cadazolid and Enterocolitis--Pseudomembranous

Topics: Clostridioides difficile; Clostridium Infections; Double-Blind Method; Enterocolitis, Pseudomembranous; Humans; Oxazolidinones

The promotion of colonization with vancomycin-resistant enterococci (VRE) is one potential side effect during treatment of Clostridium difficile-associated diarrhea (CDAD), resulting from disturbances in gut microbiota. Cadazolid (CDZ) is an investigational antibiotic with potent in vitro activity against C. difficile and against VRE and is currently in clinical development for the treatment of CDAD. We report that CDZ treatment did not lead to intestinal VRE overgrowth in mice.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Clostridioides difficile; Colony Count, Microbial; Diarrhea; Enterocolitis, Pseudomembranous; Fidaxomicin; Intestines; Metronidazole; Mice; Microbial Sensitivity Tests; Oxazolidinones; Streptococcal Infections; Treatment Outcome; Vancomycin; Vancomycin Resistance; Vancomycin-Resistant Enterococci

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.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Bacterial Proteins; Bacterial Toxins; Clostridioides difficile; Clostridium Infections; Cricetinae; Enterocolitis, Pseudomembranous; Enterotoxins; Female; Fluoroquinolones; Humans; Linezolid; Male; Metronidazole; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Oxazolidinones; Spores, Bacterial; Survival Analysis; Vancomycin