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Combatting Bacterial Resistance in Europe - Clostridium Difficile Infections

Periodic Reporting for period 3 - COMBACTE-CDI (Combatting Bacterial Resistance in Europe - Clostridium Difficile Infections)

Reporting period: 2019-11-01 to 2021-04-30

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 in testing frequency and 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.
In year one, 12 countries took part in the project, with 3163 samples submitted for testing at the European Coordinating Laboratory in Leeds, UK. A case/control study was performed in year two, as well as a survey of current knowledge and practices for CDI diagnosis, treatment and management across participating countries. The results of the survey were used to develop a health economics model in year three. In addition, a transmission model was developed in year three, simulating the transmission of C. difficile between patients in a hospital setting, over a five year time period.

Overview of the key results disseminated in year three:
1. Infographic (https://www.combacte.com/news/combacte-cdi-launches-infographic/). The infographic contains key data on the sample testing, case/control, and survey studies; data disseminated as conference presentations.
2. Key differences in diagnosis and patient populations between community and in-patient Clostridioides difficile infections (CDI) (http://dx.doi.org/10.2139/ssrn.3812436 or https://ssrn.com/abstract=3812436)
3. The Bioinformatic database associated with this publication (available at doi: 10.1093/jac/dkab097) is the NCBI Bioproject Genome Resources ID679767, a public repository of DNA sequencing and descriptive sample information data (https://www.ncbi.nlm.nih.gov/bioproject/?term=679767%5Buid%5D).

Results presented in the full manuscript (2) demonstrate that the diagnosed burden of CDI varies markedly across Europe in both hospital and community settings.The proportion of missed cases in community vs hospital settings was almost 30-fold higher, highlighting lack of recognition of CDI as a community-onset infection. The full manuscript (2) describes 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, and differences in outcome between patients diagnosed as toxin positive vs positive only for the organism. CDI patients within the hospital setting were older than those in the community, had more severe infections and more cases of recurrence. Risk factors for the development of toxin positive CDI were observed (including when diagnosed by the ultra-sensitive toxin assay, a diagnostic tool accessed via the EFPIA partners); no risk factors were identified for the presence of the organism alone. Exposure to antibiotics is a risk factor in both settings, but is associated with different classes of antibiotic; cephalosporins/fluoroquinolones (hospital) and penicillin (community). The data from the BioFire GI panel highlighted that 80% of CDI patients have no other pathogen detected (2). In addition, 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. Outbreaks of specific RBTs were common in Eastern European countries (2), whilst Northern and Southern European countries had more RBT diversity; this may suggest that there are more effective infection prevention strategies in the latter countries. The sequencing data also allowed the identification of the molecular basis of antimicrobial (metronidazole) resistance among C. difficile isolates, data presented in full manuscript and bioinformatic database (3).

The transmission model estimates that countries with the smallest difference between known and true incidence of CDI are the countries with the highest levels of sampling and testing. Predictions from the model suggest that many European countries are significantly underestimating the incidence of CDI in hospitals through missed opportunities to test patients and that decreased antimicrobial consumption and increased testing could result in a reduction in CDI incidence in hospitals. These results presented at the European Society of Clinical Microbiology and Infectious Diseases (ECCMID) July 2021 (Title: Impact of testing on C. difficile infection in hospitals across Europe: a mathematical model. No link available yet) will be disseminated as full scientific manuscript.

Awareness of European CDI treatment and healthcare costs of CDI diagnostic and treatment measures vary markedly according to countries and healthcare settings (1). A higher health-economic burden of patients developing recurrent CDI was observed, with compliance to national/international treatment guidelines improving health-economic outcomes of CDI patients (results presented at ECCMID 2021, Title: A pan-European Cost-of-Illness analysis of patients with Clostridioides difficile infection: Results of COMBACTE-CDI. No link available yet).
Our ambitious proposal aimed 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, comparing overall costs in different European healthcare settings to allow simulation of the economic impact of novel CDI treatment options, even prior to market authorization. The consortium achieved these goals within the project period.
Results show that prevention of recurrent CDI should be the focus of patient care to identify a clinically and economically sound prevention strategy. Awareness of CDI and guidelines has improved in hospital sites across Europe but there is still disparity between countries and a lack of awareness and testing for CDI in the community. No consistent approach across the different healthcare economies was identified (better compliance with guidelines in hospital did not necessarily reflect better recognition of cases in the community). These highlight the need for widespread education, as well as emphasizing the lack of good quality evidence about community cases within guidelines; something the consortium is well placed to address. 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. COMBACTE-CDI will provide a research platform to enable future clinical trials of novel CDI diagnostics, therapeutics and preventative options.
Figure 1. Schematic representation of study design (WP1 &WP2).
Figure 2. COMBACTE-CDI project structure.