; Howland, K. T.; Van Praagh, A. D. G.; Zhang, S.; Arya, A.; Chuong, C. L.; Kang, C.; Li, T.; Silverman, J. A. In Vitro and In Vivo Characterization of CB-183,315, a Novel Lipopeptide Antibiotic for Treatment of Clostridium difficile Antimicrob. Agents Chemother. 2012, 56, 5023-5030
69. Pharmacokinetics and Safety of Tigecycline in the Treatment of C. difficile Associated Diarrhea (CDAD). Identifier NCT01401023. http://clinicaltrials.gov/ct2/show/NCT01401023 (accessed Mar 21, 2013).
70. Study of Nitazoxanide in the Treatment of Clostridium difficile Colitis. Identifier NCT00417872. http://www.clinicaltrials.gov/ct2/show/NCT00417872?term=clostridium+difficile&rank=22 (accessed Mar 20, 2013).
71. Study of a Candidate Clostridium difficile Toxoid Vaccine in Subjects at Risk for C. difficile Infection. Identifier NCT01887912. http://clinicaltrials.gov/ct2/show/NCT01887912?term=c+difficile+and+vaccine&rank=2 (accessed Oct 23, 2014).
72. An Open-Label Study Assessing Safety, Immunogenicity and Dose Response of IC84. Identifier NCT01296386. http://clinicaltrials.gov/ct2/show/NCT01296386?term=IC84&rank=1 (accessed Oct 23, 2014).
73. Johnson, S.; Louie, T. J.; Gerding, D. N.; Cornely, O. A.; Chasan-Taber, S.; Fitts, D.; Gelone, S. P.; Broom, C.; Davidson, D. M. Polymer Alternative for CDI Treatment (PACT) investigators. Vancomycin, Metronidazole, or Tolevamer for Clostridium difficile Infection: Results From Two Multinational, Randomized, Controlled Trials Clin. Infect. Dis. 2014, 59, 345-354
74. A Study of MK-3415, MK-6072, and MK-3415A in Participants Receiving Antibiotic Therapy for Clostridium difficile Infection (MK-3415A-001 AM2). Identifier NCT01241552. http://www.clinicaltrials.gov/ct2/show/NCT01241552?term=clostridium+difficile&rank=6 (accessed Mar 20, 2013).
75. Safety and Efficacy Study of VP20621 for Prevention of Recurrent Clostridium difficile Infection. Identifier NCT01259726. http://clinicaltrials.gov/ct2/show/NCT01259726?term=VP20621&rank=1 (accessed Jan 21, 2015).
76. Brouwer, M. S. M.; Roberts, A. P.; Hussain, H.; Williams, R. J.; Allan, E.; Mullany, P. Horizontal Gene Transfer Converts Non-Toxigenic Clostridium difficile Strains into Toxin Producers Nat. Commun. 2013, 4, 1-6
77. Villano, S. A.; Seiberling, M.; Tatarowicz, W.; Monnot-Chase, E.; Gerding, D. N. Evaluation of an Oral Suspension of VP20621, Spores of Nontoxigenic Clostridium difficile Strain M3, in Healthy Subjects Antimicrob. Agents Chemother. 2012, 56, 5224-5229
78. Buffie, C. G.; Bucci, V.; Stein, R. R.; McKenney, P. T.; Ling, L.; Gobourne, A.; No, D.; Liu, H.; Kinnebrew, M.; Viale, A.; Littmann, E.; van den Brink, M. R. M.; Jenq, R. R.; Taur, Y.; Sander, C.; Cross, J.; Toussaint, N. C.; Xavier, J. B.; Pamer, E. G. Precision Microbiome Reconstitution Restores Bile Acid Mediated Resistance to Clostridium difficile Nature 2015, 517, 205-208
79. Gao, X. W.; Mubasher, M.; Fang, C. Y.; Reifer, C.; Miller, L. E. Dose-Response Efficacy of a Proprietary Probiotic Formula of Lactobacillus acidophilus Cl1285 and Lactobacillus casei Lbc80r for Antibiotic-Associated Diarrhea and Clostridium difficile -Associated Diarrhea Prophylaxis in Adult Patients Am. J. Gastroenterol. 2010, 105, 1636-1641
80. Microbiota Restoration Therapy for Recurrent Clostridium difficile -associated Diarrhea. Identifier NCT01925417. https://clinicaltrials.gov/ct2/show/NCT01925417?term=FMT&phase=1&rank=17 (accessed Oct 28, 2014).
