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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.
J Antimicrob Chemother. 2015; 70(6):1751-6.JA

Abstract

OBJECTIVES

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+Show Affiliations

Evotec (UK), Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.Evotec (UK), Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.Evotec (UK), Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.Evotec (UK), Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.Department of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK.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.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.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.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.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.Summit plc, 85b Park Drive, Milton Park, Abingdon, Oxfordshire OX14 4RY, UK richard.vickers@summitplc.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25652750

Citation

Corbett, D, et al. "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." The Journal of Antimicrobial Chemotherapy, vol. 70, no. 6, 2015, pp. 1751-6.
Corbett D, Wise A, Birchall S, et al. 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. J Antimicrob Chemother. 2015;70(6):1751-6.
Corbett, D., Wise, A., Birchall, S., Warn, P., Baines, S. D., Crowther, G., Freeman, J., Chilton, C. H., Vernon, J., Wilcox, M. H., & Vickers, R. J. (2015). 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. The Journal of Antimicrobial Chemotherapy, 70(6), 1751-6. https://doi.org/10.1093/jac/dkv006
Corbett D, et al. 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. J Antimicrob Chemother. 2015;70(6):1751-6. PubMed PMID: 25652750.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Corbett,D, AU - Wise,A, AU - Birchall,S, AU - Warn,P, AU - Baines,S D, AU - Crowther,G, AU - Freeman,J, AU - Chilton,C H, AU - Vernon,J, AU - Wilcox,M H, AU - Vickers,R J, Y1 - 2015/02/03/ PY - 2014/10/24/received PY - 2014/12/31/accepted PY - 2015/2/6/entrez PY - 2015/2/6/pubmed PY - 2016/2/6/medline KW - C. difficile KW - PAE KW - antimicrobial SP - 1751 EP - 6 JF - The Journal of antimicrobial chemotherapy JO - J. Antimicrob. Chemother. VL - 70 IS - 6 N2 - OBJECTIVES: 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. SN - 1460-2091 UR - https://www.unboundmedicine.com/medline/citation/25652750/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_ L2 - https://academic.oup.com/jac/article-lookup/doi/10.1093/jac/dkv006 DB - PRIME DP - Unbound Medicine ER -