Current Treatment Options in Infectious Diseases

, Volume 7, Issue 4, pp 317–334 | Cite as

Clostridium difficile Infection: Current and Emerging Therapeutics

  • Angie M. Jarrad
  • Mark A. T. Blaskovich
  • Dena Lyras
  • Matthew A. Cooper
Bacterial Infections and Drug Resistant Pathogens (H Wisplinghoff, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Bacterial Infections and Drug Resistant Pathogens

Opinion statement

Clostridium difficile infection (CDI) has been identified as a significant threat to human health in the twenty-first century. Patients with CDI experience diarrhea, gastrointestinal pain, and colonic inflammation that can be life-threatening. Antibiotic therapy is successful at treating the majority of patients with CDI, but an increased number of CDI cases over the last 15 years, including severe and recurrent disease, is problematic and must be addressed with a multifaceted approach. Cleaning and infection prevention protocols are necessary to eradicate C. difficile spores and minimize both disease transmission and recurrent infection. Appropriate antibiotic treatment with metronidazole, vancomycin, or fidaxomicin should be selected based on consideration of the disease severity, relative cost-benefit, and likelihood of treatment failure. When antibiotics fail, treatment of severe, recurrent CDI with fecal microbiota transplantation (FMT) may be justified. While caution is warranted due to the unknown long-term side effects of FMT, clinical evidence has shown excellent patient outcomes. However, difficulties associated with the lack of a standardized, FDA-approved prescription treatment must be overcome before FMT can be considered a mainstay treatment. Surgery has a role for treatment of severe fulminant CDI which is not improving with medical management. Research and development is focused on preventing infections, improving patient outcomes, and reducing recurrent disease. C. difficile-specific antibiotics and biotherapeutic approaches such as vaccines and human monoclonal antibodies currently in phase III clinical trials offer hope for improved treatment options available in the near future.


Clostridium difficile Infection Treatment Fecal transplant Antibiotics Biologics Surgery Pediatric Antibiotic resistance Vancomycin Metronidazole Fidaxomicin Spore Microbiota 


