Actoxumab + bezlotoxumab combination: what promise for Clostridium difficile treatment?

References

• Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014;370:1198–1208.
   PubMed Web of Science ®Google Scholar
• Freedberg DE, Salmasian H, Cohen B, et al. Receipt of antibiotics in hospitalized patients and risk for Clostridium difficile infection in subsequent patients who occupy the same bed. JAMA Intern Med. 2016;176:1801–1808. Epub 2017/ 12/01.
   PubMed Web of Science ®Google Scholar
• McCollum DL, Rodriguez JM. Detection, treatment, and prevention of Clostridium difficile infection. Clin Gastroenterol Hepatol. 2012;10:581–592. Epub 2012/ 03/17.
   PubMed Web of Science ®Google Scholar
• Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372:825–834.
   PubMed Web of Science ®Google Scholar
• Warny M, Pépin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet. 2005;366:1079–1084.
   PubMed Web of Science ®Google Scholar
• Pépin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. 2005;41:1254–1260. Epub 2005/ 09/20.
   PubMed Web of Science ®Google Scholar
• See I, Mu Y, Cohen J, et al. NAP1 strain type predicts outcomes from Clostridium difficile infection. Clin Infect Dis. 2014;58:1394–1400. Epub 2014/ 03/05.
   PubMed Web of Science ®Google Scholar
• Valiente E, Cairns MD, Wren BW. The Clostridium difficile PCR ribotype 027 lineage: a pathogen on the move. Clin Microbiol Infect. 2014;20:396–404. Epub 2014/ 04/28.
   PubMed Web of Science ®Google Scholar
• Stabler RA, He M, Dawson L, et al. Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium. Genome Biol. 2009;10:R102. Epub 2009/ 09/25.
   PubMed Web of Science ®Google Scholar
• Dingle KE, Didelot X, Quan TP, et al. Effects of control interventions on Clostridium difficile infection in England: an observational study. Lancet Infect Dis. 2017;17:411–421. Epub 2017/ 01/25.
   PubMed Web of Science ®Google Scholar
• Shields K, Araujo-Castillo RV, Theethira TG, et al. Recurrent Clostridium difficile infection: from colonization to cure. Anaerobe. 2015;34:59–73. Epub 2015/ 04/27.
   PubMed Web of Science ®Google Scholar
• Sheitoyan-Pesant C, Abou Chakra CN, Pépin J, et al. Clinical and healthcare burden of multiple recurrences of Clostridium difficile infection. Clin Infect Dis. 2016;62:574–580. Epub 2015/ 11/17.
   PubMed Web of Science ®Google Scholar
• Zanella Terrier MC, Simonet ML, Bichard P, et al. Recurrent Clostridium difficile infections: the importance of the intestinal microbiota. World J Gastroenterol. 2014;20:7416–7423.
   PubMed Web of Science ®Google Scholar
• Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol. 2009;7:526–536.
   PubMed Web of Science ®Google Scholar
• Theriot CM, Young VB. Interactions between the gastrointestinal microbiome and Clostridium difficile. Annu Rev Microbiol. 2015;69:445–461.
   PubMed Web of Science ®Google Scholar
• Buffie CG, Pamer EG. Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol. 2013;13:790–801.
   PubMed Web of Science ®Google Scholar
• Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother. 2014;69: 881–891. Epub 2013/ 12/08.
   PubMed Web of Science ®Google Scholar
• Freedberg DE, Salmasian H, Friedman C, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection among inpatients. Am J Gastroenterol. 2013;108:1794–1801. Epub 2013/ 09/24.
   PubMed Web of Science ®Google Scholar
• Tariq R, Singh S, Gupta A, et al. Association of gastric acid suppression with recurrent Clostridium difficile infection: a systematic review and meta-analysis. JAMA Intern Med. 2017;177:784–791.
   PubMed Web of Science ®Google Scholar
• McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Feb 15. [Epub ahead of print].
   Google Scholar
• Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478–498;quiz 499. Epub 2013/ 02/26.
   PubMed Web of Science ®Google Scholar
• Debast SB, Bauer MP, Kuijper EJ, et al. 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. Epub 2013/ 10/5.
   PubMed Web of Science ®Google Scholar
• Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59:345–354. Epub 2014/ 05/05.
