Abstract
ObjectivesWe investigated the efficacy of the novel antimicrobial agent SMT19969 in treating simulated Clostridium difficile infection using an in vitro human gut model.MethodsConcentrations of the predominant cultivable members of the indigenous gut microfloras and C. difficile (total and spore counts) were determined by viable counting. Cytotoxin titres were determined using cell cytotoxicity and expressed as log10 relative units (RU). Clindamycin was used to induce simulated C. difficile PCR ribotype 027 infection. Once high-level cytotoxin titres (≥4 RU) were observed, SMT19969 was instilled for 7 days. Two SMT19969 dosing regimens (31.25 and 62.5 mg/L four times daily) were evaluated simultaneously in separate experiments. MICs of SMT19969 were determined against 30 genotypically distinct C. difficile ribotypes.ResultsSMT19969 was 7- and 17-fold more active against C. difficile than metronidazole and vancomycin, respectively, against a panel of genotypically distinct isolates (P < 0.05). Both SMT19969 dosing regimens demonstrated little antimicrobial activity against indigenous gut microflora groups except clostridia. SMT19969 inhibited C. difficile growth and repressed C. difficile cytotoxin titres in the gut model.ConclusionsThese data suggest that SMT19969 is a narrow-spectrum and potent antimicrobial agent against C. difficile. Additional studies evaluating SMT19969 in other models of C. difficile infection are warranted, with human studies to place these gut model observations in context.
Highlights
Clostridium difficile infection (CDI) is the leading cause of infectious nosocomial diarrhoea
Metronidazole and vancomycin were considered for many years to be effective, but later studies indicated that the former antimicrobial agent is inferior, in severe CDI.[6,7,8,9,10]
Fidaxomicin is active in vitro and in vivo against C. difficile,[11,12] and a fidaxomicin-resistant C. difficile was isolated from a recurrent CDI patient (MIC of 16 mg/L) during Phase III clinical trials,[11] the significance of this result remains to be determined
Summary
Clostridium difficile infection (CDI) is the leading cause of infectious nosocomial diarrhoea. Metronidazole and vancomycin were considered for many years to be effective, but later studies indicated that the former antimicrobial agent is inferior, in severe CDI.[6,7,8,9,10] Fidaxomicin is active in vitro and in vivo against C. difficile,[11,12] and a fidaxomicin-resistant C. difficile was isolated from a recurrent CDI patient (MIC of 16 mg/L) during Phase III clinical trials,[11] the significance of this result remains to be determined. Recurrent CDI remains a therapeutic challenge, despite the recent availability of fidaxomicin, which is less efficacious against CDI due to PCR ribotype 027.6
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