Efficacy of novel antimicrobial agent SMT-19969 (SMT) against simulated Clostridium difficile infection in an in vitro human gut model

Abstract

Background: C. difficile infection (CDI) is the leading cause of nosocomial diarrhoea. Current CDI therapy is limited to metronidazole (M) or vancomycin. Recent evidence suggests reduced M efficacy and emergence of reduced susceptibility in epidemic CD strains. Evaluation of new therapies for CDI is essential. Methods: A 3-stage chemostat human gut model was inoculated with pooled faeces (5 healthy elderly volunteers). Clindamycin (CLIN, 33.9 mg/L qid,7d) was dosed to simulate CDI by CD ribotype 027 (NAP1/BI) (SMT MIC = 0.125mg/L). Two 7d SMT dosing regimens were evaluated: 31.25 & 62.5 mg/L QID. Gut bacteria, CD vegetative cells (V) and spores (SP), cytotoxin titres (CYT) & antimicrobial levels (HPLC & bioassay) were determined. Emergence of CD SMT resistance was monitored on breakpoint agar (4xMIC). Results: CLIN elicited CD CYT (4 relative units, RU) in both experiments at which point SMT dosing started. Both SMT regimens caused little adverse antimicrobial activity against gut microflora groups except total clostridia (1.4-2 log cfu/mL decrease). During SMT dosing, CD V and SP declined by ~1.5 log10cfu/mL over 7 d in all vessels of both models. CD V were detectable thereafter, increasing slightly by the end of both experiments. CYT declined to undetectable (ND) or 1 RU during SMT dosing, but recurred at low levels after stopping (<2 RU). CYT was ND for the last 5-6 days of both models. No SMT resistant CD were isolated. SMT persisted in both models to experiment end, with higher concentrations in the SMT 62.5 mg/L model. HPLC & bioassay indicated incomplete drug solubility. Conclusions: SMT treatment was sparing of gut microflora, and by the end of SMT dosing, all groups except total clostridia had recovered to normal levels; this could be expected to have benefit in prevention of recurrent disease. Inhibition of CD growth and CYT, without cell death, indicate SMT is bacteriostatic for CD. There was no evidence of SMT resistance. Evaluation of further dosing regimens are warranted to optimise SMT efficacy