Compliance with Ethics Guidelines

Conflict of Interest Angie Jarrad have no conflicts of interest. Mark Blaskovich have no conflicts of interest. Dena Lyras have no conflicts of interest. Matthew Cooper have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by the author.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Owens RC, Donskey CJ, Gaynes RP, Loo VG, Muto CA. Antimicrobial-associated risk factors for Clostridium difficile infection. Clin Infect Dis. 2008;46 Suppl 1:S19–31.CrossRefPubMedGoogle Scholar
  2. 2.•
    Antibiotic Resistance Threats in the United States, 2013 [Internet]. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2013 pp. 1–114. Available from: An excellent resource highlighting the threat of antimicrobial resistance.
  3. 3.
    Warny M, Pepin J, Fang A, Killgore G, Thompson A, Brazier J, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet. 2005;366:1079–84.CrossRefPubMedGoogle Scholar
  4. 4.•
    Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA. 2015;313:398–408. A recent guideline to the diagnosis and treatment of CDI.CrossRefPubMedGoogle Scholar
  5. 5.
    Doan L, Forrest H, Fakis A, Craig J, Claxton L, Khare M. Clinical and cost effectiveness of eight disinfection methods for terminal disinfection of hospital isolation rooms contaminated with Clostridium difficile 027. J Hosp Infect. 2012;82:114–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Sunkesula VCK, Kundrapu S, Jury LA, Deshpande A, Sethi AK, Donskey CJ. Potential for transmission of spores by patients awaiting laboratory testing to confirm suspected Clostridium difficile infection. Infection Control and Hospital Epidemiology. University of Chicago Press Chicago, IL; 2013;34:306–8.Google Scholar
  7. 7.
    Babakhani F, Bouillaut L, Gomez A, Sears P, Nguyen L, Sonenshein AL. Fidaxomicin inhibits spore production in Clostridium difficile. Clin Infect Dis. 2012;55 Suppl 2:S162–9.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Bouillaut L, McBride S, Sorg JA, Schmidt DJ, Suárez JM, Tzipori S, et al. Effects of surotomycin on Clostridium difficile viability and toxin production in vitro. Antimicrob Agents Chemother Am Soc Microbiol. 2015;59:4199–205.CrossRefGoogle Scholar
  9. 9.•
    Louie TJ, Cannon K, Byrne B, Emery J, Ward L, Eyben M, et al. 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:S132–42. A study examining the potential advantages of fidaxomicin over existing therapies.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Jarrad AM, Karoli T, Blaskovich MAT, Lyras D, Cooper MA. Clostridium difficile drug pipeline: challenges in discovery and development of new agents. J Med Chem. 2015;58:5164–85.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Wilcox MH. Updated guidance on the management and treatment of Clostridium difficile infection. Public Health England; 2013. pp. 1–29.Google Scholar
  12. 12.
    Edwards DI. Nitroimidazole drugs—action and resistance mechanisms. II. Mechanisms of resistance. J Antimicrob Chemother. 1993;31:201–10.CrossRefPubMedGoogle Scholar
  13. 13.
    Bolton RP, Culshaw MA. Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile. Gut. 1986;27:1169–72.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    Debast SB, Bauer MP, Kuijper EJ. European society of clinical microbiology of infectious diseases. European society of clinical microbiology and infectious diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014;20:1–28.CrossRefPubMedGoogle Scholar
  16. 16.
    Product Information Flagyl. Sanofi-aventis Australia pty ltd; 2012 Mar.Google Scholar
  17. 17.•
    Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478–98. Recommendations on CDI diagnosis, management, prevention and control of disease outbreaks to supplement the Infectious Disease Society of America (IDSA)/Society of Hospital Epidemiologists of America (SHEA) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines.CrossRefPubMedGoogle Scholar
  18. 18.