   PubMed Web of Science ®Google Scholar
• Venugopal AA, Johnson S. Fidaxomicin: a novel macrocyclic antibiotic approved for treatment of Clostridium difficile infection. Clin Infect Dis. 2012;54: 568–574. Epub 2011/ 12/07.
   PubMed Web of Science ®Google Scholar
• Louie TJ, Cannon K, Byrne B, 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):S132–142.
   PubMed Web of Science ®Google Scholar
• Babakhani F, Seddon J, Sears P. Comparative microbiological studies of transcription inhibitors fidaxomicin and the rifamycins in Clostridium difficile. Antimicrob Agents Chemother. 2014;58:2934–2937. Epub 2014/ 02/18.
   PubMed Web of Science ®Google Scholar
• Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364:422–431.
   PubMed Web of Science ®Google Scholar
• Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012;12:281–289. Epub 2012/ 02/08.
   PubMed Web of Science ®Google Scholar
• Fuentes S, van Nood E, Tims S, et al. Reset of a critically disturbed microbial ecosystem: faecal transplant in recurrent Clostridium difficile infection. ISME J. 2014;8:1621–1633. Epub 2014/ 02/27.
   PubMed Web of Science ®Google Scholar
• Kassam Z, Lee CH, Hunt RH. Review of the emerging treatment of Clostridium difficile infection with fecal microbiota transplantation and insights into future challenges. Clin Lab Med. 2014;34:787–798. Epub 2014/ 09/30.
   PubMed Web of Science ®Google Scholar
• van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–415. Epub 2013/ 01/16.
   PubMed Web of Science ®Google Scholar
• Cammarota G, Masucci L, Ianiro G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015;41:835–843. Epub 2015/ 03/01.
   PubMed Web of Science ®Google Scholar
• Kelly CR, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014;109:1065–1071. Epub 2014/ 06/03.
   PubMed Web of Science ®Google Scholar
• Di Bella S, Gouliouris T, Petrosillo N. Fecal microbiota transplantation (FMT) for Clostridium difficile infection: focus on immunocompromised patients. J Infect Chemother. 2015;21:230–237. Epub 2015/ 01/31.
   PubMed Web of Science ®Google Scholar
• Kelly CR, Khoruts A, Staley C, et al. Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: a randomized trial. Ann Intern Med. 2016;165:609–616. Epub 2016/ 08/23.
   PubMed Web of Science ®Google Scholar
• Couture-Cossette A, Carignan A, Ilangumaran S, et al. Bezlotoxumab for the prevention of Clostridium difficile recurrence. Expert Opin Biol Ther. 2017;17:1439–1445. Epub 2017/ 08/13.
   PubMed Web of Science ®Google Scholar
• Lewis PO, Lundberg TS, Tharp JL, et al. Implementation of global strategies to prevent hospital-onset Clostridium difficile infection: targeting proton pump inhibitors and probiotics. Ann Pharmacother. 2017;51:848–854.
   PubMed Web of Science ®Google Scholar
• Janoir C. Virulence factors of Clostridium difficile and their role during infection. Anaerobe. 2016;37:13–24. Epub 2015/ 10/24.
   PubMed Web of Science ®Google Scholar
• Kuehne SA, Collery MM, Kelly ML, et al. Importance of toxin A, toxin B, and CDT in virulence of an epidemic Clostridium difficile strain. J Infect Dis. 2014;209:83–86. Epub 2013/ 08/09.
   PubMed Web of Science ®Google Scholar
• Cowardin CA, Buonomo EL, Saleh MM, et al. The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. Nat Microbiol. 2016;1:16108.
   PubMed Web of Science ®Google Scholar
• Lyon SA, Hutton ML, Rood JI, et al. CdtR regulates TcdA and TcdB production in Clostridium difficile. PLoS Pathog. 2016;12:e1005758.
   PubMed Web of Science ®Google Scholar
• Kuehne SA, Cartman ST, Heap JT, et al. The role of toxin A and toxin B in Clostridium difficile infection. Nature. 2010;467:711–713. Epub 2010/ 09/15.
   PubMed Web of Science ®Google Scholar
• Smits WK, Lyras D, Lacy DB, et al. Clostridium difficile infection. Nat Rev Dis Primers. 2016;2:16020.
   PubMed Web of Science ®Google Scholar
• Kociolek LK, Gerding DN. Breakthroughs in the treatment and prevention of Clostridium difficile infection. Nat Rev Gastroenterol Hepatol. 2016;13:150–160. Epub 2016/ 02/10.
