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

点击翻译按钮获取中文摘要

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.pdf2. https://longitudeprize.org/challenge