Abstract
ObjectivesSMT19969 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.MethodsMICs 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).ResultsSMT19969 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.ConclusionsThese 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.
Highlights
Clostridium difficile infection (CDI) is a significant cause of morbidity and mortality in both the acute care setting and the wider healthcare system.[1,2] The global increase in the incidence of CDI is driven, in part, by the emergence of fluoroquinolone-resistant ribotype 027 C. difficile strains,[3] which continue to account for30% of CDI cases in North America.[4]
CDI pathogenesis is associated with antimicrobial use that causes reduced diversity of the gut microbiota, reducing the host’s ability to resist colonization by, and expansion of, C. difficile
Susceptibility testing was carried out using C. difficile clinical isolates collected in the UK from subjects with CDI
Summary
Clostridium difficile infection (CDI) is a significant cause of morbidity and mortality in both the acute care setting and the wider healthcare system.[1,2] The global increase in the incidence of CDI is driven, in part, by the emergence of fluoroquinolone-resistant ribotype 027 C. difficile strains,[3] which continue to account for30% of CDI cases in North America.[4]. Clostridium difficile infection (CDI) is a significant cause of morbidity and mortality in both the acute care setting and the wider healthcare system.[1,2] The global increase in the incidence of CDI is driven, in part, by the emergence of fluoroquinolone-resistant ribotype 027 C. difficile strains,[3] which continue to account for. CDI pathogenesis is associated with antimicrobial use that causes reduced diversity of the gut microbiota, reducing the host’s ability to resist colonization by, and expansion of, C. difficile. These conditions allow C. difficile spores to germinate, with resultant toxin production leading to disease symptoms
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