title: SMT19969 for Clostridium difficile infection (CDI): in vivo efficacy compared with fidaxomicin and vancomycin in the hamster model of CDI.
abstract: OBJECTIVE
  SMT19969 is a novel narrow-spectrum antimicrobial under development for the treatment of Clostridium difficile infection (CDI). The objectives were to assess the relative efficacies of SMT19969, vancomycin and fidaxomicin in the hamster model of CDI.
  
  
  METHODS
  Hamsters were infected with either C. difficile BI1 (ribotype 027) or C. difficile 630 (ribotype 012) prior to treatment with vehicle, SMT19969, fidaxomicin or vancomycin for 5 days. Animals were further monitored through to day 28 and survival recorded. Plasma and gastrointestinal concentrations of SMT19969 following single and repeat administration in infected hamsters were determined.
  
  
  RESULTS
  Following infection with C. difficile BI1, treatment with SMT19969, vancomycin and fidaxomicin resulted in 100% survival during the 5 day dosing period, with 90%-100% of animals receiving SMT19969 and fidaxomicin surviving during the post-dosing follow-up period. Whilst protective during treatment, onset of mortality was observed on day 11 in animals treated with vancomycin, with a 10% survival recorded by day 28. Similar results were observed for SMT19969 and vancomycin following infection with C. difficile 630, with day 28 survival rates of 80%-100% and 0%, respectively. Fidaxomicin protected animals infected with C. difficile 630 from mortality during dosing, although day 28 survival rates varied from 0% to 40% depending on dose. Plasma levels of SMT19969 were typically below the limit of quantification, but levels in the gastrointestinal tract remained far in excess of the MIC.
  
  
  CONCLUSIONS
  These data show that SMT19969 is highly effective at treating both acute infection and preventing recurrent disease and support continued investigation of SMT19969 as a potential therapy for CDI.
authors: Evotec (UK), Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.
authors: Abdul
authors: A
authors: Sattar
authors: Evotec (UK), Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.
authors: Pia
authors: P
authors: Thommes
authors: Evotec (UK), Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.
authors: Lloyd
authors: L
authors: Payne
authors: Evotec (UK), Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.
authors: Peter
authors: P
authors: Warn
authors: Summit plc, Abingdon, Oxfordshire, UK richard.vickers@summitplc.com.
authors: Richard J
authors: RJ
authors: Vickers
mesh_terms: D000617:Aminoglycosides / Q000008:administration & dosage*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016360:Clostridioides difficile / Q000187:drug effects*; D003015:Clostridium Infections / Q000188:drug therapy* / Q000382:microbiology; D004195:Disease Models, Animal; D000077732:Fidaxomicin; D041981:Gastrointestinal Tract / Q000737:chemistry; D008647:Mesocricetus; D008826:Microbial Sensitivity Tests; D010949:Plasma / Q000737:chemistry; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012008:Recurrence; D016019:Survival Analysis; D016896:Treatment Outcome; D014640:Vancomycin / Q000008:administration & dosage*
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D011725:Pyridines; C000601750:ridinilazole; D014640:Vancomycin; D000077732:Fidaxomicin
keywords: C. difficile; antimicrobial; treatment
references: Antimicrob Agents Chemother. 1991 Jun;35(6):1108-11
references: 1929250
references: Methods Mol Biol. 2010;646:215-27
references: 20597012
references: Clin Infect Dis. 2014 Aug 1;59(3):345-54
references: 24799326
references: J Med Microbiol. 1987 Aug;24(1):53-64
references: 3612744
references: Nat Genet. 2013 Jan;45(1):109-13
references: 23222960
references: Clin Infect Dis. 2012 Aug;55 Suppl 2:S162-9
references: 22752866
references: Antimicrob Agents Chemother. 2013 Oct;57(10):4872-6
references: 23877700
references: Gut Microbes. 2012 Mar-Apr;3(2):145-67
references: 22555466
references: Infect Immun. 2012 Aug;80(8):2704-11
references: 22615253
references: J Infect Dis. 2014 Jan 1;209(1):83-6
references: 23935202
references: Antimicrob Agents Chemother. 2014 Oct;58(10):5714-8
references: 25022586
references: Infect Immun. 2009 Sep;77(9):3661-9
references: 19564382
references: Clin Microbiol Infect. 2012 Dec;18 Suppl 6:21-7
references: 23121551
references: PLoS One. 2012;7(10):e46966
references: 23071679
references: Clin Infect Dis. 2012 Aug;55(3):351-7
references: 22523271
references: Lancet Infect Dis. 2012 Apr;12(4):281-9
references: 22321770
references: Antimicrob Agents Chemother. 2014 Jul;58(7):4214-8
references: 24752264
references: Antimicrob Agents Chemother. 2014;58(2):1187-91
references: 24247123
references: N Engl J Med. 2011 Feb 3;364(5):422-31
references: 21288078
references: Lancet Infect Dis. 2014 Dec;14(12):1208-19
references: 25455988
references: Therap Adv Gastroenterol. 2014 Mar;7(2):72-86
references: 24587820