2,502
Views
29
CrossRef citations to date
0
Altmetric
REVIEWS

The potential for emerging therapeutic options for Clostridium difficile infection

, , , &
Pages 696-710 | Received 12 May 2014, Accepted 13 Oct 2014, Published online: 26 Jan 2015

References

  • Hall IC, O'Toole E. Intestinal flora in new-born infants with a description of a new pathogenic anaerobe, Bacillus difficilis. Am J Dis Child 1935; 49:390-402; http://dx.doi.org/10.1001/archpedi.1935.01970020105010
  • George RH, Symonds JM, Dimock F, Brown JD, Arabi Y, Shinagawa N, Keighley MR, Alexander-Williams J, Burdon DW. Identification of Clostridium difficile as a causative agent of pseudomembranous colitis. BMJ 1978; 1:695; PMID:630301; http://dx.doi.org/10.1136/bmj.1.6114.695
  • Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin Infect Dis 2012; 55:S88-92; PMID:22752870; http://dx.doi.org/10.1093/cid/cis335
  • Vedantam, Clark A, Chu M, McQuade R, Mallozzi M, Viswanathan VK. Clostridium difficile infection: toxins and non-toxin virulence factors, and their contributions to disease establishment and host response. Gut Microbes 2012; 3:121-34; PMID:22555464; http://dx.doi.org/10.4161/gmic.19399
  • Carter GP, Lyras D, Allen DL, Mackin KE, Howarth PM, O’Connor JR, Rood JI. Binary toxin production in Clostridium difficile is regulated by CdtR, a LytTR family response regulator. J Bacteriol 2007; 189:7290-301; PMID:17693517; http://dx.doi.org/10.1128/JB.00731-07
  • Heap JT, Pennington OJ, Cartman ST, Carter GP, Minton NP. The ClosTron: a universal gene knock-out system for the genus Clostridium. J Microbiol Methods 2007; 70:452-64; PMID:17658189; http://dx.doi.org/10.1016/j.mimet.2007.05.021
  • O’Connor JR, Lyras D, Farrow KA, Adams V, Powell DR, Hinds J, Cheung JK, Rood JI. Construction and analysis of chromosomal Clostridium difficile mutants. Mol Microbiol 2006; 61:1335-51; http://dx.doi.org/10.1111/j.1365-2958.2006.05315.x
  • Dupuy B, Govind R, Antunes A, Matamouros S. Clostridium difficile toxin synthesis is negatively regulated by TcdC. J Med Microbiol 2008; 57:685-90; PMID:18480323; http://dx.doi.org/10.1099/jmm.0.47775-0
  • Carter GP, Rood JI, Lyras D. The role of toxin A and toxin B in the virulence of Clostridium difficile. Trends Microbiol 2012; 20:21-9; PMID:22154163; http://dx.doi.org/10.1016/j.tim.2011.11.003
  • Mani, Dupuy B. Regulation of toxin synthesis in Clostridium difficile by an alternative RNA polymerase sigma factor. Proc Natl Acad Sci U S A 2001; 98:5844-9; PMID:11320220; http://dx.doi.org/10.1073/pnas.101126598
  • Bakker D, Smits WP, Kuijper EJ, Corver J. TcdC does not significantly repress toxin expression in Clostridium difficile 630Δerm. PLoS One 2012; 7:e43247; PMID:22912837; http://dx.doi.org/10.1371/journal.pone.0043247
  • Carter GP, Douce GR, Govind R, Howarth PM, Mackin KE, Spencer J, Buckley AM, Antunes A, Kotsanas D, Jenkin GA, Dupuy B, Rood JI, Lyras D. The anti-sigma factor TcdC modulates hypervirulence in an epidemic BINAP11487;027 clinical isolate of Clostridium difficile. PLoS Pathog 2011; 7:e1002317; PMID:22022270; http://dx.doi.org/10.1371/journal.ppat.1002317
  • Matamouros S, England P, Dupuy B. Clostridium difficile toxin expression is inhibited by the novel regulator TcdC. Mol Microbiol 2007; 64:1274-88; PMID:17542920; http://dx.doi.org/10.1111/j.1365-2958.2007.05739.x
  • Murray R, Boyd D, Levett PN, Mulvey MR, Alfa M. Truncation in the tcdC region of the Clostridium difficile PathLoc of clinical isolates does not predict increased biological activity of Toxin B or Toxin A. BMC Infect Dis 2009; 9:103; PMID:19558711; http://dx.doi.org/10.1186/1471-2334-9-103
  • Merrigan M, Venugopal A, Mallozzi M, Roxas B, Viswanathan VK, Johnson S, Gerding DN, Vedantam G. Human hypervirulent Clostridium difficile strains exhibit increased sporulation as well as robust toxin production. J Bacteriol 2010; 192:4904-11; PMID:20675495; http://dx.doi.org/10.1128/JB.00445-10
  • Vohra P, Poxton IR. Comparison of toxin and spore production in clinically relevant strains of Clostridium difficile. Microbiology 2011; 157:1343-53; PMID:21330434; http://dx.doi.org/10.1099/mic.0.046243-0
