title: In vitro susceptibility of Clostridium difficile to SMT19969 and comparators, as well as the killing kinetics and post-antibiotic effects of SMT19969 and comparators against C. difficile.
abstract: OBJECTIVE
  SMT19969 is a novel antimicrobial under clinical development for the treatment of Clostridium difficile infection (CDI). The objective was to determine the comparative susceptibility of 82 C. difficile clinical isolates (which included ribotype 027 isolates and isolates with reduced metronidazole susceptibility) to SMT19969, fidaxomicin, vancomycin and metronidazole and to determine the killing kinetics and post-antibiotic effects of SMT19969, fidaxomicin and vancomycin against C. difficile.
  
  
  METHODS
  MICs were determined by agar incorporation. Killing kinetics and post-antibiotic effects were determined against C. difficile BI1, 630 and 5325 (ribotypes 027, 012 and 078, respectively).
  
  
  RESULTS
  SMT19969 showed potent inhibition of C. difficile (MIC90=0.125 mg/L) and was markedly more active than either metronidazole (MIC90 = 8 mg/L) or vancomycin (MIC90 = 2 mg/L). There were no differences in susceptibility to SMT19969 between different ribotypes. Fidaxomicin was typically one doubling dilution more active than SMT19969 and both agents maintained activity against isolates with reduced susceptibility to metronidazole. In addition, SMT19969 was bactericidal against the C. difficile strains tested, with reductions in viable counts to below the limit of detection by 24 h post-inoculation. Vancomycin was bacteriostatic against all three strains. Fidaxomicin was bactericidal although reduced killing was observed at concentrations <20 × MIC against C. difficile BI1 (ribotype 027) compared with other strains tested.
  
  
  CONCLUSIONS
  These data demonstrate that SMT19969 is associated with potent and bactericidal activity against the strains tested and support further investigation of SMT19969 as potential therapy for CDI.
authors: Evotec (UK), Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.
authors: D
authors: D
authors: Corbett
authors: Evotec (UK), Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.
authors: A
authors: A
authors: Wise
authors: Evotec (UK), Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.
authors: S
authors: S
authors: Birchall
authors: Evotec (UK), Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.
authors: P
authors: P
authors: Warn
authors: Department of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK.
authors: S D
authors: SD
authors: Baines
authors: Department of Microbiology, Leeds Teaching Hospitals NHS Trust and Healthcare Associated Infections Research Group, The University of Leeds, Old Medical School, Leeds LS1 3EX, UK.
authors: G
authors: G
authors: Crowther
authors: Department of Microbiology, Leeds Teaching Hospitals NHS Trust and Healthcare Associated Infections Research Group, The University of Leeds, Old Medical School, Leeds LS1 3EX, UK.
authors: J
authors: J
authors: Freeman
authors: Department of Microbiology, Leeds Teaching Hospitals NHS Trust and Healthcare Associated Infections Research Group, The University of Leeds, Old Medical School, Leeds LS1 3EX, UK.
authors: C H
authors: CH
authors: Chilton
authors: Department of Microbiology, Leeds Teaching Hospitals NHS Trust and Healthcare Associated Infections Research Group, The University of Leeds, Old Medical School, Leeds LS1 3EX, UK.
authors: J
authors: J
authors: Vernon
authors: Department of Microbiology, Leeds Teaching Hospitals NHS Trust and Healthcare Associated Infections Research Group, The University of Leeds, Old Medical School, Leeds LS1 3EX, UK.
authors: M H
authors: MH
authors: Wilcox
authors: Summit plc, 85b Park Drive, Milton Park, Abingdon, Oxfordshire OX14 4RY, UK richard.vickers@summitplc.com.
authors: R J
authors: RJ
authors: Vickers
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D016360:Clostridioides difficile / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification / Q000502:physiology*; D003015:Clostridium Infections / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D011725:Pyridines; C000601750:ridinilazole
keywords: C. difficile; PAE; antimicrobial
references: N Engl J Med. 2008 Oct 30;359(18):1932-40
references: 18971494
references: J Antimicrob Chemother. 2008 Nov;62(5):1046-52
references: 18693234
references: J Med Microbiol. 2011 Aug;60(Pt 8):1213-1217
references: 21349983
references: J Antimicrob Chemother. 2015 Jan;70(1):182-9
references: 25190720
references: Clin Infect Dis. 2014 Aug 1;59(3):345-54
references: 24799326
references: Lancet. 2011 Jan 1;377(9759):63-73
references: 21084111
references: Nat Rev Microbiol. 2009 Jul;7(7):526-36
references: 19528959
references: Lancet Infect Dis. 2014 Dec;14(12):1208-19
references: 25455988
references: J Infect Dis. 2008 Feb 1;197(3):435-8
references: 18199029
references: Chemotherapy. 2007;53(4):267-74
references: 17595541
references: Lancet Infect Dis. 2012 Apr;12(4):281-9
references: 22321770
references: Clin Infect Dis. 2014 Jun;58(12):1723-30
references: 24704722
references: Clin Infect Dis. 1997 Sep;25(3):729-32
references: 9314469
references: Antimicrob Agents Chemother. 2011 Sep;55(9):4427-9
references: 21709084
references: Antimicrob Agents Chemother. 2014 Jul;58(7):4214-8
references: 24752264
references: N Engl J Med. 2011 Feb 3;364(5):422-31
references: 21288078
references: Clin Microbiol Infect. 2012 Dec;18 Suppl 6:21-7
references: 23121551
references: J Antimicrob Chemother. 2001 Nov;48(5):741-2
references: 11679570
references: Antimicrob Agents Chemother. 2009 Jan;53(1):261-3
references: 18955523
references: Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4639-44
references: 20616009
references: Clin Infect Dis. 2007 Aug 1;45(3):302-7
references: 17599306
references: Clin Microbiol Infect. 2009 Dec;15(12):1067-79
references: 19929973
references: Antimicrob Agents Chemother. 2013 Oct;57(10):4872-6
references: 23877700
references: Clin Infect Dis. 2012 Aug;55(3):351-7
references: 22523271
references: Nat Genet. 2013 Jan;45(1):109-13
references: 23222960
references: Clin Infect Dis. 2013 Jun;56(11):1589-600
references: 23463640