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Combatting Bacterial Resistance in Europe - Clostridium Difficile Infections

Periodic Reporting for period 2 - COMBACTE-CDI (Combatting Bacterial Resistance in Europe - Clostridium Difficile Infections)

Reporting period: 2018-11-01 to 2019-10-31

Clostridium difficile infection (CDI) is one of the most prevalent healthcare associated infections, affecting both hospitalized patients and, more recently recognized, individuals in the community. CDI poses an extensive burden of morbidity, mortality and healthcare resource utilization, and so requires effective prevention and management strategies. Epidemiological data are limited and studies typically examine part of a healthcare economy, mostly focused on single countries/healthcare systems. Thus, there is a lack of robust, comprehensive data on the impact of CDI across Europe. Furthermore, we know that large variations of testing frequency and the sensitivity of CDI tests across Europe mean the size of the problem is underestimated. Combating Bacterial Resistance in Europe-CDI (COMBACTE-CDI) therefore aims to develop a detailed understanding of the epidemiology and clinical impact of CDI across multiple European countries.
During the first year the consortium successfully recruited sites in 12 countries to take part in the project, with 3163 samples submitted for testing at the European Coordinating Laboratory in Leeds, UK. Analysis demonstrates that the diagnosed burden of CDI varies markedly across Europe in both hospital and community settings. Reduced sampling/testing in Eastern Europe appears to be inversely related to the proportion of RBT027 strains identified, suggesting lack of suspicion leads to under-diagnosis and outbreaks of infection. The proportion of missed cases in community vs hospital settings was almost 30-fold higher, indicating CDI is under-recognised as a community-onset infection. In addition, the consortium was able to leverage new state of the art diagnostic assays via the EFPIA partners. Correlation between ultra-sensitive toxin assay results and patient data are lacking however; this is an important subset to include in the case/control study. The data from the BioFire GI panel showed that co-infecting pathogens differed between hospital and community samples. Comparisons of strains of C. difficile show that there are marked differences in PCR-ribotypes (RBTS) from hospital vs community samples, with certain strains only in hospital cases. The proportion of RBT078, however, was similar in both settings, suggesting there may be a common transmission source for this strain. Outbreaks of specific RBTs were common in Eastern European countries, whilst Northern and Southern European countries had more RBT diversity; this suggests there may be more effective infection prevention strategies in the latter countries.

In year two the case/control studies have shown significant differences in both risk factors for developing CDI, and outcomes of CDI between those diagnosed within a hospital setting and those in the community. There are significant differences in outcome between patients diagnosed as toxin positive vs positive only for the organism. In addition, there are differences between toxin positive patients within the hospital setting and those in the community, with those in hospital appearing to be older, have more severe infections and more cases of recurrence. Interestingly, toxin positive community patients had significantly more days of diarrhoea before they had a sample taken vs those in the hospital setting, suggesting they either take longer to seek medical care or there is less propensity to test in the community. This may be because clinical suspicion is lower in the community, with GP’s less likely to request testing, or because guidelines in some countries suggesting only those with persistent symptoms should be tested. Risk factors for the development of toxin positive CDI were observed; no risk factors were identified for the presence of the organism alone. While there are some similarities in risk factors for the development of toxin positive CDI in both the community and the hospital, there are also differences. Exposure to antibiotics is a risk factor in both settings, but is associated with different classes of antibiotic; cephalosporins/fluoroquinolones (hospital) and penicillin (community). In addition, contact with an infant showed increasing risk in the community but not in the hospital, although this was not significant. These unique data provide the building blocks for a CDI transmission model (year 3).

All of this data suggests that there are disparities between countries and across healthcare economies, with disproportionately more cases missed in the community. This was further supported by data gathered on a survey of current knowledge/ practices for CDI diagnosis, treatment and management. There was wide variability in awareness and compliance with guidelines across Europe, both in and out of the hospital setting, but with a lower knowledge base in community practitioners. The need for widespread education has been highlighted, as well as emphasizing the lack of good quality evidence about community cases within guidelines; something the consortium is well placed to address. The survey also provided data on health economics within each country, again showing wide variation. These data will be coupled with the data from the case/control study to allow the consortium to build a best-practice model that can be adapted to different healthcare settings (year 3). Thereby providing the tools to reduce burden of disease, morbidity and mortality; improving the health of citizens across Europe. The participants in the COMBACTE-CDI consortium play key roles in multiple, relevant parallel European CDI activities, creating the leverage needed to put the findings into real-world practice.
Our ambitious proposal aims to go beyond the state of the art in 8 aspects: quantification of CDI in the whole healthcare economy; contemporaneous comparison of animal/ food/human isolates; identification of potential drivers of strain clustering, providing enhanced information to aid further trial/study design and conduct; use of a novel highly sensitive diagnostic assay for more accurate CDI case definition; provision of both cost-effectiveness and transmission models to enable further evaluation of interventions; and finally, by comparing overall costs in different European healthcare settings, we will allow simulation of the economic impact of novel CDI treatment options, even prior to market authorization.
COMBACTE-CDI is the merger of European expertise on clinical, diagnostic, and therapeutic CDI issues and the expertise and input of 7 EFPIA partners. It brings together experts from CDI projects (EUCLID, ECDIS-NET), the largest existing (IMI-funded) clinical and laboratory network in Europe (CLIN-Net and LAB-Net) , and a network that maps all surveillance activities related to AMR in Europe (EPI-Net, also IMI-funded). COMBACTE-CDI, therefore, maximizes the integration of previously initiated collaborations within Europe to develop a detailed understanding of CDI burden, transmission, and control practices in Europe.
COMBACTE-CDI will have major impacts on European citizen health, and will significantly increase knowledge and expertise on CDI, as well as providing a research platform to enable future clinical trials of novel CDI diagnostics, therapeutics and preventative options.