  • Lyras LD, O'Connor JR, Howarth PM, Sambol SP, Carter GP, Phumoonna T, Poon R, Adams V, Vedantam G, Johnson S, et al. Toxin B is essential for virulence of Clostridium difficile. Nature 2009; 458:1176-9; PMID:19252482; http://dx.doi.org/10.1038/nature07822
  • Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A, Minton NP. The role of toxin A and toxin B in Clostridium difficile infection. Nature 2010; 467:711-3; PMID:20844489; http://dx.doi.org/10.1038/nature09397
  • Geric B, Carman RJ, Rupnik M, Genheimer CW, Sambol SP, Lyerly DM, Gerding DN, Johnson S. Binary toxin-producing, large clostridial toxin-negative Clostridium difficile strains are enterotoxic but do not cause disease in hamsters. J Infect Dis 2006; 193:1143-50; PMID:16544255; http://dx.doi.org/10.1086/501368
  • Perelle S, Gibert M, Bourlioux P, corthier G, Popoff MR. Production of a complete binary toxin (actin-specific ADP-ribosyltransferase) by Clostridium difficile CD196. Infect Immunol 1997; 65:1402-7
  • Modena S, Gollamudi S, Friedenberg F. Continuation of antibiotics is associated with failure of metronidazole for Clostridium difficile-associated diarrhea. J Clin Gastroenterol 2006; 40:49-54; PMID:16340634; http://dx.doi.org/10.1097/01.mcg.0000190761.80615.0f
  • Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45:302-7; PMID:17599306; http://dx.doi.org/10.1086/519265
  • Fernandez A, Anand G, Friedenberg F. Factors associated with failure of metronidazole in Clostridium difficile-associated disease. J Clin Gastroenterol 2004; 38:414-8; PMID:15100520; http://dx.doi.org/10.1097/00004836-200405000-00005
  • Zilberberg MD, Shorr AF, Micek ST, Doherty JA, Kollef MH. Clostridium difficile-associated disease and mortality among the elderly critically ill. Crit Care Med 2009; 37:2583-9; PMID:19623053; http://dx.doi.org/10.1097/CCM.0b013e3181ab8388
  • Cornely OA, Miller MA, Louie TJ, Crook DW, Gorbach SL. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin vs. vancomycin. Clin Infect Dis 2012; 55:S154-61; PMID:22752865; http://dx.doi.org/10.1093/cid/cis462
  • Karadsheh Z, Sule S. Fecal transplantation for the treatment of recurrent Clostridium difficile infection. N Am J Med Sci 2013; 5:339-43; PMID:23923106; http://dx.doi.org/10.4103/1947-2714.114163
  • Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH. 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; PMID:20307191; http://dx.doi.org/10.1086/651706
  • Wenisch JM, Schmid D, Kuo HW, Allerberger F, Michl V, Tesik P, Tucek G, Laferl H, Wenisch C. Prospective observational study comparing three different treatment regimes in patients with Clostridium difficile infection. Antimicrob Agents Chemother 2012; 56:1974-8; PMID:22252830; http://dx.doi.org/10.1128/AAC.05647-11
  • Bauer MP, Kuijper EJ, van Dissel JT. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): treatment guidance document for Clostridium difficile infection (CDI). Clin Microbiol Infect 2009; 15:1067-79; PMID:19929973; http://dx.doi.org/10.1111/j.1469-0691.2009.03099.x
  • Barbut F, Richard A, Hamadi K, Chomette V, Burghoffer B, Petit JC. Epidemiology of recurrences or reinfections of Clostridium difficile-associated diarrhea. J Clin Microbiol 2000; 38:2386-8; PMID:10835010
  • McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002; 97:1769-75; PMID:12135033; http://dx.doi.org/10.1111/j.1572-0241.2002.05839.x
  • Kim PK, Huh HC, Cohen HW, Feinberg EJ, Ahmad S, Coyle C, Teperman S, Boothe H. Intracolonic vancomycin or severe Clostridium difficile colitis. Surg Infect (Larchmt) 2013; 14:532-9; PMID:23560732; http://dx.doi.org/10.1089/sur.2012.158
  • Apisarnthanarak A, Razavi B, Mundy LM. Adjunctive intracolonic vancomycin for severe Clostridium difficile colitis: case series and review of the literature. Clin Infect Dis 2002; 35:690-6; PMID:12203166; http://dx.doi.org/10.1086/342334
  • Johnson AP, Wilcox MH. Fidaxomicin: a new option for the treatment of Clostridium difficile infection. J Antimicrob Chemother 2012; 67:2788-92; PMID:22865382; http://dx.doi.org/10.1093/jac/dks302
  • Babakhani F, Bouillaut L, Gomez A, Sears P, Nguyen L, Sonenshein AL. Fidaxomicin inhibits spore production in Clostridium difficile. Clin Infect Dis 2012; 55:162-9; http://dx.doi.org/10.1093/cid/cis453
