Abstract
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.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Department of Microbiology, Leeds Teaching Hospitals Trust, Leeds, UKHealthcare Associated Infections Research Group, The LeedsInstitute of Medical Research, University of Leeds, Leeds, UKAstellas Pharma, Inc., Chertsey, UKClostridium difficile infection (CDI) represents a major healthcare burden in the developed world [18].Metronidazole and vancomycin have been the mainstays of CDI treatment in recent decades [24]; high recurrence rates and reports of reduced susceptibility to metronidazole among epidemic C. difficile PCR ribotypes (RTs) have highlighted the need for new agents [1, 24]
There was a degree of variation between RTs with regard to prior occurrence of CDI (Table 2); these data should be interpreted with caution due to the lack of information for the majority of samples
We report a single fidaxomicin-resistant isolate of RT344 (MIC ≥ 4 mg/L), isolated in year 5 of the study; this isolate was resistant to moxifloxacin, clindamycin and imipenem, but sensitive to all other antimicrobials tested
Summary
Healthcare Associated Infections Research Group, The Leeds. Clostridium difficile infection (CDI) represents a major healthcare burden in the developed world [18]. Metronidazole and vancomycin have been the mainstays of CDI treatment in recent decades [24]; high recurrence rates and reports of reduced susceptibility to metronidazole among epidemic C. difficile PCR ribotypes (RTs) have highlighted the need for new agents [1, 24]. In two phase 3, double-blind, randomized, parallelgroup trials, it demonstrated non-inferiority in initial cure of CDI and lower rates of recurrence, compared with oral vancomycin [5, 15]. Fidaxomicin is associated with greater preservation of the intestinal microbiota compared with vancomycin [14]
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