    Al-Nassir WN, Sethi AK, Li Y, Pultz MJ, Riggs MM, Donskey CJ. Both oral metronidazole and oral vancomycin promote persistent overgrowth of vancomycin-resistant enterococci during treatment of Clostridium difficile-associated disease. Antimicrob Agents Chemother. 2008;52:2403–6.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Lynch T, Chong P, Zhang J, Hizon R, Du T, Graham MR, et al. Characterization of a stable, metronidazole-resistant Clostridium difficile clinical isolate. PLoS One Public Library Sci. 2013;8, e53757.CrossRefGoogle Scholar
  20. 20.
    Peláez T, Cercenado E, Alcalá L, Marín M, Martín-López A, Martínez-Alarcón J, et al. Metronidazole resistance in Clostridium difficile is heterogeneous. J Clin Microbiol. 2008;46:3028–32.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    ViroPharma Incorporated. Vancocin (vancomycin hydrochloride, USP) Capsules [Internet]. 2011. pp. 1–13. Available from:
  22. 22.
    Baxter International Inc. Vancomycin hydrochloride (vancomycin hydrochloride) Injection, Solution [Internet]. 2007. pp. 1–14. Available from:
  23. 23.
    Product information Vancocin Capsules. Aspen Pharmacare Australia Pty Ltd; 2009 Mar pp. 1–6.Google Scholar
  24. 24.
    Cubist Pharmaceuticals Canada, Inc. Product Monograph: PrDIFICID. 2014 Jun pp. 1–31.Google Scholar
  25. 25.
    Iarikov DE, Alexander J, Nambiar S. Hypersensitivity reactions associated with fidaxomicin use. Clin Infect Dis. 2014;58:537–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Does fidaxomicin therapy reduce spread of Clostridium difficile? NCT02461901 [Internet]. [cited 2015 Jun 5]. Available from:
  27. 27.
    Nathwani D, Cornely OA, Van Engen AK, Odufowora-Sita O, Retsa P, Odeyemi IAO. Cost-effectiveness analysis of fidaxomicin versus vancomycin in Clostridium difficile infection. J Antimicrob Chemother. 2014;69:2901–12.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Stranges PM, Hutton DW, Collins CD. Cost-effectiveness analysis evaluating fidaxomicin versus oral vancomycin for the treatment of Clostridium difficile infection in the United States. Value Health. 2013;16:297–304.CrossRefPubMedGoogle Scholar
  29. 29.
    Simon MS. Cost-effectiveness of fidaxomicin for Clostridium difficile treatment. Clin Infect Dis. 2014;58:603–3.CrossRefPubMedGoogle Scholar
  30. 30.
    Venugopal AA, Johnson S. Current state of Clostridium difficile treatment options. Clin Infect Dis. 2012;55 Suppl 2:S71–6.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Drekonja DM. Clostridium difficile infection: current, forgotten and emerging treatment options. J Comp Eff Res. 2014;3:547–57.CrossRefPubMedGoogle Scholar
  32. 32.
    Goldstein EJC, Johnson S, Maziade P-J, McFarland LV, Trick W, Dresser L, et al. Pathway to prevention of nosocomial Clostridium difficile infection. Clin Infect Dis Oxford Univ Press. 2015;60:S148–58.CrossRefGoogle Scholar
  33. 33.
    Rebmann T, Carrico RM, Association for Professionals in Infection Control and Epidemiology. Preventing Clostridium difficile infections: an executive summary of the Association for Professionals in Infection Control and Epidemiology’s elimination guide. Am J Infect Control. 2011. pp. 239–42.Google Scholar
  34. 34.
    Gao XW, Mubasher M, Fang CY, Reifer C, Miller LE. Dose–response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus Cl1285 and Lactobacillus casei Lbc80r for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients. Am J Gastroenterol. 2010;105:1636–41.CrossRefPubMedGoogle Scholar
  35. 35.
    Bio-K. Bio-K+ | Probiotic product | Canada [Internet]. 2015 [cited 2015 Jul 23]. Available from:
  36. 36.
    Kamdeu Fansi AA, Guertin JR, LeLorier J. Savings from the use of a probiotic formula in the prophylaxis of antibiotic-associated diarrhea. J Med Econ. 2012;15:53–60.CrossRefPubMedGoogle Scholar
  37. 37.
    Allegretti JR, Korzenik JR, Hamilton MJ. Fecal microbiota transplantation via colonoscopy for recurrent C. difficile infection. J. Visualized Exp. 2014;94:e52154–4.Google Scholar
  38. 38.
    Satokari R, Mattila E, Kainulainen V, Arkkila PET. Simple faecal preparation and efficacy of frozen inoculum in faecal microbiota transplantation for recurrent Clostridium difficile infection—an observational cohort study. Aliment Pharmacol Ther. 2014;41:46–53.CrossRefPubMedGoogle Scholar
