Epidemiological and genetic investigations into carbapenem resistance caused by horizontal gene transfer within hospitals.

Antibiotics are used to treat infections but some are developing resistance (AMR). This is a serious problem as it threatens many of the medical procedures we take for granted, including surgery and chemotherapy. The government estimates that by 2050, 10 million lives a year are at risk due to AMR. Bacteria can develop resistance by acquiring genes that protect them from antibiotics. The bacteria and the resistance genes can spread between patients, particularly within healthcare environments.

Cases of antibiotic resistant bacteria are increasing worldwide and also within Imperial College Healthcare Trust (ICHNT). This is of great concern as infections with resistant bacteria are hard to treat and often result in worse patient outcomes. Infection control procedures try and restrict the spread of resistant bacteria within healthcare settings. To do this they focus on strategies such as hand washing between patients and good cleaning and maintenance of the hospital environment. To support this work, infection control teams need detailed information on the type of bacteria and their underlying cause of resistance. As some patients can carry many different species of antibiotic resistant bacteria in their gut, it can be difficult to track how spread from one patient to another has occurred. To complicate the picture more, there are lots of different ways that antibiotic resistance can occur, and some bacteria carry more than one gene coding for resistance.The methods used to track the spread of antibiotic resistant bacteria currently are very slow and delay effective infection control responses. Without this patient outcomes are worse and the bacteria can spread to other patients causing outbreaks of AMR.

This project will develop new ways to demonstrate the spread of bacteria around hospitals, detecting possible links between cases of AMR that have not been found before, and including pathways of where patients have been in the hospital and how much antibiotic use there has been. The project will use faster methods to characterise resistant bacteria by examining their genome sequence. It will also look at the small pieces of genes that can be spread between different bacteria (plasmids) in more detail.

Putting all this information together will allow rapid infection control responses at ICHNT, to stop the spread of infections. The sequencing tool will also allow us to better understand which resistant bacteria are circulating within patients and the environment at ICHNT and how they have become resistant so that we can limit their patient to patient spread. By identifying these additional risk factors, the infection control team at ICHNT will be able to directly tackle the problem of silent CPE spread, and it will provide valuable information to other hospitals in both in the UK and across the world attempting to tackle the threat of these resistant bacteria.

The systems put in place will continue to benefit patients long after the project has finished, as they will be built entirely within the hospital, and it will be possible to easily adapt them to future emerging AMR.

Objective 1: Enhanced epidemiological tracking using spatial-temporal outbreak analysis, incorporating antibiotic resistance mechanism profiling to allow accurate modelling of spread of CPE around hospitals. Conventional CPE outbreak tracking relies on manual interpretation of microbiology data and patient bed movements to track and identify clusters. This project will enhance the hospital level outbreak picture by using spatial-temporal data analysis on R to make use of data readily available at ICHNT. Integrating this data will provide a novel, responsive and live updated system to predict outbreaks and track CPE transmission, and allow comparison of resistance mechanism without being reliant on specific bacterial species.
Objective 2: Use of whole genome sequencing (WGS) to enhance conventional typing mechanisms, to investigate whether spread of CPEs is clonal in "hospital strains" of bacteria. Using strains identified as potentially healthcare acquired at ICHNT, bacterial DNA will be extracted, purified and prepared for Illumina Sequencing. Sequences will be assembled and compared to establish multi-locus sequence type (MLST) and resistance genes. Comparison to existing sequencing data from previous ICHNT outbreaks will be performed to look at bacterial strain evolution over time.
Objective 3: Investigate whether there is evidence of inter-species transfer of plasmids driving polyclonal outbreaks, using blaIMP as a model of an emerging CPE. IMP carbapenemase is an emerging CPE strongly associated with plasmid transmission, with colonising isolates seen in a diverse range of bacteria at ICHNT since 2018. Additional long read MinION sequencing will be performed on a selection of blaIMP isolates to establish whether spread is due to conserved plasmid transmission between species.
Data from both WGS and MinioN will be analysed to reconstruct potential outbreaks, and will ultimately be fed back into the spatial-temporal models described.

This proposal addresses the challenges of antimicrobial resistance (AMR) through a multifaceted approach, incorporating the development of innovative rapid AMR sequencing and intelligent use of hospital data to improve AMR research and interventions at the local level. The potential outcomes for the research are far reaching, and will influence a wide range of researchers, healthcare providers, environmental researchers, policy makers, industry and the public. The main impact from this research will be in the following areas:

Societal Benefit: AMR is an increasing global health problem, causing significant morbidity and mortality and healthcare costs. Patients with CPE infections are treated with last line antibiotics with less efficacy and more side effects. Accurately tracking the mechanisms by which AMR is spreading is key to halting the spread and preventing resistance becoming endemic.

Translation: ICHNT is currently a world leader in AMR research; this project will build upon and be supported by extensive local interdisciplinary collaborations to address the challenge of AMR. A wide range of stakeholders will benefit from this research including academic researchers (both clinical and non-clinical), healthcare providers, policy makers, industry and the public. The benefits will be to these groups both the UK setting and abroad.
The data generated will improve our understanding of how AMR emerges and spread within hospitals, and will be used to develop a sequencing pipeline for the timely characterisation of CPE. The tools will ensure the Trust is advancing technological developments for translational research within the field of AMR to benefit local ICHNT service provision and hospitals worldwide.

Scientific and academic dissemination: The project is expected to result in high impact publications and the results will also be presented at national and International conferences, including IPS, HIS and ECCMID. The work will be incorporated into existing seminars and workshop series hosted by the Antimicrobial research collaborative (ARC) and NIRH Health protection research unit (HPRU).

Communications, engagement and society: Professor Holmes' research team recognise the importance of patient involvement in directing the development and adoption of research. They have extensive experience in Public Patient Involvement (PPI) activities including patient, public research cafes and interactive exhibits at Imperial College Festival. The project will be supported by the HPRU PPI committee and a patient representative, who will support and inform the research and WGS pipeline development. The team has also performed and published extensive work on patient engagement. The team regularly engages with public scientific events and has established web portals and social media links to increase public awareness of CPE and AMR.

This project is expected to improve the cross-disciplinary clinical and IPC management of AMR cases. In turn this should improve patient outcomes and reduce transmission rates, ward closures and CPE outbreaks. The benefits of the project will be available to healthcare professionals at ICHNT within the first year of the project, and will be sustained after the project has been completed, leaving a legacy of healthcare improvement.