  • Tannock GW, Munro K, Taylor C, Lawley B, Young W, Byrne B, Emery J, Louie T. A new macrocyclic antibiotic, fidaxomicin (OPT-80), causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin. Microbiology 2010; 156:3354-9; PMID:20724385; http://dx.doi.org/10.1099/mic.0.042010-0
  • Rashid MU, Dalhoff A, Weintraub A, Nord CE. In vitro activity of MCB3681 against Clostridium difficile strains. Anaerobe 2014; 28C:216-9; http://dx.doi.org/10.1016/j.anaerobe.2014.07.001
  • Babakhani F, Bouillaut L, Sears P, Sims C, Gomez A, Sonenshein AL. Fidaxomicin prevents toxin production in Clostridium difficile. J Antimicrob Chemother 2013; 68: 515-22; http://dx.doi.org/10.1093/jac/dks450
  • 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; PMID:23887866; http://dx.doi.org/10.1093/jac/dkt302
  • Juang P, Hardesty JS. Role of fidaxomicin for the treatment of Clostridium difficile infection. J Pharm Pract 2013; 26:491-7; PMID:24064437; http://dx.doi.org/10.1177/0897190013499526
  • Babakhani F, Seddon J, Sears P. Comparative microbiological studies of transcription inhibitors fidaxomicin and the rifamycins in Clostridium difficile. Antimicrob Agents Chemother 2014; 58:2934-7; PMID:24550338; http://dx.doi.org/10.1128/AAC.02572-13
  • Koon HW, Ho S, Hing TC, Cheng M, Chen X, Ichikawa Y, Kelly CP, Pothoulakis C. Fidaxomicin inhibits Clostridium difficile toxin A-mediated enteritis in the mouse ileum. Antimicrob Agents Chemother 2014; 58:4642-50; PMID:24890583; http://dx.doi.org/10.1128/AAC.02783-14
  • Chilton CH, Crowther GS, Freeman J, Todhunter SL, Nicholson S, Longshaw CM, Wilcox MH. Successful treatment of simulated Clostridium difficile infection in a human gut model by fidaxomicin first line and after vancomycin or metronidazole failure. J Antimicrob Chemother 2014; 69:451-62; PMID:24003182; http://dx.doi.org/10.1093/jac/dkt347
  • Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue YK. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011; 364:422-31; PMID:21288078; http://dx.doi.org/10.1056/NEJMoa0910812
  • Johnson S, Crook DW, Cornely OA. High KP, Miller M, Gorbach SL. Randomized clinical trial in Clostridium difficile infection confirms superiority of fidaxomicin over vancomycin. Gastroenterol 2010; 139: e17; http://dx.doi.org/10.1053/j.gastro.2010.05.063
  • Crook DW, Walker AS, Kean Y, Weiss K, Cornely OA, Miller MA, Esposito R, Louie TJ, Stoesser NE, Young BC, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis 2012; 55:S93-103; PMID:22752871; http://dx.doi. org/10.1093/cid/cis499.
  • Shue YK, Sears PS, Shangle S, Walsh RB, Lee C, Gorbach SL, Okumu F, Preston RA. Safety, tolerance, and pharmacokinetic studies of OPT-80 in healthy volunteers following single and multiple oral doses. Antimicrob Agents Chemother 2008; 52:1391-1395; PMID:18268081; http://dx.doi.org/10.1128/AAC.01045-07
  • Sullivan KM, Spooner LM. Fidaxomicin: a macrocyclic antibiotic for the management of Clostridium difficile infection. Ann Pharmacother 2010; 44:352-9; PMID:20071495; http://dx.doi.org/10.1345/aph.1M351
  • Poxton IR. Fidaxomicin: a new macrocyclic, RNA polymerase-inhibiting antibiotic for the treatment of Clostridium difficile infections. Future Microbiol 2010; 5:539-48; PMID:20353295; http://dx.doi.org/10.2217/fmb.10.20
  • Louie T, Miller M, Donskey C, Mullane K, Goldstein EJ. Clinical outcomes, safety, and pharmacokinetics of OPT-80 in a phase 2 trial with patients with Clostridium difficile infection. Antimicrob Agents Chemother 2009; 53:223-8; PMID:18955525; http://dx.doi.org/10.1128/AAC.01442-07
  • Johnson S, Gerding DN, Louie TJ, Ruiz NM, Gorbach SL. Sustained clinical response as an endpoint in treatment trials of Clostridium difficile-associated diarrhea. Antimicrob Agents Chemother 2012; 56:4043-5; PMID:22615287; http://dx.doi.org/10.1128/AAC.00605-12
  • Eyre DW, Babakhani F, Griffiths D, Seddon J, Del Ojo Elias C, Gorbach SL, Peto TE, Crook DW, Walker AS. Whole-genome sequencing demonstrates that fidaxomicin is superior to vancomycin for preventing reinfection and relapse of infection with Clostridium difficile. J Infect Dis 2014; 209:1446-51; PMID:24218500; http://dx.doi.org/10.1093/infdis/jit598
