Drugs

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Bezlotoxumab: A Review in Preventing Clostridium difficile Infection Recurrence

Adis Drug Evaluation

Abstract

Bezlotoxumab (Zinplava™) is a fully human monoclonal antibody against Clostridium difficile toxin B indicated for the prevention of C. difficile infection (CDI) recurrence in patients with a high recurrence risk. It is the first agent approved for recurrence prevention and is administered as a single intravenous infusion in conjunction with standard-of-care (SoC) antibacterial treatment for CDI. In well-designed, placebo-controlled, phase 3 trials (MODIFY 1 and 2), a single infusion of bezlotoxumab, given in combination with SoC antibacterial therapy for CDI in adults, was effective in reducing CDI recurrence in the 12 weeks post-treatment, with this benefit being seen mainly in the patients at high recurrence risk. Bezlotoxumab did not impact the efficacy of the antibacterials being used to treat the CDI and, consistent with its benefits on CDI recurrence, appeared to reduce the need for subsequent antibacterials, thus minimizing further gut microbiota disruption. Longer term, there were no further CDI recurrences over 12 months’ follow-up among patients who had received bezlotoxumab in MODIFY 2 and entered an extension substudy. Bezlotoxumab has low immunogenicity and is generally well tolerated, although the potential for heart failure in some patients requires consideration; cost-effectiveness data for bezlotoxumab are awaited with interest. Thus, a single intravenous infusion of bezlotoxumab during SoC antibacterial treatment for CDI is an emerging option for reducing CDI recurrence in adults at high risk of recurrence.

