title: In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections.
abstract: Clostridium difficile is a leading cause of health care-associated diarrhea with significant morbidity and mortality, and new options for the treatment of C. difficile-associated diarrhea (CDAD) are needed. Cadazolid is a new oxazolidinone-type antibiotic that is currently in clinical development for treatment of CDAD. Here, we report the in vitro and in vivo antibacterial evaluation of cadazolid against C. difficile. Cadazolid showed potent in vitro activity against C. difficile with a MIC range of 0.125 to 0.5 μg/ml, including strains resistant to linezolid and fluoroquinolones. In time-kill kinetics experiments, cadazolid showed a bactericidal effect against C. difficile isolates, with >99.9% killing in 24 h, and was more bactericidal than vancomycin. In contrast to metronidazole and vancomycin, cadazolid strongly inhibited de novo toxin A and B formation in stationary-phase cultures of toxigenic C. difficile. Cadazolid also inhibited C. difficile spore formation substantially at growth-inhibitory concentrations. In the hamster and mouse models for CDAD, cadazolid was active, conferring full protection from diarrhea and death with a potency similar to that of vancomycin. These findings support further investigations of cadazolid for the treatment of CDAD.
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Locher
authors.forename: Peter
authors.initials: P
authors.lastname: Seiler
authors.forename: Xinhua
authors.initials: X
authors.lastname: Chen
authors.forename: Susanne
authors.initials: S
authors.lastname: Schroeder
authors.forename: Philippe
authors.initials: P
authors.lastname: Pfaff
authors.forename: Michel
authors.initials: M
authors.lastname: Enderlin
authors.forename: Axel
authors.initials: A
authors.lastname: Klenk
authors.forename: Elvire
authors.initials: E
authors.lastname: Fournier
authors.forename: Christian
authors.initials: C
authors.lastname: Hubschwerlen
authors.forename: Daniel
authors.initials: D
authors.lastname: Ritz
authors.forename: Ciaran P
authors.initials: CP
authors.lastname: Kelly
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Keck
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016360:Clostridioides difficile / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D003015:Clostridium Infections / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D006224:Cricetinae; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D004768:Enterotoxins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology; D006801:Humans; D000069349:Linezolid; D008297:Male; D008795:Metronidazole / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D023303:Oxazolidinones / Q000494:pharmacology*; D013171:Spores, Bacterial / Q000187:drug effects* / Q000254:growth & development; D016019:Survival Analysis; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D024841:Fluoroquinolones; D023303:Oxazolidinones; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D008795:Metronidazole; C000591679:cadazolid; D014640:Vancomycin; D000069349:Linezolid