Efficacy of LFF571 in a hamster model of Clostridium difficile infection.
LFF571 is a novel semisynthetic thiopeptide antibiotic with potent activity against a variety of Gram-positive pathogens, including Clostridium difficile. In vivo efficacy of LFF571 was compared to vancomycin in a hamster model of C. difficile infection (CDI). Infection was induced in Golden Syrian hamsters using a toxigenic strain of C. difficile. Treatment started 24 h postinfection and consisted of saline, vancomycin, or LFF571. Cox regression was used to analyze survival data from a cohort of animals evaluated across seven serial experimental groups treated with vancomycin at 20 mg/kg, LFF571 at 5 mg/kg, or vehicle alone. Survival was right censored; animals were not observed beyond day 21. At death or end of study, cecal contents were tested for C. difficile toxins A and B. In summary, the data showed that 5 mg/kg LFF571 decreased the risk of death by 79% (P < 0.0001) and 69% (P = 0.0022) compared with saline and 20 mg/kg vancomycin, respectively. Further analysis of the pooled data indicated that the survival benefit of LFF571 treatment at 5 mg/kg compared to vancomycin at 20 mg/kg was due primarily to a decrease in the risk of recurrence after end of treatment. Animals successfully treated with LFF571 or vancomycin had no detectable C. difficile toxin. Overall, LFF571 was more efficacious at the end of the study, at a lower dose, and with fewer recurrences, than vancomycin in the hamster model of CDI. LFF571 is being assessed in humans for safety and efficacy in the treatment of C. difficile infections.
Novartis Institutes for Biomedical Research, Infectious Disease Area, Emeryville, California, USA.
Anna
A
Trzasko
Jennifer A
JA
Leeds
Jens
J
Praestgaard
Matthew J
MJ
Lamarche
David
D
McKenney
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000032:analysis; D001427:Bacterial Toxins / Q000032:analysis; D016360:Clostridioides difficile / Q000187:drug effects*; D006224:Cricetinae; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy*; D004768:Enterotoxins / Q000032:analysis; D008297:Male; D008647:Mesocricetus; D012008:Recurrence; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014640:Vancomycin / Q000494:pharmacology / Q000627:therapeutic use*; D010456:Peptides, Cyclic
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D013844:Thiazoles; D014640:Vancomycin; C573298:LFF571; D010456:Peptides, Cyclic; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile