Five-year Pan-European, longitudinal surveillance of Clostridium difficile ribotype prevalence and antimicrobial resistance: the extended ClosER study.

Clostridium difficile infection (CDI) has been primarily treated with metronidazole or vancomycin. High recurrence rates, the emergence of epidemic PCR ribotypes (RTs) and the introduction of fidaxomicin in Europe in 2011 necessitate surveillance of antimicrobial resistance and CDI epidemiology. The ClosER study monitored antimicrobial susceptibility and geographical distribution of C. difficile RTs pre- and post-fidaxomicin introduction. From 2011 to 2016, 28 European countries submitted isolates or faecal samples for determination of PCR ribotype, toxin status and minimal inhibitory concentrations (MICs) of metronidazole, vancomycin, rifampicin, fidaxomicin, moxifloxacin, clindamycin, imipenem, chloramphenicol and tigecycline. RT diversity scores for each country were calculated and mean MIC results used to generate cumulative resistant scores (CRSs) for each isolate and country. From 40 sites, 3499 isolates were analysed, of which 95% (3338/3499) were toxin positive. The most common of the 264 RTs isolated was RT027 (mean prevalence 11.4%); however, RT prevalence varied greatly between countries and between years. The fidaxomicin geometric mean MIC for years 1-5 was 0.04 mg/L; only one fidaxomicin-resistant isolate (RT344) was submitted (MIC ≥ 4 mg/L). Metronidazole and vancomycin geometric mean MICs were 0.46 mg/L and 0.70 mg/L, respectively. Of prevalent RTs, RT027, RT017 and RT012 demonstrated resistance or reduced susceptibility to multiple antimicrobials. RT diversity was inversely correlated with mean CRS for individual countries (Pearson coefficient r = - 0.57). Overall, C. difficile RT prevalence remained stable in 2011-2016. Fidaxomicin susceptibility, including in RT027, was maintained post-introduction. Reduced ribotype diversity in individual countries was associated with increased antimicrobial resistance.

Omadacycline Gut Microbiome Exposure Does Not Induce Clostridium difficile Proliferation or Toxin Production in a Model That Simulates the Proximal, Medial, and Distal Human Colon.

A clinically reflective model of the human colon was used to investigate the effects of the broad-spectrum antibiotic omadacycline on the gut microbiome and the subsequent potential to induce simulated Clostridium difficile infection (CDI). Triple-stage chemostat gut models were inoculated with pooled human fecal slurry from healthy volunteers (age, ≥60 years). Models were challenged twice with 107 CFU C. difficile spores (PCR ribotype 027). Omadacycline effects were assessed in a single gut model. Observations were confirmed in a parallel study with omadacycline and moxifloxacin. Antibiotic instillation was performed once daily for 7 days. The models were observed for 3 weeks postantibiotic challenge. Gut microbiota populations and C. difficile total viable and spore counts were enumerated daily by culture. Cytotoxin titers and antibiotic concentrations were also measured. Gut microbiota populations were stable before antibiotic challenge. Moxifloxacin instillation caused an ∼4 log10 CFU/ml decline in enterococci and Bacteroides fragilis group populations and an ∼3 log10 CFU/ml decline in bifidobacteria and lactobacilli, followed by simulated CDI (vegetative cell proliferation and detectable toxin). In both models, omadacycline instillation decreased populations of bifidobacteria (∼8 log10 CFU/ml), B. fragilis group populations (7 to 8 log10 CFU/ml), lactobacilli (2 to 6 log10 CFU/ml), and enterococci (4 to 6 log10 CFU/ml). Despite these microbial shifts, there was no evidence of C. difficile bacteria germination or toxin production. In contrast to moxifloxacin, omadacycline exposure did not facilitate simulated CDI, suggesting this antibiotic may have a low propensity to induce CDI in the clinical setting.