title: Disease Progression and Resolution in Rodent Models of Clostridium difficile Infection and Impact of Antitoxin Antibodies and Vancomycin.
abstract: Clostridium difficile causes infections of the colon in susceptible patients. Specifically, gut dysbiosis induced by treatment with broad-spectrum antibiotics facilitates germination of ingested C. difficile spores, expansion of vegetative cells, and production of symptom-causing toxins TcdA and TcdB. The current standard of care for C. difficile infections (CDI) consists of administration of antibiotics such as vancomycin that target the bacterium but also perpetuate gut dysbiosis, often leading to disease recurrence. The monoclonal antitoxin antibodies actoxumab (anti-TcdA) and bezlotoxumab (anti-TcdB) are currently in development for the prevention of recurrent CDI. In this study, the effects of vancomycin or actoxumab/bezlotoxumab treatment on progression and resolution of CDI were assessed in mice and hamsters. Rodent models of CDI are characterized by an early severe phase of symptomatic disease, associated with high rates of morbidity and mortality; high intestinal C. difficile burden; and a disrupted intestinal microbiota. This is followed in surviving animals by gradual recovery of the gut microbiota, associated with clearance of C. difficile and resolution of disease symptoms over time. Treatment with vancomycin prevents disease initially by inhibiting outgrowth of C. difficile but also delays microbiota recovery, leading to disease relapse following discontinuation of therapy. In contrast, actoxumab/bezlotoxumab treatment does not impact the C. difficile burden but rather prevents the appearance of toxin-dependent symptoms during the early severe phase of disease, effectively preventing disease until the microbiota (the body's natural defense against C. difficile) has fully recovered. These data provide insight into the mechanism of recurrence following vancomycin administration and into the mechanism of recurrence prevention observed clinically with actoxumab/bezlotoxumab.
authors.affiliation: Evotec (UK) Ltd., Manchester, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Warn
authors.affiliation: Evotec (UK) Ltd., Manchester, United Kingdom.
authors.forename: Pia
authors.initials: P
authors.lastname: Thommes
authors.affiliation: Evotec (UK) Ltd., Manchester, United Kingdom.
authors.forename: Abdul
authors.initials: A
authors.lastname: Sattar
authors.affiliation: Evotec (UK) Ltd., Manchester, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Corbett
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Flattery
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Zuo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Black
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Lorraine D
authors.initials: LD
authors.lastname: Hernandez
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA alex_therien@merck.com.
authors.forename: Alex G
authors.initials: AG
authors.lastname: Therien
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D000992:Antitoxins / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000080908:Broadly Neutralizing Antibodies; D016360:Clostridioides difficile / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D003015:Clostridium Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D003289:Convalescence; D003412:Cricetulus; D004195:Disease Models, Animal; D018450:Disease Progression; D004768:Enterotoxins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000069196:Gastrointestinal Microbiome / Q000187:drug effects / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D014640:Vancomycin / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000992:Antitoxins; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D000080908:Broadly Neutralizing Antibodies; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; C000613978:bezlotoxumab; D014640:Vancomycin; C000613979:actoxumab