81. Monarch Labs. Monarch Labs and BTER Foundation collaborate to develop fecal transplantion products http://www.monarchlabs.com/Monarch-Labs-and-BTER-Foundation-collaborate-to-develop-fecal-transplantion-products (accessed Aug 18, 2013).
82. Gaulton, A.; Bellis, L. J.; Bento, A. P.; Chambers, J.; Davies, M.; Hersey, A.; Light, Y.; McGlinchey, S.; Michalovich, D.; Al-Lazikani, B.; Overington, J. P. ChEMBL: A Large-Scale Bioactivity Database for Drug Discovery Nucleic Acids Res. 2012, 40, D1100-D1107
83. Ballard, T. E.; Wang, X.; Olekhnovich, I.; Koerner, T.; Seymour, C.; Hoffman, P. S.; Macdonald, T. L. Biological Activity of Modified and Exchanged 2-Amino-5-Nitrothiazole Amide Analogues of Nitazoxanide Bioorg. Med. Chem. Lett. 2010, 20, 3537-3539
84. Ballard, T. E.; Wang, X.; Olekhnovich, I.; Koerner, T.; Seymour, C.; Salamoun, J.; Warthan, M.; Hoffman, P. S.; Macdonald, T. L. Synthesis and Antimicrobial Evaluation of Nitazoxanide-Based Analogues: Identification of Selective and Broad Spectrum Activity ChemMedChem 2011, 6, 362-377
85. Katsura, Y.; Nishino, S.; Ohno, M.; Sakane, K.; Matsumoto, Y.; Morinaga, C.; Ishikawa, H.; Takasugi, H. Anti- Helicobacter pylori Agents. 3. 2-[(Arylalkyl)Guanidino]-4-furylthiazoles J. Med. Chem. 1999, 42, 2920-2926
86. Katsura, Y.; Nishino, S.; Tomishi, T.; Sakane, K.; Matsumoto, Y.; Ishikawa, H.; Takasugi, H. Anti- Helicobacter pylori Agents. 2. Structure Activity Relationships in a New Series of 2-Alkylguanidino-4-furylthiazoles Bioorg. Med. Chem. Lett. 1998, 8, 1307-1312
87. Emerging Drugs for Active Tuberculosis. http://www.thieme-connect.de/DOI/DOI?10.1055/s-0028-1085706 (accessed Apr 9, 2014).
88. Pankuch, G. A.; Appelbaum, P. C. Activities of Tizoxanide and Nitazoxanide Compared to Those of Five Other Thiazolides and Three Other Agents against Anaerobic Species Antimicrob. Agents Chemother. 2006, 50, 1112-1117
89. Costello, C.; Karpanen, T.; Lambert, P. A.; Mistry, P.; Parker, K. J.; Rathbone, D. L.; Ren, J.; Wheeldon, L.; Worthington, T. Thiosemicarbazones Active Against Clostridium difficile Bioorg. Med. Chem. Lett. 2008, 18, 1708-1711
90. Miyamoto, Y.; Kalisiak, J.; Korthals, K.; Lauwaet, T.; Cheung, D. Y.; Lozano, R.; Cobo, E. R.; Upcroft, P.; Upcroft, J. A.; Berg, D. E.; Gillin, F. D.; Fokin, V. V.; Sharpless, K. B.; Eckmann, L. Expanded Therapeutic Potential in Activity Space of Next-Generation 5-Nitroimidazole Antimicrobials with Broad Structural Diversity Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 17564-17569
91. Jeong, J. Y.; Mukhopadhyay, A. K.; Akada, J. K.; Dailidiene, D.; Hoffman, P. S.; Berg, D. E. Roles of FrxA and RdxA Nitroreductases of Helicobacter pylori in Susceptibility and Resistance to Metronidazole J. Bacteriol. 2001, 183, 5155-5162
92. Segreti, J.; Goodman, L. J.; Trenholme, G. M. In Vitro Activity of New Quinoxaline Compounds against Campylobacter Species and Clostridium difficile Diagn. Microbiol. Infect. Dis. 1993, 17, 177-179