  • Hecht DW, Galang MA, Sambol SP, Osmolski JR, Johnson S, Gerding DN. In vitro activities of 15 antimicrobial agents against 110 toxigenic Clostridium difficile clinical isolates collected from 1983 to 2004. Antimicrob Agents Chemother 2007; 51:2716-9; PMID:17517836; http://dx.doi.org/10.1128/AAC.01623-06
  • Neff G, Zacharias V, Kaiser TE, Gaddis A, Kemmer N. Rifaximin for the treatment of recurrent Clostridium difficile infection after liver transplantation: a case series. Liver Transpl 2010; 16:960-3; PMID:20677286; http://dx.doi.org/10.1002/lt.22092
  • Garey KW, Salazar M, Shah D, Rodrigue R, DuPont HL. Rifamycin antibiotics for treatment of Clostridium difficile-associated diarrhea. Ann Pharmacother 2008; 42:827-35; PMID:18430792; http://dx.doi.org/10.1345/aph.1K675
  • Nomura K, Matsumoto Y, Yoshida N, Taji S, Wakabayashi N, Mitsufuji S, Horiike S, Morita M, Okanoue T, Taniwaki M. Successful treatment with rifampin for fulminant antibiotic-associated colitis in a patient with non-Hodgkin's lymphoma. World J Gastroenterol 2004; 10:765-6; PMID:14991957
  • Lagrotteria D, Holmes S, Smieja M, Smaill F, Lee C. Prospective, randomized inpatient study of oral metronidazole versus oral metronidazole and rifampin for treatment of primary episode of Clostridium difficile-associated diarrhea. Clin Infect Dis 2006; 43:547-52; PMID:16886144; http://dx.doi.org/10.1086/506354
  • O'Connor JR, Galang MA, Sambol SP, Hecht DW, Vedantam G, Gerding DN, Johnson S. Rifampin and rifaximin resistance in clinical isolates of Clostridium difficile. Antimicrob Agents Chemother 2008; 52:2813-7; PMID:18559647; http://dx.doi.org/10.1128/AAC.00342-08
  • Lynch T, Chong P, Zhang J, Hizon R, Du T, Graham MR, Beniac DR, Booth TF, Kibsey P, Miller M, et al. Characterization of a stable, metronidazole-resistant Clostridium difficile clinical isolate. PLoS One 2013; 8:e53757; PMID:23349739; http://dx.doi.org/10.1371/journal.pone.0053757
  • 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; 33:846-8; http://dx.doi.org/10.1086/511870
  • Patrick-Basu P, Dinani A, Rayapudi K, Pacana T, Shah NJ, Hampole H, Krishnaswamy NV, Mohan V. Rifaximin therapy for metronidazole-unresponsive Clostridium difficile infection: a prospective pilot trial. Therap Adv Gastroenterol 2010; 3:221-5; PMID:21180604; http://dx.doi.org/10.1177/1756283X10372985
  • Huang JS, Jiang ZD, Garey KW, Lasco T, Dupont HL. Use of rifamycin drugs and development of infection by rifamycin-resistant strains of Clostridium difficile. Antimicrob Agents Chemother 2013; 57:2690-3; PMID:23545528; http://dx.doi.org/10.1128/AAC.00548-13
  • Obuch-Woszczatyński P, Dubiel G, Harmanus C, Kuijper E, Duda U, Wultańska D, van Belkum A, Pituch H. Emergence of Clostridium difficile infection in tuberculosis patients due to a highly rifampicin-resistant PCR ribotype 046 clone in Poland. Eur J Clin Microbiol Infect Dis 2013; 32:1027-30; PMID:23443474; http://dx.doi.org/10.1007/s10096-013-1845-5
  • 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; PMID:22908175; http://dx.doi.org/10.1128/AAC.00974-12
  • Anderson VR, Curran MP. Nitazoxanide: a review of its use in the treatment of gastrointestinal infections. Drugs 2007; 67:1947-67; PMID:17722965; http://dx.doi.org/10.2165/00003495-200767130-00015
  • Musher DM, Logan N, Hamill RJ, Dupont HL, Lentnek A, Gupta A, Rossignol JF. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis 2006; 43:421-7; PMID:16838229; http://dx.doi.org/10.1086/506351
  • Musher DM, Logan N, Mehendiratta V, Melgarejo NA, Garud S, Hamill RJ. Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide. J Antimicrob Chemother 2007; 59:705-10; PMID:17337513; http://dx.doi.org/10.1093/jac/dkl553
  • 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; PMID:19133801; http://dx.doi.org/10.1086/596552
  • Rafiullah F, Kanwal S, Majeed UM, Korsten MA, Cheema FH, Luthra M, Sohail MR. Successful use of nitazoxanide in the treatment of recurrent Clostridium difficile infection. BMJ Case Rep 2011; pii:bcr0420114123; PMID:22674696
  • Herpers BL, Vlaminckx B, Burkhardt O, Blom H, Biemond-Moeniralam HS, Hornef M, Welte T, Kuijper EJ. Intravenous tigecycline as adjunctive or alternative therapy for severe refractory Clostridium difficile infection. Clin Infect Dis 2009; 48:1732-5; PMID:19435431; http://dx.doi.org/10.1086/599224