  39. 39.
    Tauxe WM, Dhere T, Ward A, Racsa LD, Varkey JB, Kraft CS. Fecal microbiota transplant protocol for Clostridium difficile infection. Lab Med Am Soc Clin Pathol. 2015;46:e19–23.Google Scholar
  40. 40.
    Drekonja D, Reich J, Gezahegn S, Greer N, Shaukat A, MacDonald R, et al. Fecal microbiota Transplantation for Clostridium difficile infection: a systematic review of the evidence. VA ESP; 2014 pp. 1–85. Project: #09-009.Google Scholar
  41. 41.
    Rao K, Young VB. Fecal microbiota transplantation for the management of Clostridium difficile infection. Infect Dis Clinics NA. 2015;29:109–22.CrossRefGoogle Scholar
  42. 42.
    Postigo R, Kim JH. Colonoscopic versus nasogastric fecal transplantation for the treatment of Clostridium difficile infection: a review and pooled analysis. Inf Springer-Verlag. 2012;40:643–8.Google Scholar
  43. 43.
    Di Bella S, Gouliouris T, Petrosillo N. Fecal microbiota transplantation (FMT) for Clostridium difficile infection: focus on immunocompromised patients. J Infect Chemother. 2015;21:230–7.CrossRefPubMedGoogle Scholar
  44. 44.••
    Van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–15. A randomised trial demonstrating significantly better results for treatment of CDI using FMT compared to vancomycin therapy.CrossRefPubMedGoogle Scholar
  45. 45.
    Alang N, Kelly CR. Weight gain after fecal microbiota transplantation. Open Forum Inf Dis. 2015;2, ofv004–4.Google Scholar
  46. 46.
    Ratner M. Fecal transplantation poses dilemma for FDA. Nat Biotechnol. 2014;32:401–2.CrossRefPubMedGoogle Scholar
  47. 47.
    Kelly CR, Kunde SS, Khoruts A. Guidance on preparing an investigational new drug application for fecal microbiota transplantation studies. Clin Gastroenterol Hepatol Elsevier Inc. 2014;12:283–8.CrossRefGoogle Scholar
  48. 48.
    Kaiser AM, Hogen R, Bordeianou L, Alavi K, Wise PE, Sudan R, et al. Clostridium difficile infection from a surgical perspective. J Gastrointest Surg. 2015;19:1363–77.CrossRefPubMedGoogle Scholar
  49. 49.
    Costello SP, Chung A, Andrews JM, Fraser RJ. Fecal microbiota transplant for Clostridium difficile colitis–induced toxic megacolon. Am J Gastroenterol. 2015;110:775–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Gweon T-G, Lee KJ, Kang DH, Park SS, Kim KH, Seong HJ, et al. A case of toxic megacolon caused by Clostridium difficile infection and treated with fecal microbiota transplantation. Gut Liver. 2015;9:247–50.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Yu S, Abdelkarim A, Nawras A, Hinch BT, Mbaso C, Valavoor S, et al. Fecal transplant for treatment of toxic megacolon associated with Clostridium difficile colitis in a patient with Duchenne muscular dystrophy. Am J Ther. 2014. doi: 10.1097/MJT.0000000000000062.Google Scholar
  52. 52.
    Hall JF, Berger D. Outcome of colectomy for Clostridium difficile colitis: a plea for early surgical management. Am J Surg. 2008;196:384–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Jaber MR, Olafsson S, Fung WL, Reeves ME. Clinical review of the management of fulminant Clostridium difficile infection. Am J Gastroenterol. 2008;103:3195–203.CrossRefPubMedGoogle Scholar
  54. 54.•
    Neal MD, Alverdy JC, Hall DE, Simmons RL, Zuckerbraun BS. Diverting loop ileostomy and colonic lavage. Ann Surg. 2011;254:423–9. A description of the diverting loop ileostomy procedure as an alternative to total abdominal colectomy for surgical treatment of CDI.CrossRefPubMedGoogle Scholar
  55. 55.
    Villano SA, Seiberling M, Tatarowicz W, Monnot-Chase E, Gerding DN. Evaluation of an oral suspension of VP20621, spores of nontoxigenic Clostridium difficile strain M3, in healthy subjects. Antimicrob Agents Chemother. 2012;56:5224–9.PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Maziade PJ, Andriessen JA, Pereira P, Currie B, Goldstein EJC. Impact of adding prophylactic probiotics to a bundle of standard preventative measures for Clostridium difficile infections: enhanced and sustained decrease in the incidence and severity of infection at a community hospital. Curr Med Res Opin. 2013;29:1341–7.CrossRefPubMedGoogle Scholar