93. Zhang, S.-J.; Yang, Q.; Xu, L.; Chang, J.; Sun, X. Synthesis and Antibacterial Activity against Clostridium difficile of Novel Demethylvancomycin Derivatives Bioorg. Med. Chem. Lett. 2012, 22, 4942-4945
94. Kirst, H. A.; Toth, J. E.; Debono, M.; Willard, K. E.; Truedell, B. A.; Ott, J. L.; Counter, F. T.; Felty-Duckworth, A. M.; Pekarek, R. S. Synthesis and Evaluation of Tylosin-Related Macrolides Modified at the Aldehyde Function: A New Series of Orally Effective Antibiotics J. Med. Chem. 1988, 31, 1631-1641
95. Terasawa, T.; Watanabe, M.; Okubo, T.; Mitsuhashi, S. In Vitro Activity of YM133, a New Semisynthesized Macrolide Antimicrob. Agents Chemother. 1991, 35, 1370-1375
96. Sanchez, J. P.; Gogliotti, R. D.; Domagala, J. M.; Gracheck, S. J.; Huband, M. D.; Sesnie, J. A.; Cohen, M. A.; Shapiro, M. A. The Synthesis, Structure-Activity, and Structure-Side Effect Relationships of a Series of 8-Alkoxy- and 5-Amino-8-alkoxyquinolone Antibacterial Agents J. Med. Chem. 1995, 38, 4478-4487
97. Rosen, T.; Fernandes, P. B.; Marovich, M. A.; Shen, L.; Mao, J.; Pernet, A. G. Aromatic Dienoyl Tetramic Acids. Novel Antibacterial Agents with Activity against Anaerobes and Staphylococci J. Med. Chem. 1989, 32, 1062-1069
98. Ueda, C.; Tateda, K.; Horikawa, M.; Kimura, S.; Ishii, Y.; Nomura, K.; Yamada, K.; Suematsu, T.; Inoue, Y.; Ishiguro, M.; Miyairi, S.; Yamaguchi, K. Anti- Clostridium difficile Potential of Tetramic Acid Derivatives from Pseudomonas Aeruginosa Quorum-Sensing Autoinducers Antimicrob. Agents Chemother. 2010, 54, 683-688
99. Karwowski, J. P.; Jackson, M.; Theriault, R. J.; Barlow, G. J.; Coen, L.; Hensey, D. M.; Humphrey, P. E. Tirandalydigin, a Novel Tetramic Acid of the Tirandamycin-Streptolydigin Type. I. Taxonomy of the Producing Organism, Fermentation and Biological Activity J. Antibiot. 1992, 45, 1125-1132
100. Shoji, J.; Sakazaki, R.; Hattori, T.; Matsumoto, K.; Uotani, N.; Yoshida, T. Isolation and Characterization of Agglomerins A, B, C and D J. Antibiot. 1989, 42, 1729-1733
101. Terui, Y.; Sakazaki, R.; Shoji, J. Structures of Agglomerins J. Antibiot. 1990, 43, 1245-1253
102. Butler, M. M.; Williams, J. D.; Peet, N. P.; Moir, D. T.; Panchal, R. G.; Bavari, S.; Shinabarger, D. L.; Bowlin, T. L. Comparative in Vitro Activity Profiles of Novel Bis-Indole Antibacterials against Gram-Positive and Gram-Negative Clinical Isolates Antimicrob. Agents Chemother. 2010, 54, 3974-3977
103. Panchal, R. G.; Ulrich, R. L.; Lane, D.; Butler, M. M.; Houseweart, C.; Opperman, T.; Williams, J. D.; Peet, N. P.; Moir, D. T.; Nguyen, T.; Gussio, R.; Bowlin, T.; Bavari, S. Novel Broad-Spectrum Bis-(imidazolinylindole) Derivatives with Potent Antibacterial Activities against Antibiotic-Resistant Strains Antimicrob. Agents Chemother. 2009, 53, 4283-4291
104. Ambrus, J. I.; Kelso, M. J.; Bremner, J. B.; Ball, A. R.; Casadei, G.; Lewis, K. Structure-Activity Relationships of 2-Aryl-1 H -Indole Inhibitors of the NorA Efflux Pump in Staphylococcus aureus Bioorg. Med. Chem. Lett. 2008, 18, 4294-4297
105. Ternansky, R. J.; Jordan, C. L.; Eudaly, J. A.; Kasher, J. S. Synthesis and Anaerobic Activity of Novel 1-Carba-1-dethiacephalosporins J. Med. Chem. 1993, 36, 2332-2334
