COMBACTE-CDI

Background

The highly contagious bug Clostridioidies difficile or C. diff causes thousands of deaths every year in Europe. It can cause extremely unpleasant, sometimes severe or even fatal diarrhoea, often in the elderly or other vulnerable groups. It’s linked to a taking a course of antibiotics and the overgrowth of C. diff bacteria that leads to the production of a toxin that damages the lining of the gut.

A lack of studies has masked the real cost of the illness, both in terms of mortality and quality of life, as well as the financial cost to public health systems. People who get infected often get a second or third bout of the infection, which can lead to long hospital stays and a prolonged illness. That’s why in 2017, COMBACTE-CDI was launched in order to create an epidemiological snapshot of C. diff infection (CDI), both inside and outside healthcare settings. The mission was to produce an overview of the prevalence of the disease and its costs beyond single healthcare or regional settings, but on an EU-wide scale.

Sizing up the problem – inside and outside hospitals

The most recent data on the scale of CDI infection across European healthcare economies was published more than a decade ago by the European Centres for Disease Prevention and Control (ECDC). The data generated by COMBACTE-CDI is an update on this data, but it is also unique in that it covers both cases that occur in the community and hospital-onset cases.

The project was able to show that there are as many as three times more undiagnosed adults with CDI in the community compared to hospitals, but that there is a ‘lack of clinical suspicion’, meaning people are simply not being tested for it. This lack of testing, they conclude, should be addressed to improve patient care.

Exposure to antibiotics, they found, is a risk factor both inside and outside healthcare settings, and which antibiotic a person is exposed to differs in the two places. In terms of who is at risk, the more co-morbidities, the bigger the risk, regardless of where the CDI infection is picked up. Although certain strains were only found in hospital cases, others, notably one called RT078, had similar rates in both hospital and community settings, which suggests a common transmission source. The high number of cases in the community suggests that people are potentially being exposed to spores on a constant basis.

Dynamic transmission model and regional differences

The project developed a dynamic transmission model of CDI for hospitalised patients with the aim of examining the impact of testing rates and antimicrobial stewardship on the incidence of CDI in different countries across Europe. The team demonstrated that the true incidence of colonised and infected cases in hospital settings within different European countries can be predicted based on differences in national sampling and testing rates.

This dynamic transmission model predicts that many European countries are significantly underestimating the incidence of CDI due to lack testing, and that countries with high antimicrobial use are driving infection rates. Ultimately, they conclude that decreased antimicrobial use and increased testing could result in a reduction in CDI incidence in hospitals. They also found that the bacterial strains that are associated with hospital epidemics were also common in community cases in those same countries.

Outbreaks of specific types of C. difficile are common in eastern European countries. However, northern and southern European countries have more diversity in C. diff types and fewer outbreaks, suggesting more effective infection prevention strategies. This knowledge on the regional diversity is also important for the design of clinical studies and impacts on efforts for CDI therapeutic intervention development.

Reservoirs

The project also studied three different C. diff reservoirs at the same time: humans, animals, food; finding that potatoes are heavily infected with C. diff. This was the first time all three reservoirs had been studied in parallel. This new knowledge, which is based on a large sampled collection, is important not only to healthcare professionals and public health decision-makers, but also to pharmaceutical companies, diagnostics manufacturers, and companies that work in microbiome health, because it gives them a better idea where they can target their respective research efforts.

Economic cost

In terms of economics, the project findings show that the healthcare costs of CDI diagnostic and treatment measures vary quite a lot across countries and within healthcare settings, with treatment on general hospital wards costing the most.  They also found that there were higher costs associated with recurrent episodes, and that patients with CDI recurrence had a 3.5-fold prolonged overall hospital stay compared to a patient with a single episode of CDI. This prolonged hospitalisation results in almost four times higher overall costs. They conclude that prevention of recurrent CDI should be the focus of patient care to help weed out an appropriate prevention strategy.

Compliance with guidelines

They also identified differences in awareness of and compliance with guidelines in different settings and different geographical areas. The majority of the hospitals they surveyed used recommended CDI diagnostic testing, while lower compliance in some countries seems to impact the reported case rate. Their study highlighted poor practice associated with poor awareness of guidelines, for example continuing to use metronidazole in cases of recurrent CDI, which is advised against. This highlights opportunity for education.

Legacy – data and strain collection

COMBACTE-CDI amassed a well-characterised collection of C. diff strains whose genomes have been sequenced (their genetic makeup described in detail), which helped compare strain similarities. This was used in the testing of a bio-informatic tool called EPISEQ® CS, under development by the French diagnostics company BIOMERIEUX. They demonstrated the power of whole genome sequencing for C. diff, and the potential to move away from standard ways of characterising bacterial strains.

This large database is available online open access to anybody who wants it via a public repository (Bioproject Genome Resources). The database was also used to support and manage outbreaks in European countries during the course of the project, and even provided evidence to challenge the incorrect assignment of strains in an outbreak in Greece. It also helped the project partners understand the molecular basis of resistance to the antibiotic metronidazole among some C. diff strains, and revealed a new form of metronidazole resistance that is transmissible and should be investigated.

What’s next?

The datasets and models created during the project are available to be used as a resource by other researchers, whether for human, food or animal research. A group at the University of Leeds have used the transmission models and data from the project to create a model of best diagnostic practice and performance, which has fed into the development of a new rapid, point of care CDI diagnostic assay, funded by UK Research and Innovation (UKRI). This could potentially lead to the creation of a new SME.

COMBACTE-CDI created a network of academic and EFPIA partners for future collaboration via a new entity called ECRAID – the European Clinical Research Alliance on Infectious Diseases – a clinical research organisation and network for infectious diseases that offers a single point of access to a pan-European clinical research network, with the ultimate aim of driving down the impact of infectious disease and AMR across Europe.