  • Baines SD, Saxton K, Freeman J, Wilcox MH. Tigecycline does not induce proliferation or cytotoxin production by epidemic Clostridium difficile strains in a human gut model. J Antimicrob Chemother 2006; 58:1062-5; PMID:17030519; http://dx.doi.org/10.1093/jac/dkl364
  • Jump RL, Li Y, Pultz MJ, Kypriotakis G, Donskey CJ. Tigecycline exhibits inhibitory activity against Clostridium difficile in the colon of mice and does not promote growth or toxin production. Antimicrob Agents Chemother 2011; 55:546-9; PMID:21135181; http://dx.doi.org/10.1128/AAC.00839-10
  • Lao D II, Chiang T, Gomez E. Refractory Clostridium difficile infection successfully treated with tigecycline, rifaximin, and vancomycin. Case Rep Med 2012; 70291; PMID:22829841; http://dx.doi.org/10.1155/2012/702910
  • Lu CL, Liu CY, Liao CH, Huang YT, Wang HP, Hsueh PR. Severe and refractory Clostridium difficile infection successfully treated with tigecycline and metronidazole. Int J Antimicrob Agents 2010; 35:311-2; PMID:20045292; http://dx.doi.org/10.1016/j.ijantimicag.2009.11.008
  • 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; PMID:24590475; http://dx.doi.org/10.1128/AAC.02262-13
  • Kopterides P, Papageorgiou C, Antoniadou A, Papadomichelakis E, Tsangaris I, Dimopoulou I, Armaganidis A. Failure of tigecycline to treat severe Clostridium difficile infection. Anaesth Intensive Care 2010; 38:755-8; PMID:20715744
  • Freeman J, Baines SD, Wilcox MH. Comparison of the efficacy of ramoplanin vs vancomycin in both in vitro and in vivo models of clindamycin-induced Clostridium difficile infection. J Antimicrob Chemother 2005; 56:717-25; PMID:16143709; http://dx.doi.org/10.1093/jac/dki321
  • Fulco P, Wenzel RP. Ramoplanin: a topical lipoglycodepsipeptide antibacterial agent. Expert Rev Anti Infect Ther 2006; 4:939-45; PMID:17181409; http://dx.doi.org/10.1586/14787210.4.6.939
  • Jabes D, Candiani C, Riva S, Mosconi G. Superior efficacy of short treatment duration of ramoplanin over vancomycin in the hamster model of C. difficile-associated colitis, abstr. B-328. Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother 2003; American Society for Microbiology, Washington, DC
  • Pullman J, Prieto J, Leach TS. Ramoplanin vs. vancomycin in the treatment of Clostridium difficile diarrhea: A Phase II study (abstract). Presented at: 44th Interscience Conference Antimicrob Agents Chemother 2004.
  • Cotter PD, Hill C, Ross RP. Bacteriocins: developing innnate immunity for food. Nat Rev Microbiol 2005; 3:777-88; PMID:16205711; http://dx.doi.org/10.1038/nrmicro1273
  • Rea MC, Dobson A, O'Sullivan O, Crispie F, Fouhy F, Cotter PD, Shanahan F, Kiely B, Hill C, Ross RP. Effect of broad- and narrow-spectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon. Proc Natl Acad Sci U S A 2011; 108:4639-44; PMID:20616009; http://dx.doi.org/10.1073/pnas.1001224107
  • Field D, Quigley L, O'Connor PM, Rea MC, Daly K, Cotter PD, Hill C, Ross RP. Studies with bioengineered nisin peptides highlight the broad-spectrum potency of nisin V. Microb Biotechnol 2010; 3:473-86; PMID:21255345; http://dx.doi.org/10.1111/j.1751-7915.2010.00184.x
  • Rea MC, Clayton E, O'Connor PM, Shanahan F, Kiely B, Ross RP, Hill C. Antimicrobial activity of lacticin 3147 against clinical Clostridium difficile strains. J Med Microbiol 2007; 56:940-6; PMID:17577060; http://dx.doi.org/10.1099/jmm.0.47085-0
  • 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; PMID:22526797; http://dx.doi.org/10.1007/s00253-012-4041-0
  • 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; PMID:22966180; http://dx.doi.org/10.1093/jac/dks359
  • Selva E, Beretta G, Montanini N, Saddler GS, Gastaldo L, Ferrari P, Lorenzetti R, Landini P, Ripamonti F, Goldstein BP et al. Antibiotic GE2270 a: a novel inhibitor of bacterial protein synthesis. Isolation and characterization. J Antibiot (Tokyo) 1991; 44:693-701; PMID:1908853; http://dx.doi.org/10.7164/antibiotics.44.693
  • LaMarche MJ, Leeds JA, Amaral A, Brewer JT, Bushell SM, Deng G, Dewhurst JM, Ding J, Dzink-Fox J, Gamber G, Jain A et al. Discovery of LFF571: an investigational agent for Clostridium difficile infection. J Med Chem 2012; 55:2376-87; PMID:22315981; http://dx.doi.org/10.1021/jm201685h