   PubMed Web of Science ®Google Scholar
• Mizrahi A, Collignon A, Péchiné S. Passive and active immunization strategies against Clostridium difficile infections: state of the art. Anaerobe. 2014;30:210–219. Epub 2014/ 07/29.
   PubMed Web of Science ®Google Scholar
• Kelly CP, Kyne L. The host immune response to Clostridium difficile. J Med Microbiol. 2011;60:1070–1079. Epub 2011/ 03/17.
   PubMed Web of Science ®Google Scholar
• Ofosu A. Clostridium difficile infection: a review of current and emerging therapies. Ann Gastroenterol. 2016;29:147–154.
   PubMed Web of Science ®Google Scholar
• Péchiné S, Janoir C, Collignon A. Emerging monoclonal antibodies against Clostridium difficile infection. Expert Opin Biol Ther. 2017;17:415–427. Epub 2017/ 03/05.
   PubMed Web of Science ®Google Scholar
• Reichert JM. Antibodies to watch in 2015. MAbs. 2015;7:1–8.
   PubMed Web of Science ®Google Scholar
• Chapin RW, Lee T, McCoy C, et al. Bezlotoxumab: could this be the answer for Clostridium difficile recurrence? Ann Pharmacother. 2017;51:804–810.
   PubMed Web of Science ®Google Scholar
• Kufel WD, Devanathan AS, Marx AH, et al. Bezlotoxumab: A novel agent for the prevention of recurrent Clostridium difficile infection. Pharmacotherapy. 2017;37:1298–1308. Epub 2017/ 09/12.
   PubMed Web of Science ®Google Scholar
• 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;74:6339–6347. Epub 2006/ 09/11.
   PubMed Web of Science ®Google Scholar
• Hernandez LD, Kroh HK, Hsieh E, et al. Epitopes and mechanism of action of the Clostridium difficile toxin A-neutralizing antibody actoxumab. J Mol Biol. 2017;429:1030–1044. Epub 2017/ 02/21.
   PubMed Web of Science ®Google Scholar
• Markham A. Bezlotoxumab: first global approval. Drugs. 2016;76:1793–1798.
   PubMed Web of Science ®Google Scholar
• Taylor CP, Tummala S, Molrine D, et al. Open-label, dose escalation phase I study in healthy volunteers to evaluate the safety and pharmacokinetics of a human monoclonal antibody to Clostridium difficile toxin A. Vaccine. 2008;26:3404–3409. Epub 2008/ 05/07.
   PubMed Web of Science ®Google Scholar
• Food and Drug Administration. BLA 761046: bezlotoxumab injection Antimicrobial Drugs Advisory Committee (AMDAC) Advisory Committee (AC) meeting. Food and Drug Administration; 2016 [cited 2017 Sept 12]. Available from: https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm505291.pdf
   Google Scholar
• Lyerly DM, Phelps CJ, Toth J, et al. Characterization of toxins A and B of Clostridium difficile with monoclonal antibodies. Infect Immun. 1986;54:70–76.
   PubMed Web of Science ®Google Scholar
• Corthier G, Muller MC, Wilkins TD, et al. Protection against experimental pseudomembranous colitis in gnotobiotic mice by use of monoclonal antibodies against Clostridium difficile toxin A. Infect Immun. 1991;59:1192–1195.
   PubMed Web of Science ®Google Scholar
• Hussack G, Tanha J. Toxin-specific antibodies for the treatment of Clostridium difficile: current status and future perspectives. Toxins. 2010;2:998–1018. Epub 2010/ 05/7.
   PubMed Web of Science ®Google Scholar
• 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;207:323–330. Epub 2012/ 11/02.
   PubMed Web of Science ®Google Scholar
• Lyras D, O’Connor JR, Howarth PM, et al. Toxin B is essential for virulence of Clostridium difficile. Nature. 2009;458:1176–1179. Epub 2009/ 03/01.
   PubMed Web of Science ®Google Scholar
• Carter GP, Chakravorty A, Pham Nguyen TA, et al. Defining the roles of TcdA and TcdB in localized gastrointestinal disease, systemic organ damage, and the host response during Clostridium difficile infections. MBio. 2015;6:e00551.
   PubMed Web of Science ®Google Scholar
• 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;59:1052–1060. Epub 2014/ 12/01.