106. Corraz, A. J.; Dax, S. L.; Dunlap, N. K.; Georgopapadakou, N. H.; Keith, D. D.; Pruess, D. L.; Rossman, P. L.; Then, R.; Unowsky, J.; Wei, C. C. Dual-Action Penems and Carbapenems J. Med. Chem. 1992, 35, 1828-1839
107. Mani, N.; Gross, C. H.; Parsons, J. D.; Hanzelka, B.; Müh, U.; Mullin, S.; Liao, Y.; Grillot, A.-L.; Stamos, D.; Charifson, P. S.; Grossman, T. H. In Vitro Characterization of the Antibacterial Spectrum of Novel Bacterial Type II Topoisomerase Inhibitors of the Aminobenzimidazole Class Antimicrob. Agents Chemother. 2006, 50, 1228-1237
108. Charifson, P. S.; Grillot, A.-L.; Grossman, T. H.; Parsons, J. D.; Badia, M.; Bellon, S.; Deininger, D. D.; Drumm, J. E.; Gross, C. H.; LeTiran, A.; Liao, Y.; Mani, N.; Nicolau, D. P.; Perola, E.; Ronkin, S.; Shannon, D.; Swenson, L. L.; Tang, Q.; Tessier, P. R.; Tian, S.-K.; Trudeau, M.; Wang, T.; Wei, Y.; Zhang, H.; Stamos, D. Novel Dual-Targeting Benzimidazole Urea Inhibitors of DNA Gyrase and Topoisomerase IV Possessing Potent Antibacterial Activity: Intelligent Design and Evolution through the Judicious Use of Structure-Guided Design and Structure-Activity Relationships J. Med. Chem. 2008, 51, 5243-5263
109. Grillot, A.-L.; Tiran, A. L.; Shannon, D.; Krueger, E.; Liao, Y.; O'Dowd, H.; Tang, Q.; Ronkin, S.; Wang, T.; Waal, N.; Li, P.; Lauffer, D.; Sizensky, E.; Tanoury, J.; Perola, E.; Grossman, T. H.; Doyle, T.; Hanzelka, B.; Jones, S.; Dixit, V.; Ewing, N.; Liao, S.; Boucher, B.; Jacobs, M.; Bennani, Y.; Charifson, P. S. Second-Generation Antibacterial Benzimidazole Ureas: Discovery of a Preclinical Candidate with Reduced Metabolic Liability J. Med. Chem. 2014, 57, 8792-8816
110. Perola, E.; Stamos, D.; Grillot, A.-L.; Ronkin, S.; Wang, T.; LeTiran, A.; Tang, Q.; Deininger, D. D.; Liao, Y.; Tian, S.-K.; Drumm, J. E.; Nicolau, D. P.; Tessier, P. R.; Mani, N.; Grossman, T. H.; Charifson, P. S. Successful Application of Serum Shift Prediction Models to the Design of Dual Targeting Inhibitors of Bacterial Gyrase B and Topoisomerase IV with Improved in Vivo Efficacy Bioorg. Med. Chem. Lett. 2014, 24, 2177-2181
111. Stokes, N. R.; Thomaides-Brears, H. B.; Barker, S.; Bennett, J. M.; Berry, J.; Collins, I.; Czaplewski, L. G.; Gamble, V.; Lancett, P.; Logan, A.; Lunniss, C. J.; Peasley, H.; Pommier, S.; Price, D.; Smee, C.; Haydon, D. J. Biological Evaluation of Benzothiazole Ethyl Urea Inhibitors of Bacterial Type II Topoisomerases Antimicrob. Agents Chemother. 2013, 57, 5977-5986
112. Miesel, L.; Hecht, D. W.; Osmolski, J. R.; Gerding, D.; Flattery, A.; Li, F.; Lan, J.; Lipari, P.; Polishook, J. D.; Liang, L.; Liu, J.; Olsen, D. B.; Singh, S. B. Kibdelomycin Is a Potent and Selective Agent against Toxigenic Clostridium difficile Antimicrob. Agents Chemother. 2014, 58, 2387-2392
113. Dipexium Pharmaceuticals, Inc. Clinical Trials: Mild Infections of Diabetic Foot Ulcers http://www.dipexiumpharmaceuticals.com/locilex/clinical-trials (accessed Jan 21, 2015).
