title: Effects of cefotaxime and desacetylcefotaxime upon Clostridium difficile proliferation and toxin production in a triple-stage chemostat model of the human gut.
abstract: Clostridium difficile is recognized as an important nosocomial pathogen. C. difficile infection (CDI) is thought to arise as a result of depletion of the normal gut flora by antimicrobial agents. Cefotaxime (CTX) is well-known for its propensity to cause CDI, but the reasons behind its particular predisposition to the disease remain unclear. Previous investigations have so far relied upon the hamster model of CDI or human volunteers. We have used a triple-stage chemostat model of the human gut to investigate the behaviour of C. difficile and components of the normal gut flora, in response to exposure to CTX alone, and in combination with its active metabolite desacetylcefotaxime (dCTX). C. difficile remained in a steady state during non-antibiotic exposed periods, with no detectable cytotoxin. During both antibiotic exposure regimens, proliferation of C. difficile and elevated cytotoxin levels were observed. Cessation of antibiotic instillation produced a reduction in cytotoxin levels and viable counts. Decreases in bacterial counts were observed in response to both antibiotic exposure regimens, notably for bifidobacteria and bacteroides. Numbers of bacteroides were profoundly affected by exposure to the CTX/dCTX combination, and this may indicate a possible role for bacteroides in colonization resistance. We believe that the gut model is a promising method for studying C. difficile pathogenesis in conditions analogous to the in vivo situation.
authors.affiliation: Department of Microbiology, University of Leeds and The General Infirmary, Leeds LS2 9JT, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Freeman
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: O'Neill
authors.forename: Mark H
authors.initials: MH
authors.lastname: Wilcox
mesh_terms: D001427:Bacterial Toxins / Q000096:biosynthesis*; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology*; D016360:Clostridioides difficile / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D015169:Colony Count, Microbial; D003470:Culture Media; D004064:Digestive System / Q000187:drug effects / Q000382:microbiology*; D005243:Feces / Q000382:microbiology; D006801:Humans; D008954:Models, Biological; D013171:Spores, Bacterial / Q000187:drug effects
chemical_list: D001427:Bacterial Toxins; D002511:Cephalosporins; D003470:Culture Media; C029281:desacetylcefotaxime; D002439:Cefotaxime