  57. 57.
    Tracey K. Successful implementation of a phase 2 study of a novel microbiota-based drug for recurrent Clostridium difficile infection. Society of Gastroenterology Nurses and Associates. Baltimore; 2015. pp. 1–1.Google Scholar
  58. 58.•
    Faust SN, Wilcox MH, Banaszkiewicz A, Bouza E, Raymond J, Gerding DN. Lack of evidence for an unmet need to treat Clostridium difficile infection in infants aged <2 years: expert recommendations on how to address this issue. Clin Infect Dis Oxford Univ Press. 2015;60:912–8. Describes the lack of an unmet medical need for new treatments to treat CDI in infants <2 years.CrossRefGoogle Scholar
  59. 59.
    Kronman MP, Nielson HJ, Adler AL, Giefer MJ, Wahbeh G, Singh N, et al. Fecal microbiota transplantation via nasogastric tube for recurrent Clostridium difficile infection in pediatric patients. J Pediatr Gastroenterol Nutr. 2015;60:23–6.CrossRefPubMedGoogle Scholar
  60. 60.
    Lynch SV. Fecal microbiota transplantation for recurrent Clostridium difficile infection in pediatric patients. J Pediatr Gastroenterol Nutr. 2015;60:1–3.CrossRefPubMedGoogle Scholar
  61. 61.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  62. 62.••
    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. A key paper demonstrating the successful use of oral capsulized frozen fecal administration to treat CDI.CrossRefPubMedGoogle Scholar
  63. 63.
    Hirsch BE, Saraiya N, Poeth K, Schwartz RM, Epstein ME, & Honig G. Effectiveness of fecal-derived microbiota transfer using orally administered capsules for recurrent Clostridium difficile infection. BMC Infectious Diseases. 2015;15:191. doi: 10.1186/s12879-015-0930-z.
  64. 64.
    Jorup-Rönström C, Håkanson A, Sandell S, Edvinsson O, Midtvedt T, Persson A-K, et al. Fecal transplant against relapsing Clostridium difficile-associated diarrhea in 32 patients. Scand J Gastroenterol. 2012;47:548–52.CrossRefPubMedGoogle Scholar
  65. 65.
    Norin E. Experience with cultivated microbiota transplant: ongoing treatment of Clostridium difficile patients in Sweden. Microbial Ecol Health Dis. 2015;26:1–2.Google Scholar
  66. 66.••
    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. 2013;1:3. A report of successful use of a defined artificial substitute mixture of bacteria to treat CDI.Google Scholar
  67. 67.
    Cadazolid [Internet]. Actelion Pharmaceuticals Ltd. 2015 [cited 2015 Jun 5]. Available from:
  68. 68.
    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.CrossRefPubMedGoogle Scholar
  69. 69.
    Study of CB-183,315 in patients with Clostridium difficile associated diarrhea. NCT01597505 [Internet]. [cited 2015 Jun 5]. Available from:
  70. 70.
    Patino H, Stevens C, Louie T, Bernardo P, Friedland I, Cubist Pharmaceuticals. Efficacy and safety of the lipopeptide CB-183,315 for the treatment of Clostridium difficile infection. ICAAC. Chicago; 2011.Google Scholar
  71. 71.
    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. [Internet]. [cited 2013 Mar 20]. Available from:
  72. 72.
    Lowy I, Molrine DC, Leav BA, Blair BM, Baxter R, Nichol G, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med. 2010;362:197–205.CrossRefPubMedGoogle Scholar
  73. 73.
    Vaccines for tomorrow, Sanofi Pasteur, vaccine research and innovation, vaccine development | R & D [Internet]. [cited 2015 Jun 5]. Available from:
  74. 74.
    Ivarsson ME, Leroux J-C, Castagner B. Investigational new treatments for Clostridium difficile infection. Drug Discov Today. 2015;20:602–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Angie M. Jarrad
    • 1
  • Mark A. T. Blaskovich
    • 1
  • Dena Lyras
    • 2
  • Matthew A. Cooper
    • 1
  1. 1.The Institute for Molecular BioscienceThe University of QueenslandSt LuciaAustralia
  2. 2.School of Biomedical Sciences, Monash UniversityThe University of QueenslandClaytonAustralia

Personalised recommendations