114. Fuchs, P. C.; Barry, A. L.; Brown, S. D. In Vitro Antimicrobial Activity of MSI-78, a Magainin Analog Antimicrob. Agents Chemother. 1998, 42, 1213-1216
115. Ge, Y.; MacDonald, D. L.; Holroyd, K. J.; Thornsberry, C.; Wexler, H.; Zasloff, M. In Vitro Antibacterial Properties of Pexiganan, an Analog of Magainin Antimicrob. Agents Chemother. 1999, 43, 782-788
116. Oh, H.; Hedberg, M.; Wade, D.; Edlund, C. Activities of Synthetic Hybrid Peptides against Anaerobic Bacteria: Aspects of Methodology and Stability Antimicrob. Agents Chemother. 2000, 44, 68-72
117. Liu, R.; Suárez, J. M.; Weisblum, B.; Gellman, S. H.; McBride, S. M. Synthetic Polymers Active against Clostridium difficile Vegetative Cell Growth and Spore Outgrowth J. Am. Chem. Soc. 2014, 136, 14498-14504
118. Nakashio, S.; Iwasawa, H.; Dun, F. Y.; Kanemitsu, K.; Shimada, J. Everninomicin, a New Oligosaccharide Antibiotic: Its Antimicrobial Activity, Post-Antibiotic Effect and Synergistic Bactericidal Activity Drugs Exp. Clin. Res. 1995, 21, 7-16
119. Tanaka, K.; Kato, N.; Watanabe, K. In Vitro Activity of an Evernimicin Derivative, SCH27899, against Anaerobic Bacteria and Propionibacterium Acnes J. Antimicrob. Chemother. 2000, 46, 465-469
120. Hanada, M.; Kaneta, K.; Nishiyama, Y.; Hoshino, Y.; Konishi, M.; Oki, T. Hydramycin, a New Antitumor Antibiotic. Taxonomy, Isolation, Physico-Chemical Properties, Structure and Biological Activity J. Antibiot. 1991, 44, 824-831
121. McCullough, J. E.; Muller, M. T.; Howells, A. J.; Maxwell, A.; O'Sullivan, J.; Summerill, R. S.; Parker, W. L.; Wells, J. S.; Bonner, D. P.; Fernandes, P. B. Clerocidin, a Terpenoid Antibiotic, Inhibits Bacterial DNA Gyrase J. Antibiot. 1993, 46, 526-530
122. Nadai, M.; Palù, G.; Palumbo, M.; Richter, S. N. Differential Targeting of Unpaired Bases within Duplex DNA by the Natural Compound Clerocidin: A Valuable Tool To Dissect DNA Secondary Structure PLoS One 2012, 7, e52994
123. Banskota, A. H.; Aouidate, M.; rensen, D. S. O.; Ibrahim, A.; Piraee, M.; Zazopoulos, E.; Alarco, A.-M.; Gourdeau, H.; Mellon, C.; Farnet, C. M.; Falardeau, P.; McAlpine, J. B. TLN-05220, TLN-05223, New Echinosporamicin-Type Antibiotics, and Proposed Revision of the Structure of Bravomicins J. Antibiot. 2009, 62, 565-570
124. Sakoulas, G.; Nam, S.-J.; Loesgen, S.; Fenical, W.; Jensen, P. R.; Nizet, V.; Hensler, M. Novel Bacterial Metabolite Merochlorin a Demonstrates in Vitro Activity against Multi-Drug Resistant Methicillin-Resistant Staphylococcus aureus PLoS One 2012, 7, e29439
125. Pepper, H. P.; George, J. H. Biomimetic Total Synthesis of (±)-Merochlorin A Angew. Chem., Int. Ed. 2013, 52, 12170-12173
126. Wu, X.; Alam, M. Z.; Feng, L.; Tsutsumi, L. S.; Sun, D.; Hurdle, J. G. Prospects for Flavonoid and Related Phytochemicals as Nature-Inspired Treatments for Clostridium difficile Infection J. Appl. Microbiol. 2014, 116, 23-31
127. Feng, L.; Maddox, M. M.; Alam, M. Z.; Tsutsumi, L. S.; Narula, G.; Bruhn, D. F.; Wu, X.; Sandhaus, S.; Lee, R. B.; Simmons, C. J.; Tse-Dinh, Y.-C.; Hurdle, J. G.; Lee, R. E.; Sun, D. Synthesis, Structure-Activity Relationship Studies, and Antibacterial Evaluation of 4-Chromanones and Chalcones, as Well as Olympicin a and Derivatives J. Med. Chem. 2014, 57, 8398-8420
