title: Evaluation of antimicrobial activity of ceftaroline against Clostridium difficile and propensity to induce C. difficile infection in an in vitro human gut model.
abstract: OBJECTIVE
  To examine the effects of exposure to ceftaroline or ceftriaxone on the epidemic Clostridium difficile strain PCR ribotype 027 and the indigenous gut microflora in an in vitro human gut model. Additionally, the MICs of ceftriaxone and ceftaroline for 60 C. difficile isolates were determined.
  
  
  METHODS
  Two triple-stage chemostat gut models were primed with human faeces and exposed to ceftaroline (10 mg/L, twice daily, 7 days) or ceftriaxone (150 mg/L, once daily, 7 days). Populations of indigenous gut microorganisms, C. difficile total viable counts, spore counts, cytotoxin titres and antimicrobial concentrations were monitored throughout. MICs were determined by a standard agar incorporation method.
  
  
  RESULTS
  In the gut model, both ceftaroline and ceftriaxone induced C. difficile spore germination, proliferation and toxin production, although germination occurred 5 days later in the ceftaroline-exposed model. Toxin detection was sustained until the end of the experimental period in both models. No active antimicrobial was detected in vessel 3 of either model, although inhibitory effects on microflora populations were observed. Ceftaroline was ∼8-fold more active against C. difficile than ceftriaxone (geometric mean MICs, 3.38 versus 28.18 mg/L; MIC90s, 4 versus 64 mg/L; and MIC ranges, 0.125-16 versus 8-128 mg/L).
  
  
  CONCLUSIONS
  Ceftaroline, like ceftriaxone, can induce simulated C. difficile infection in a human gut model. However, low in vivo gut concentrations of ceftaroline and increased activity against C. difficile in comparison with ceftriaxone mean that the true propensity of this novel cephalosporin to induce C. difficile infection remains unclear.
authors.affiliation: Faculty of Health and Human Science, School of Life Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Baines
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Chilton
authors.forename: Grace S
authors.initials: GS
authors.lastname: Crowther
authors.forename: Sharie L
authors.initials: SL
authors.lastname: Todhunter
authors.forename: Jane
authors.initials: J
authors.lastname: Freeman
authors.forename: Mark H
authors.initials: MH
authors.lastname: Wilcox
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D058491:Bacterial Load; D001427:Bacterial Toxins / Q000032:analysis; D002443:Ceftriaxone / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology*; D016360:Clostridioides difficile / Q000187:drug effects* / Q000254:growth & development* / Q000302:isolation & purification; D003015:Clostridium Infections / Q000382:microbiology*; D041981:Gastrointestinal Tract / Q000382:microbiology*; D064368:Healthy Volunteers; D006802:Human Activities; D006801:Humans; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D002443:Ceftriaxone; D002511:Cephalosporins; D000097583:Ceftaroline
keywords: MICs; cephalosporins; chemostat