OneAMR: a rapid, accurate, point-of-care platform for the detection and prevention of antimicrobial resistance (AMR)

Antimicrobial resistance (AMR) is a serious threat to public health with 25,000 people a year in the EU dying from the five most common drug-resistant infections [1]. AMR is a global problem that has been accelerated by the overuse of antibiotics, if not brought under control it will leave us without any effective drugs to treat infections. One bacterial species, Klebsiella pneumoniae is frequently resistant to all antibiotics and is a major cause of hospital-acquired infections such as sepsis and pneumonia. Resistant infections are associated with longer hospital stays, increased costs of treatment and worse outcomes for patients when compared with non-resistant strains of the same species. So serious is the threat of AMR that in 2014 the Longitude Prize was created, a £10M challenge to invent a cheap, accurate and fast point-of-care test (POCT) that will help reduce the use of antibiotics [2], a prize that is currently unclaimed.

In order to treat an infection a doctor needs to know what organism it is caused by and what antibiotics will be effective against it. The gold standard antimicrobial susceptibility testing involves growing or culturing the organism to find the lowest concentration of antibiotic that will stop it growing, a value known as the minimum inhibitory concentration (MIC). This process is often automated in large hospital laboratories but can still take between two days and several weeks to complete. Doctors will prescribe a broad-spectrum antibiotic and wait to see if it is effective. This means patients may receive treatment which is ineffective or that unnecessarily selects for resistance. If treatment is targeted and fast it can improve the effectiveness of the early therapy leading to better outcomes, reduced hospital stays and less resistance in the clinical environment.

Genomic sequencing can help provide this information in much shorter time. This is done by sequencing the DNA which makes up the genomes of microbes and identifying the species by comparing it to those in a database of known sequences. By comparing to a database of known resistance genes and mutations, an attempt to predict drug sensitivity can be made, this is accurate for certain species such like Mycobacterium tuberculosis. For some pathogens it is very hard to predict resistance as it is conferred by complex genotypes that we cannot predict. Newer sequencing platforms such nanopore sequencing can run in real-time and can identify bacterial species in a matter of minutes. Such platforms could revolutionise clinical microbiology but for certain species the ability to predict AMR from just the genome is very limited. This project seeks to combine the genome and the transcriptional response to antibiotic exposure to dramatically improve the ability of rapid testing to predict antibiotic susceptibly.

The way this will be done is by encapsulating bacterial cells within microdroplets with the antibiotic of interest. After a short exposure time the genome and transcriptome of the same cell are sequenced and the information contained in the genome and transcriptome are combined to make a prediction of susceptibility. The overall aims of this project are to develop an instrument which can analyse blood and other clinical samples and provide accurate results in a rapid timeframe. This is traditional culture suitable for 21st century clinical microbiology.

1. https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/0909_TER_The_Bacterial_Challenge_Time_to_React.pdf
2. https://longitudeprize.org/challenge

OneAMR is a timely and innovative project which has the potential to have significant impact across a range of disciplines from industry to policy makers and governmental agencies;

Industry

One beneficiary of the success of OneAMR will be Oxford Nanopore Technologies a British company employing around 350 people which will experience growth resulting in an increase in taxable profilts and creation of high-quality new jobs in the UK. Nanopore sequencing is the only sequencing technology that can produce real-time data enabling OneAMR to provide rapid identification of infections and prediction of antimicrobial susceptibility. The company will benefit from consumable usage during the course of the grant but also more widely as the OneAMR sample preparation system leads to increased demand for nanopore sequencing products in the clinical setting.

The success of the project will also lead to interest from industrial partners who would like to licence the technology or run it a service. Oxford Nanopore Technologies themselves have licenced technology from academic groups in the past. The generation of intellectual property during the course of this project will promote collaboration between key stakeholders including University of Birmingham Enterprise, industrial partners and academics.

University Hospitals Birmingham NHS Foundation Trust (UHB)

A successful outcome to the clinical study in year 4 will push UHB to establish a larger trial to assess the wider implications of the new technology. Hospital management will want to establish whether the new method translates into a reduction in frequency of AMR infections they can report to NHS auditors. UHB is known for cutting edge emergency medicine and large clinical trials unit. The hospital will support further validation work because the cost of treating patients with resistant infections is extremely high are they are a risk to other patients and need to be isolated. They would rather move to a sequencing-based assay because management of reference labs are expensive to run and are more efficient at scale which reduces their responsiveness. This will promote collaboration between the academics leading the research and collaborators such as Mark Garvey, Associate Director of Infection Prevention and Control at UHB.

Policy Makers

Policy makers will benefit from the routine genome sequencing of clinical isolates at UHB which provides more accurate reporting on the numbers and classes of AMR than previous methods helping shape policy. The O'Neill report estimates $100T in global production will be at risk by 2050 if we do not act now and a figure of $30T to implement all the recommendations in the report one of which is investing in rapid diagnostics. The availability of rapid testing would allow policy makers to enact the O'Neill report guidance that hospitals and GP services refrain from prescribing antibiotics until a test has confirmed the presence of a bacterial infection achieving a key goal of the 5-year plan to reduce the unnecessary use of antibiotics.

Governmental Agencies

Government agencies such as Public Health England (PHE) would benefit from a lower work load as they are responsible for running reference services such as antimicrobial susceptibility testing which will be replaced by the OneAMR system. This allows them to focus on other important areas such as developing methods dealing with whole-genome sequences being deposited by OneAMR and other groups performing digital surveillance sequencing.

Patients and the general public

The patients of the Queen Elizabeth Hospital NHS Trust stand to benefit from the system as they will experience faster test results, more effective antibiotic treatment and reduced hospital stays. We will present our work at research showcases at the hospital every year, this is an opportunity to engage with the general public and tell them about the risks of AMR and what we are doing to tackle it.