128. Pucci, M. J.; Bronson, J. J.; Barrett, J. F.; DenBleyker, K. L.; Discotto, L. F.; Fung-Tomc, J. C.; Ueda, Y. Antimicrobial Evaluation of Nocathiacins, a Thiazole Peptide Class of Antibiotics Antimicrob. Agents Chemother. 2004, 48, 3697-3701
129. LaMarche, M. J.; Leeds, J. A.; Dzink-Fox, J.; Gangl, E.; Krastel, P.; Neckermann, G.; Palestrant, D.; Patane, M. A.; Rann, E. M.; Tiamfook, S.; Yu, D. Antibiotic Optimization and Chemical Structure Stabilization of Thiomuracin A J. Med. Chem. 2012, 55, 6934-6941
130. Heap, J. T.; Pennington, O. J.; Cartman, S. T.; Carter, G. P.; Minton, N. P. The ClosTron: A Universal Gene Knock-Out System for the Genus Clostridium J. Microbiol. Methods 2007, 70, 452-464
131. Jadhav, A.; Ezhilarasan, V.; Prakash Sharma, O.; Pan, A. Clostridium -DTDB: A Comprehensive Database for Potential Drug Targets of Clostridium difficile Comput. Biol. Med. 2013, 43, 362-367
132. Larocque, M.; Chénard, T.; Najmanovich, R. A Curated C. difficile Strain 630 Metabolic Network: Prediction of Essential Targets and Inhibitors BMC Syst. Biol. 2014, 8, 117
133. Dang, T. H. T.; de la Riva, L.; Fagan, R. P.; Storck, E. M.; Heal, W. P.; Janoir, C.; Fairweather, N. F.; Tate, E. W. Chemical Probes of Surface Layer Biogenesis in Clostridium difficile ACS Chem. Biol. 2010, 5, 279-285
134. Ratia, K.; Light, S. H.; Antanasijevic, A.; Anderson, W. F.; Caffrey, M.; Lavie, A. Discovery of Selective Inhibitors of the Clostridium difficile Dehydroquinate Dehydratase PLoS One 2014, 9, e89356
135. Puri, A. W.; Lupardus, P. J.; Deu, E.; Albrow, V. E.; Garcia, K. C.; Bogyo, M.; Shen, A. Rational Design of Inhibitors and Activity-Based Probes Targeting Clostridium difficile Virulence Factor TcdB Chem. Biol. 2010, 17, 1201-1211
136. Abdeen, S. J.; Swett, R. J.; Feig, A. L. Peptide Inhibitors Targeting Clostridium difficile Toxins A and B ACS Chem. Biol. 2010, 5, 1097-1103
137. Maurer, B.; Mathias, U.; Papatheodorou, P.; Shekfeh, S.; Orth, J.; Jank, T.; Schwan, C.; Sippl, W.; Aktories, K.; Jung, M. From Cosubstrate Similarity to Inhibitor Diversity-Inhibitors of ADP-Ribosyltransferases from Kinase Inhibitor Screening Mol. BioSyst. 2011, 7, 799-808
138. Nerandzic, M. M.; Donskey, C. J. Activate to Eradicate: Inhibition of Clostridium difficile Spore Outgrowth by the Synergistic Effects of Osmotic Activation and Nisin PLoS One 2013, 8, e54740
139. Francis, M. B.; Allen, C. A.; Shrestha, R.; Sorg, J. A. Bile Acid Recognition by the Clostridium difficile Germinant Receptor, CspC, Is Important for Establishing Infection PLoS Pathog. 2013, 9, e1003356
140. Sorg, J. A.; Dineen, S. S. Laboratory Maintenance of Clostridium difficile. Curr. Protoc. Microbiol. 2009, Chapter 9, Unit 9A.1.
141. Edwards, A. N.; Suárez, J. M.; McBride, S. M. Culturing and Maintaining Clostridium difficile in an Anaerobic Environment J. Visualized Exp. 2013, e50787
142. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria, 8 th ed.; CLSI M11-A8; Clinical and Laboratory Standards Institute: Wayne, PA, 2012; pp 1-56.