  • 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; PMID:22644020; http://dx.doi.org/10.1128/AAC.06355-11
  • Ting LS, Praestgaard J, Grunenberg N, Yang JC, Leeds JA, Pertel P. A first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study to assess the safety and tolerability of LFF571 in healthy volunteers. Antimicrob Agents Chemother 2012; 56:5946-51; PMID:22964250; http://dx.doi.org/10.1128/AAC.00867-12
  • Ackermann G, Löffler B, Adler D, Rodloff. In vitro activity of OPT-80 against Clostridium difficile. Antimicrob Agents Chemother 2004; 48:2280-2; PMID:15155234; http://dx.doi.org/10.1128/AAC.48.6.2280-2282.2004
  • Credito K, Appelbaum P. Activity of OPT-80, a novel macrocycle, compared with those of eight other agents against selected anaerobic species. Antimicrob Agents Chemother 2004; 48:4430-4; PMID:15504874; http://dx.doi.org/10.1128/AAC.48.11.4430-4434.2004
  • Finegold S, Molitoris D, Vaisanen M, Song Y, Liu C, Bolanos M. In vitro activities of OPT-80 and comparator drugs against intestinal bacteria. Antimicrob Agents Chemother 2004; 48:4898-902; PMID:15561877; http://dx.doi.org/10.1128/AAC.48.12.4898-4902.2004
  • Anton PM, O'Brien M, Kokkotou E, Eisenstein B, Michaelis A, Rothstein D, Paraschos S, Kelly CP, Pothoulakis C. Rifalazil treats and prevents relapse of Clostridium difficile-associated diarrhea in hamsters. Antimicrob Agents Chemother 2004; 48:3975-9; PMID:15388461; http://dx.doi.org/10.1128/AAC.48.10.3975-3979.2004
  • McVay CS, Rolfe RD. In vitro and in vivo activities of nitazoxanide against Clostridium difficile. Antimicrob Agents Chemother 2000; 44:2254-8; PMID:10952564; http://dx.doi.org/10.1128/AAC.44.9.2254-2258.2000
  • Edlund C, Sabouri S, Nord CE. Comparative in vitro activity of BAY 12-8039 and five other antimicrobial agents against anaerobic bacteria. Eur J Clin Microbiol Infect Dis 1998; 17:193-5; PMID:9665302; http://dx.doi.org/10.1007/BF01691117
  • Betriu C, Rodriguez-Avial I, Sanchez BA, Gomez M, Alvarez J, Picazo J. In vitro activities of tigecycline (GAR-936) against recently isolated clinical bacteria in Spain. Antimicrob Agents Chemother 2002; 46:892-5; PMID:11850282; http://dx.doi.org/10.1128/AAC.46.3.892-895.2002
  • Peláez T, Alcalá L, Alonso R, Martín-López A, García-Arias V, Marín M, Bouza E. 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; http://dx.doi.org/10.1128/AAC.49.3.1157-1159.2005
  • 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; PMID:23571539; http://dx.doi.org/10.1128/AAC.00261-13
  • Citron DM, Tyrrell KL, Merriam CV, Goldstein EJ. 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; PMID:22290948; http://dx.doi.org/10.1128/AAC.06305-11
  • Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003; 36:580-5; PMID:12594638; http://dx.doi.org/10.1086/367657
  • Bakken JS, Borody T, Brandt LJ, Brill JV, Demarco DC, Franzos MA, Kelly C, Khoruts A, Louie T, Martinelli LP, Moore TA et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011; 9:1044-9; PMID:21871249; http://dx.doi.org/10.1016/j.cgh.2011.08.014
  • Rohlke F, Stollman N. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Therap Adv Gastroenterol 2012; 5:403-20; PMID:23152734; http://dx.doi.org/10.1177/1756283X12453637
  • Russell G, Kaplan J, Ferraro M, Michelow IC. Fecal bacteriotherapy for relapsing Clostridium difficile infection in a child: a proposed treatment protocol. Pediatrics 2010; 126:e239-42; PMID:20547640; http://dx.doi.org/10.1542/peds.2009-3363
  • Cramer JP, Burchard GD, Lohse AW. Old dogmas and new perspectives in antibiotic-associated diarrhea. Med Klin (Munich) 2008; 103:325-38; PMID:18484219; http://dx.doi.org/10.1007/s00063-008-1040-0
  • Yoon SS, Brandt LJ. Treatment of refractoryrecurrent C. difficile-associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol 2010; 44:562-6; PMID:20463588; http://dx.doi.org/10.1097/MCG.0b013e3181dac035
  • Shahinas D, Silverman M, Sittler T, Chiu C, Kim P, Allen-Vercoe E, Weese S, Wong A, Low DE, Pillai DR. Toward an understanding of changes in diversity associated with fecal microbiome transplantation based on 16S rRNA gene deep sequencing. Mbio 2012; 3:e00338-12; PMID:23093385; http://dx.doi.org/10.1128/mBio.00338-12