   PubMed Web of Science ®Google Scholar
• Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med. 2010;362:197–205.
   PubMed Web of Science ®Google Scholar
• Yang Z, Ramsey J, Hamza T, et al. Mechanisms of protection against Clostridium difficile infection by the monoclonal antitoxin antibodies actoxumab and bezlotoxumab. Infect Immun. 2015;83:822–831. Epub 2014/ 12/08.
   PubMed Web of Science ®Google Scholar
• Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305–317.
   PubMed Web of Science ®Google Scholar
• Leav BA, Blair B, Leney M, et al. Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine. 2010;28:965–969. Epub 2009/ 11/24.
   PubMed Web of Science ®Google Scholar
• Walker AS, Eyre DW, Wyllie DH, et al. Relationship between bacterial strain type, host biomarkers, and mortality in Clostridium difficile infection. Clin Infect Dis. 2013;56:1589–1600. Epub 2013/ 03/05.
   PubMed Web of Science ®Google Scholar
• Lim SK, Stuart RL, Mackin KE, et al. Emergence of a ribotype 244 strain of Clostridium difficile associated with severe disease and related to the epidemic ribotype 027 strain. Clin Infect Dis. 2014;58:1723–1730. Epub 2014/ 04/04.
   PubMed Web of Science ®Google Scholar
• Merck & Co Inc. Zinplava package insert. Kenilworth (NJ): Merck & Co., Inc; 2016 [cited 2017 Sept 12]. Available from https://www.merck.com/product/usa/pi_circulars/z/zinplava/zinplava_pi.pdf
   Google Scholar
• Kyne L, Warny M, Qamar A, et al. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet. 2001;357:189–193.
   PubMed Web of Science ®Google Scholar
• Hu MY, Katchar K, Kyne L, et al. Prospective derivation and validation of a clinical prediction rule for recurrent Clostridium difficile infection. Gastroenterology. 2009;136:1206–1214. Epub 2008/ 12/13.
   PubMed Web of Science ®Google Scholar
• Gupta SB, Mehta V, Dubberke ER, et al. Antibodies to toxin B are protective against Clostridium difficile infection recurrence. Clin Infect Dis. 2016;63:730–734. Epub 2016/ 06/30.
   PubMed Web of Science ®Google Scholar
• Cornely OA, Vehreschild MJ. Editorial commentary: where to place the new treatments for Clostridium difficile infection? Clin Infect Dis. 2016;63:735–736. Epub 2016/ 06/30.
   PubMedGoogle Scholar
• Choy M. Pharmaceutical approval update. Pharm Ther. 2017;42:17–18.
   Google Scholar
• Džunková M, D’Auria G, Xu H, et al. The monoclonal antitoxin antibodies (actoxumab-bezlotoxumab) treatment facilitates normalization of the gut microbiota of mice with Clostridium difficile infection. Front Cell Infect Microbiol. 2016;6:119.
   PubMed Web of Science ®Google Scholar
• Warn P, Thommes P, Sattar A, et al. Disease progression and resolution in rodent models of Clostridium difficile infection and impact of antitoxin antibodies and vancomycin. Antimicrob Agents Chemother. 2016;60:6471–6482.
   PubMed Web of Science ®Google Scholar
• Garey KW, Sethi S, Yadav Y, et al. Meta-analysis to assess risk factors for recurrent Clostridium difficile infection. J Hosp Infect. 2008;70:298–304. Epub 2008/ 10/31.
   PubMed Web of Science ®Google Scholar
• Lapointe-Shaw L, Tran KL, Coyte PC, et al. Cost-effectiveness analysis of six strategies to treat recurrent Clostridium difficile infection. PLoS One. 2016;11:e0149521.
   PubMed Web of Science ®Google Scholar
• Reichert JM. Antibodies to watch in 2017. MAbs. 2017;9:167–181. Epub 2016/ 12/14.
   PubMed Web of Science ®Google Scholar
• Gerding DN, Meyer T, Lee C, et al. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. JAMA. 2015;313:1719–1727.
   PubMed Web of Science ®Google Scholar
• Khanna S, Pardi DS, Kelly CR, et al. .A novel microbiome therapeutic increases gut microbial diversity and prevents recurrent Clostridium difficile infection. J Infect Dis. 2016;214:173–181. Epub 2016/ 02/08.
   PubMed Web of Science ®Google Scholar