143. Dawson, L. F.; Valiente, E.; Faulds-Pain, A.; Donahue, E. H.; Wren, B. W. Characterisation of Clostridium difficile Biofilm Formation, a Role for Spo0A PLoS One 2012, 7, e50527
144. Allen, C. A.; Babakhani, F.; Sears, P.; Nguyen, L.; Sorg, J. A. Both Fidaxomicin and Vancomycin Inhibit Outgrowth of Clostridium difficile Spores Antimicrob. Agents Chemother. 2013, 57, 664-667
145. Chilton, C. H.; Freeman, J.; Baines, S. D.; Crowther, G. S.; Nicholson, S.; Wilcox, M. H. Evaluation of the Effect of Oritavancin on Clostridium difficile Spore Germination, Outgrowth and Recovery J. Antimicrob. Chemother. 2013, 68, 2078-2082
146. Francis, M. B.; Allen, C. A.; Sorg, J. A. Muricholic Acids Inhibit Clostridium difficile Spore Germination and Growth PLoS One 2013, 8, e73653
147. Baines, S. D.; O'Connor, R.; Saxton, K.; Freeman, J.; Wilcox, M. H. 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, 1078-1085
148. Crowther, G. S.; Baines, S. D.; Todhunter, S. L.; Freeman, J.; Chilton, C. H.; Wilcox, M. H. Evaluation of NVB302 Versus Vancomycin Activity in an in Vitro Human Gut Model of Clostridium difficile Infection J. Antimicrob. Chemother. 2013, 68, 168-176
149. Chilton, C. H.; Crowther, G. S.; Baines, S. D.; Todhunter, S. L.; Freeman, J.; Locher, H. H.; Athanasiou, A.; Wilcox, M. H. 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
150. Chilton, C. H.; Freeman, J.; Crowther, G. S.; Todhunter, S. L.; Wilcox, M. H. 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, 2434-2437
151. Crowther, G. S.; Chilton, C. H.; Todhunter, S. L.; Nicholson, S.; Freeman, J.; Baines, S. D.; Wilcox, M. H. Development and Validation of a Chemostat Gut Model To Study Both Planktonic and Biofilm Modes of Growth of Clostridium difficile and Human Microbiota PLoS One 2014, 9, e88396
152. Crowther, G. S.; Chilton, C. H.; Todhunter, S. L.; Nicholson, S.; Freeman, J.; Baines, S. D.; Wilcox, M. H. Comparison of Planktonic and Biofilm-Associated Communities of Clostridium difficile and Indigenous Gut Microbiota in a Triple-Stage Chemostat Gut Model J. Antimicrob. Chemother. 2014, 69, 2137-2147
153. Best, E. L.; Freeman, J.; Wilcox, M. H. Models for the Study of Clostridium difficile Infection Gut Microbes 2012, 3, 145-167
154. Kokkotou, E.; Moss, A. C.; Michos, A.; Espinoza, D.; Cloud, J. W.; Mustafa, N.; O'Brien, M.; Pothoulakis, C.; Kelly, C. P. 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, 1121-1126
155. Swanson, R. N.; Hardy, D. J.; Shipkowitz, N. L.; Hanson, C. W.; Ramer, N. C.; Fernandes, P. B.; Clement, J. J. In Vitro and in Vivo Evaluation of Tiacumicins B and C against Clostridium difficile Antimicrob. Agents Chemother. 1991, 35, 1108-1111
156. Ochsner, U. A.; Bell, S. J.; O'Leary, A. L.; Hoang, T.; Stone, K. C.; Young, C. L.; Critchley, I. A.; Janjic, N. 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, 964-971
157. Locher, H. H.; Seiler, P.; Chen, X.; Schroeder, S.; Pfaff, P.; Enderlin, M.; Klenk, A.; Fournier, E.; Hubschwerlen, C.; Ritz, D.; Kelly, C. P.; Keck, W. In Vitro and in Vivo Antibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections Antimicrob. Agents Chemother. 2014, 58, 892-900
158. Freeman, J.; Baines, S. D.; Jabes, D.; Wilcox, M. H. 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, 717-725
159. McVay, C. S.; Rolfe, R. D. In Vitro and in Vivo Activities of Nitazoxanide against Clostridium difficile Antimicrob. Agents Chemother. 2000, 44, 2254-2258
160. Anton, P. M.; O'Brien, M.; Kokkotou, E.; Eisenstein, A. M.; Rothstein, D. M.; Paraschos, S.; Kelly, C. P.; Pothoulakis, C. Rifalazil Treats and Prevents Relapse of Clostridium difficile -Associated Diarrhea in Hamsters Antimicrob. Agents Chemother. 2004, 48, 3975-3979