  • Hamilton MJ, Weingarden AR, Unno T, Khoruts A, Sadowsky MJ. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes 2013; 4:125-35; PMID:23333862; http://dx.doi.org/10.4161/gmic.23571
  • van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013; 368:407-15; PMID:23323867; http://dx.doi.org/10.1056/NEJMoa1205037
  • Petrof E, Gloor G, Vanner S, Weese S, Carter D, Daigneault M, Brown E, Schroeter K, Allen-Vercoe E. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut. Microbiome 2013; 1:3; PMID:24467987; http://dx.doi.org/10.1186/2049-2618-1-3
  • Emanuelsson F, Claesson BE, Ljungström L, Tvede M, Ung KA. Faecal microbiota transplantation and bacteriotherapy for recurrent Clostridium difficile infection: a retrospective evaluation of 31 patients. Scand J Infect Dis 2014; 46:89-97; PMID:24354958; http://dx.doi.org/10.3109/00365548.2013.858181
  • Fuentes S, van Nood E, Tims S, Heikamp-de Jong I, Ter Braak CJ, Keller JJ, Zoetendal EG, de Vos WM. Reset of a critically disturbed microbial ecosystem: faecal transplant in recurrent Clostridium difficile infection. ISME J 2014; 8:1621-33; PMID:24577353; http:; http://dx.doi.org/10.1038/ismej.2014.13
  • Weingarden AR, Chen C, Bobr A, Yao D, Lu Y, Nelson VM, Sadowsky MJ, Khoruts A. Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection. Am J Physiol Gastrointest Liver Physiol 2014; 306:G310-9; PMID:24284963; http://dx.doi.org/10.1152/ajpgi.00282.2013
  • Lawley TD, Clare S, Walker AW, Stares MD, Connor TR, Raisen C, Goulding D, Rad R, Schreiber F, Brandt C, Deakin LJ et al. Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. PLoS Pathog 2012; 8:e1002995; PMID:23133377; http://dx.doi.org/10.1371/journal.ppat.1002995
  • Zipursky TI, Sidorsky CA, Freedman MN, Sidorsky KB. Kirkland. Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. Clin Infect Dis 2012; 55:1652-8; PMID:22990849; http://dx.doi.org/10.1093/cid/cis809
  • Torres JF, Lyerly DM, Hill JE, Monath TP. Evaluation of formalin-inactivated Clostridium difficile vaccines administered by parenteral and mucosal routes of immunization in hamsters. Infect Immun 1995; 12:4619-27
  • Giannasca PJ, Zhang ZX, Lei WD, Boden JA, Giel MA, Monath TP, Thomas WD Jr. Serum antitoxin antibodies mediate systemic and mucosal protection from Clostridium difficile disease in hamsters. Infect Immun 1999; 2:527-38
  • Siddiqui F, O'Connor JR, Nagaro K, Cheknis A, Sambol SP, Vedantam G, Gerding DN, Johnson S. Vaccination with parenteral toxoid B protects hamsters against lethal challenge with toxin A-negative, toxin B-positive Clostridium difficile but does not prevent colonization. J Infect Dis 2012; 205:128-33; PMID:22124129; http://dx.doi.org/10.1093/infdis/jir688
  • Sougioultzis S, Kyne L, Drudy D, Keates S, Maroo S, Pothoulakis C, Giannasca PJ, Lee CK, Warny M, Monath TP, et al. Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea. Gastroenterology 2005; 128:764-70; PMID:15765411; http://dx.doi.org/10.1053/j.gastro.2004.11.004
  • Anosova NG, Brown AM, Li L, Liu N, Cole LE, Zhang J, Mehta H, Kleanthous H. Systemic antibody responses induced by a two-component Clostridium difficile toxoid vaccine protect against C. difficile-associated disease in hamsters. J Med Microbiol 2013; 62:1394-404; PMID:23518659; http://dx.doi.org/10.1099/jmm.0.056796-0
  • Karczewski J, Zorman J, Wang S, Miezeiewski M, Xie J, Soring K, Petrescu I, Rogers I, Thiriot DS, Cook JC, et al. Development of a recombinant toxin fragment vaccine for Clostridium difficile infection. Vaccine 2014; 32:2812-8; PMID:24662701; http://dx.doi.org/10.1016/j.vaccine.2014.02.026
  • Spencer J, Leuzzi R, Buckley A, Irvine J, Candlish D, Scarselli M, Douce GR. Vaccination against Clostridium difficile using toxin fragments: Observations and analysis in animal models. Gut Microbes 2014; 5:225-32; PMID:24637800; http://dx.doi.org/10.4161/gmic.27712
  • Gerding DN. Clostridium difficile infection prevention: biotherapeutics, immunologics, and vaccines. Discov Med 2012; 13:75-83; PMID:22284786