References

  1. 1.
    Smits WK, Lyras D, Lacy DB, et al. Clostridium difficile infection. Nat Rev Dis Prim. 2016;. doi:10.1038/nrdp.2016.20.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108(4):478–98.CrossRefPubMedGoogle Scholar
  3. 3.
    Hussack G, Tanha J. An update on antibody-based immunotherapies for Clostridium difficile infection. Clin Exp Gastroenterol. 2016;9:209–24.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
  5. 5.
    Yakob L, Riley TV, Paterson DL, et al. Mechanisms of hypervirulent Clostridium difficile ribotype 027 displacement of endemic strains: an epidemiological model. Sci Rep. 2015;5:12666.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Cohen SH, Gerding DN, Johnson S, 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(5):431–55.CrossRefPubMedGoogle Scholar
  7. 7.
    Debast SB, Bauer MP, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014;20(Suppl 2):1–26.CrossRefPubMedGoogle Scholar
  8. 8.
    Shields K, Araujo-Castillo RV, Theethira TG, et al. Recurrent Clostridium difficile infection: from colonization to cure. Anaerobe. 2015;34:59–73.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Merck Sharp. Zinplava 25 mg/mL concentrate for solution for infusion: EU summary of product characteristics. 2017. http://www.ema.europa.eu/. Accessed 21 Aug 2017.
  10. 10.
    Merck Sharp. Zinplava™ (bezlotoxumab): US prescribing information. 2016. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed 21 Aug 2017.
  11. 11.
    Babcock GJ, Broering TJ, Hernandez HJ, et al. Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters. Infect Immun. 2006;74(11):6339–47.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Orth P, Xiao L, Hernandez LD, et al. Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem. 2014;289(26):18008–21.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hernandez LD, Racine F, Xiao L, et al. Broad coverage of genetically diverse strains of Clostridium difficile by actoxumab and bezlotoxumab predicted by in vitro neutralization and epitope modeling. Antimicrob Agents Chemother. 2015;59(2):1052–60.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Koon HW, Shih DQ, Hing TC, et al. Human monoclonal antibodies against Clostridium difficile toxins A and B inhibit inflammatory and histologic responses to the toxins in human colon and peripheral blood monocytes. Antimicrob Agents Chemother. 2013;57(7):3214–23.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zhang Z, Chen X, Hernandez LD, et al. Toxin-mediated paracellular transport of antitoxin antibodies facilitates protection against Clostridium difficile infection. Infect Immun. 2015;83(1):405–16.CrossRefPubMedGoogle Scholar
  16. 16.
    Steele J, Mukherjee J, Parry N, et al. Antibody against TcdB, but not TcdA, prevents development of gastrointestinal and systemic Clostridium difficile disease. J Infect Dis. 2013;207(2):323–30.CrossRefPubMedGoogle Scholar
  17. 17.
    Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376(4):305–17.CrossRefPubMedGoogle Scholar
  18. 18.
    European Medicines Agency. Assessment report: Zinplava (international non-proprietary name: bezlotoxumab). 2016. http://www.ema.europa.eu. Accessed 21 Aug 2017.
  19. 19.
    Merck Research Laboratories. Bezlotoxumab (MK-6072) FDA Antimicrobial Drugs Advisory Committee Meeting. 2016. https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm507577.pdf. Accessed 21 Aug 2017.
  20. 20.
    Golan Y, Birch T, Rizzardini G, et al. Efficacy of bezlotoxumab based on timing of administration relative to start of antibacterial therapy for C. difficile infection (CDI) [poster no. Saturday—213]. In: ASM Microbe Meeting; 2017.Google Scholar
  21. 21.
    Johnson S, Sambol S, Best E, et al. Efficacy of bezlotoxumab in patients infected with strains of Clostridium difficile associated with poor outcomes [abstract no. 2114]. Open Forum. Infect Dis. 2016;3(Suppl 1):S599.Google Scholar
  22. 22.
    Wilcox MH, Rahav G, Dubberke E, et al. Assessment of efficacy of bezlotoxumab for prevention of CDI recurrence (rCDI) by diagnostic test method [abstract no. P1341 plus poster]. In: ECCMID; 2016.Google Scholar
  23. 23.
    Golan Y, Dubberke E, Hanson ME, et al. Bezlotoxumab (BZO) decreases recurrence and is associated with a reduction in 30-day Clostridium difficile infection (CDI)-associated readmissions in hospitalized patients with CDI [abstract Monday-449 plus poster]. In: ASM Microbe Meeting; 2016.Google Scholar
  24. 24.
    Basu A, Prabhu VS, Marcella S, et al. Bezlotoxumab is associated with a reduction in cumulative hospitalized days: analysis of the hospitalization data from the modify I and II clinical trials [abstract no. 2E−2]. In: Society for Medical Decision Making16th Biennial European Conference; 2016.Google Scholar
  25. 25.
    Gerding DN, Kelly CP, Rahav G, et al. Efficacy of bezlotoxumab, the monoclonal antibody targeting C. difficile toxin B, for prevention of C. difficile infection (CDI) recurrence in patients at high risk of recurrence or CDI-related adverse outcomes [abstract no. EP0176]. In: ECCMID; 2016.Google Scholar
  26. 26.
    Goldstein E, Citron D, Gerding D, et al. Recurrent Clostridium difficile infection (rCDI) and colonization in the 12 months following administration of bezlotoxumab (BEZ) alone and in combination with actoxumab (ACT). In: ASM Microbe Meeting; 2016.Google Scholar
  27. 27.
    Dubberke ER, Gerding D, Kelly C, et al. Efficacy of bezlotoxumab in patients receiving metronidazole, vancomycin, or fidaxomicin for treatment of Clostridium difficile infection (CDI) [abstract no. 838]. Open Forum Infect Dis. 2016;3(suppl_1).Google Scholar
  28. 28.
    Lee C, Graham DR, Wilcox MH, et al. Bezlotoxumab for prevention of C. difficile infection (CDI) recurrence in participants receiving antibacterial therapy for CDI: use of antibacterial therapy for CDI and fecal microbiota transplant in the MODIFY trials [poster Sunday 244]. In: ASM Microbe Meeting; 2017.Google Scholar
  29. 29.
    Shah DN, Aitken SL, Barragan LF, et al. Economic burden of primary compared with recurrent Clostridium difficile infection in hospitalized patients: a prospective cohort study. J Hosp Infect. 2016;93(3):286–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.SpringerAucklandNew Zealand

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