161. Freeman, J.; Marquis, M.; Crowther, G. S.; Todhunter, S. L.; Fawley, W. N.; Chilton, C. H.; Moeck, G.; Lehoux, D.; Wilcox, M. H. Oritavancin Does Not Induce Clostridium difficile Germination and Toxin Production in Hamsters or a Human Gut Model J. Antimicrob. Chemother. 2012, 67, 2919-2926
162. Hutton, M. L.; Mackin, K. E.; Chakravorty, A.; Lyras, D. Small Animal Models for the Study of Clostridium difficile Disease Pathogenesis FEMS Microbiol. Lett. 2014, 352, 140-149
163. Deakin, L. J.; Clare, S.; Fagan, R. P.; Dawson, L. F.; Pickard, D. J.; West, M. R.; Wren, B. W.; Fairweather, N. F.; Dougan, G.; Lawley, T. D. Clostridium difficile spo0A Gene Is a Persistence and Transmission Factor Infect. Immun. 2012, 80, 2704-2711
164. Sun, X.; Wang, H.; Zhang, Y.; Chen, K.; Davis, B.; Feng, H. Mouse Relapse Model of Clostridium difficile Infection Infect. Immun. 2011, 79, 2856-2864
165. Eyre, D. W.; Cule, M. L.; Wilson, D. J.; Griffiths, D.; Vaughan, A.; O'Connor, L.; Ip, C. L. C.; Golubchik, T.; Batty, E. M.; Finney, J. M.; Wyllie, D. H.; Didelot, X.; Piazza, P.; Bowden, R.; Dingle, K. E.; Harding, R. M.; Crook, D. W.; Wilcox, M. H.; Peto, T. E. A.; Walker, A. S. Diverse Sources of C. difficile Infection Identified on Whole-Genome Sequencing N. Engl. J. Med. 2013, 369, 1195-1205
166. A Trial To Compare Xifaxan to Vancomycin for the Treatment of Clostridium difficile -Associated Diarrhea (CDAD). Identifier NCT00269399. https://clinicaltrials.gov/ct2/show/NCT00269399?term=NCT00269399&rank=1 (accessed Oct 21, 2014).
167. Fecal Microbiota Transplant for Relapsing Clostridium difficile Infection in Adults and Children Using a Frozen Encapsulated Inoculum. Identifier NCT01914731. http://clinicaltrials.gov/ct2/show/NCT01914731?term=FMT&phase=0&rank=9.
168. Youngster, I.; Sauk, J.; Pindar, C.; Wilson, R. G.; Kaplan, J. L.; Smith, M. B.; Alm, E. J.; Gevers, D.; Russell, G. H.; Hohmann, E. L. Fecal Microbiota Transplant for Relapsing Clostridium difficile Infection Using a Frozen Inoculum rrom Unrelated Donors: A Randomized, Open-Label, Controlled Pilot Study Clin. Infect. Dis. 2014, 58, 1515-1522
169. Defined Fecal Microbiota Transplantation for Clostridium difficile Diarrhea. Identifier NCT01868373. https://clinicaltrials.gov/ct2/show/NCT01868373?term=FMT&phase=0&rank=10 (accessed Oct 28, 2014).
170. A Study To Investigate a Clostridium difficile Vaccine in Healthy Adults Aged 50 to 85 Years, Who Will Each Receive 3 Doses of Vaccine. Identifier NCT02117570. http://clinicaltrials.gov/ct2/show/NCT02117570?term=vaccine+difficile&rank=4 (accessed Oct 23, 2014).
171. Lowy, I.; Molrine, D. C.; Leav, B. A.; Blair, B. M.; Baxter, R.; Nichol, G.; Thomas, W. D., Jr.; Leney, M.; Sloan, S.; Hay, C. A.; Ambrosino, D. M. Treatment with Monoclonal Antibodies against Clostridium difficile Toxins N. Engl. J. Med. 2010, 362, 197-205
172. FMT Versus Antimicrobials for Initial Treatment of Recurrent CDI. Identifier NCT02255305. https://clinicaltrials.gov/ct2/show/NCT02255305?term=FMT&phase=1&rank=1 (accessed Oct 28, 2014).
173. Stool Transplant in Pediatric Patients with Recurring C. difficile Infection. Identifier NCT01972334. http://clinicaltrials.gov/ct2/show/NCT01972334?term=FMT&phase=1&rank=5 (accessed Jan 20, 2014).
174. Fecal Transplant for Relapsing C. difficile Infection. Identifier NCT01703494. http://clinicaltrials.gov/ct2/show/NCT01703494 (accessed Oct 28, 2014).
175. Fecal Microbiota Transplantation by Colonoscopy for Recurrent C. difficile Infection. NCT02148601. https://clinicaltrials.gov/ct2/show/NCT02148601?term=FMT&phase=1&rank=15 (accessed Oct 28, 2014).
176. FMT Delivered by Capsule Versus Colonoscopy for Recurrent C. diff. Identifier NCT02254811. http://clinicaltrials.gov/ct2/show/NCT02254811?term=FMT&phase=2&rank=1 (accessed Oct 23, 2014).