  • Ghose C, Verhagen JM, Chen X, Yu J, Huang Y, Chenesseau O, Kelly CP, Ho DD. Toll-like receptor 5-dependent immunogenicity and protective efficacy of a recombinant fusion protein vaccine containing the nontoxic domains of Clostridium difficile toxins A and B and Salmonella enterica serovar typhimurium flagellin in a mouse model of Clostridium difficile disease. Infect Immun 2013; 81:2190-6; PMID:23545305; http://dx.doi.org/10.1128/IAI.01074-12
  • Donald RG, Flint M, Kalyan N, Johnson E, Witko SE, Kotash C, Zhao P, Megati S, Yurgelonis I, Lee PK, et al. A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile. Microbiology 2013;159:1254-66; PMID:23629868; http://dx.doi.org/10.1099/mic.0.066712-0
  • Wang H, Sun X, Zhang Y, Li S, Chen K, Shi L, Nie W, Kumar R, Tzipori S, Wang J, et al. A chimeric toxin vaccine protects against primary and recurrent Clostridium difficile infection. Infect Immun 2012; 80:2678-88; PMID:22615245; http://dx.doi.org/10.1128/IAI.00215-12
  • Bertolo L, Boncheff AG, Ma Z, Chen YH, Wakeford T, Friendship RM, Rosseau J, Weese JS, Chu M, Mallozzi M, 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; 354:79-86; PMID:22533919; http://dx.doi.org/10.1016/j.carres.2012.03.032
  • Jiao Y, Ma Z, Hodgins D, Pequegnat B, Bertolo L, Arroyo L, Monteiro MA. Clostridium difficile PSI polysaccharide: synthesis of pentasaccharide repeating block, conjugation to exotoxin B subunit, and detection of natural anti-PSI IgG antibodies in horse serum. Carbohydr Res 2013; 378:15-25; PMID:23597587; http://dx.doi.org/10.1016/j.carres.2013.03.018
  • Adamo R, Romano MR, Berti F, Leuzzi R, Tontini M, Danieli E, Cappelletti E, Cakici OS, Swennen E, Pinto V, et al. Phosphorylation of the synthetic hexasaccharide repeating unit is essential for the induction of antibodies to Clostridium difficile PSII cell wall polysaccharide. ACS Chem Biol; 7:1420-8; PMID:22620974; http://dx.doi.org/10.1021/cb300221f
  • Bertolo L, Boncheff AG, Ma Z, Chen YH, Wakeford T, Friendship RM, Rosseau J, Weese JS, Chu M, Mallozzi M, 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;354:79-86; PMID:22533919; http://dx.doi.org/10.1016/j.carres.2012.03.032
  • Ganeshapillai J, Vinogradov E, Rousseau J, Weese JS, Monteiro MA. Clostridium difficile cell-surface polysaccharides composed of pentaglycosyl and hexaglycosyl phosphate repeating units. Carbohydr Res 2008;343:703-10; PMID:18237724; http://dx.doi.org/10.1016/j.carres.2008.01.002
  • Monteiro MA, Ma Z, Bertolo L, Jiao Y, Arroyo L, Hodgins D, Mallozzi M, Vedantam G, Sagermann M, Sundsmo J, Chow H. Carbohydrate-based Clostridium difficile vaccines. Expert Rev Vaccines 2013; 12:421-31; PMID:23560922; http://dx.doi.org/10.1586/erv.13.9
  • Martin CE, Broecker F, Oberli MA, Komor J, Mattner J, Anish C, Seeberger PH. 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; PMID:23795894; http://dx.doi.org/10.1021/ja401410y
  • Romano MR, Leuzzi R, Cappelletti E, Tontini M, Nilo A, Proietti D, Berti F, Costantino P, Adamo R, Scarselli M. Recombinant Clostridium difficile toxin fragments as carrier protein for PSII surface polysaccharide preserve their neutralizing activity. Toxins (Basel) 2014; 6:1385-96; PMID:24759173
  • Cox AD, St Michael F, Aubry A, Cairns CM, Strong PC, Hayes AC, Logan SM. Investigating the candidacy of a lipoteichoic acid-based glycoconjugate as a vaccine to combat Clostridium difficile infection. Glycoconj J 2013; 30:843-55; PMID:23974722; http://dx.doi.org/10.1007/s10719-013-9489-3
  • 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; PMID:21609839; http://dx.doi.org/10.1016/j.chembiol.2011.03.009
  • Baliban SM, Michael A, Shammassian B, Mudakha S, Khan AS, Cocklin S, Zetner I, Latimer BP, Bouillaut L, Hunter M, 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; pii:IAI.01950-14
  • 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; PMID:19464540; http://dx.doi.org/10.1016/j.vaccine.2009.03.058
  • 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 Vaccin Immunother 2013; 9:63-73; PMID:23143772; http://dx.doi.org/10.4161/hv.22434
  • Seregin SS, Aldhamen YA, Rastall DP, Godbehere S, Amalfitano A. Adenovirus-based vaccination against Clostridium difficile toxin A allows for rapid humoral immunity and complete protection from toxin A lethal challenge in mice. Vaccine 2012; 30:1492-501; PMID:22200503; http://dx.doi.org/10.1016/j.vaccine.2011.12.064

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.