Metagenomic sequencing in public health – can long read sequencing be used to tackle antimicrobial resistance?

Antimicrobial resistance (AMR) is one of the greatest challenges facing health systems, causing an estimated 4.71 million deaths globally in 2021. It has been ten years since the World Health Organisation declared AMR to be a global health emergency, yet little progress has been made in slowing the development of resistance or finding alternative therapies. 

As AMR continues its dogged spread, it is more important than ever to ensure that the right treatment is provided at the right time. Empirical prescribing, where an antibiotic is prescribed before the infecting pathogen and its antimicrobial susceptibility has been identified, places unnecessary selective pressures on pathogens, driving the increase in drug resistance. Progression to sepsis, a dysregulated immune response to infection, becomes more likely where a growing number of patients have infections resistant to treatment.

Pathogen whole genome sequencing is a powerful tool to identify the cause of infection, find AMR determinants and inform surveillance of emerging drug resistance. Pathogen sequencing does not occur routinely for patient care. The majority of pathogen sequencing for bacterial characterisation and surveillance has been carried out as part of grant funded research to answer specific questions, rather than provide routine services. Most sequencing focuses on one pathogen requiring precise isolation and culture. This creates a bottleneck when considered in a clinical context, because patients with serious infections may not have the time to wait for sequencing of a pure culture. 

Metagenomics: sequencing the haystack to find the needle

Innovative solutions to combat AMR and bacterial transmission are critical as treatment resistance, and even multi-drug resistance, increase. Metagenomic sequencing represents a promising step towards translation of pathogen genomics into routine clinical practice. Where traditionally, pathogen sequencing isolates and sequences a single pathogen, metagenomics sequences all microorganisms in a sample. The use of long read sequencing increases the accuracy for identifying pathogens or presence of drug resistance. This data offers exciting opportunities, especially in the push towards clinical diagnostics and surveillance for AMR. 

UK government lays foundations to develop metagenomic sequencing

The UK Health Security Agency (UKHSA) Pathogen Genomics Strategy , released in 2024, aims to advance the clinical development and implementation of pathogen whole genome sequencing. The strategy encourages the use of genomic data to optimise clinical and public health decision making, drive improvements in diagnostics and therapeutics, and push innovation in pathogen genomics. As part of this, two new services utilising metagenomic sequencing technologies have recently been launched in collaboration with UKHSA, NHS England and academic partnerships. 

The first is an expansion of Guy’s and St Thomas’ (GSTT) NHS Foundation Trust rapid metagenomics programme in partnership with Oxford Nanopore Technologies. Building on a successful pilot where rapid metagenomic testing was used to match patients with respiratory disease to the right treatment within 6 hours, this new diagnostic service represents a major step forward for patients, improving timeliness and effectiveness of treatment.

The respiratory metagenomic service has demonstrated clinical utility in supporting prescribing decisions and getting the correct treatment to patients in faster time frames. Scaled up, this process has the potential to benefit large numbers of patients immediately and in the long-term by reducing empirical prescribing. 

Secondly, in January 2025, the UKHSA launched a world first initiative to aid in the rapid detection of infectious diseases. This pilot work, known as the ‘metagenomics Surveillance Collaboration and Analysis Programme’ or ‘mSCAPE’, will utilise metagenomic data for public health surveillance. mSCAPE will establish the first real-time, pathogen-agnostic bio-surveillance system across as many as 30 hospitals in NHS England. The consortium of clinical and academic partners will use national level metagenomic data to detect and respond to emerging pandemics and biological threats. Rapid response is key in the face of emerging or transmitting pathogens therefore mSCAPE has the potential to further a proactive model of disease prevention. The addition of genomic data will enhance existing surveillance networks used to monitor key healthcare associated pathogens.

Looking ahead, provision will need to be made for rapid and interoperable sharing of data to identify emerging trends or clinically significant variations in metagenomic analyses. These needs reflect those identified in the Sudlow Review which called for an overhaul of the handling of health data in the UK. The recommendations made by Professor Sudlow are transferable to pathogen genomics and this area would benefit from adopting the lessons identified in the report.

Metagenomics in the evolving health policy landscape 

Change NHS seeks to transform the NHS in England to deliver better health services for patients and populations. The UK Government has proposed three shifts through which they want to realise this vision. Implementation of metagenomics at this stage recognises the compelling evidence for the use of this novel technology in clinical practice. The potential for metagenomics to gain further traction in clinical practice can be seen in the 3 Shifts detailed within the NHS 10 Year Plan.

Shift 1, ‘Moving care from hospitals to communities’ includes the movement of diagnostic testing into community healthcare settings. In both bio-surveillance and antimicrobial stewardship, context is often key. Drug resistant strains are known to continuously circulate between different care networks, and primary care settings account for the highest antimicrobial use. Knowledge and understanding of AMR across the health system is essential to break this cycle. Expanding the pilot is a critical step, hopefully, to realise this vision.

Shift 2 seeks to ‘make better use of technology’. Both the launch of mSCAPE and expansion of the respiratory metagenomics program demonstrate recognition of the opportunities presented by long-read sequencing data. Long read data produced by platforms such as ONT’s MinION, provides high quality sequence information which increases confidence in species identification, antimicrobial resistance profiling and contextual data for local, national and international surveillance. 

In the case of shift 3, the addition of bio-surveillance begins to address the goal of ‘focussing on preventing sickness, not just treating it’ by providing an early warning system for preventing or reducing the spread of infectious diseases. These systems provide data for quicker AMR detection for antimicrobial stewardship, rapid action to be taken in the face of potential outbreaks and monitoring of emerging drug-resistant bacterial strains. 

Another step towards a preventative health system

These initiatives represent real progress towards implementation of metagenomics in a clinical context. Expansion of this pilot to more hospitals will provide essential evidence about delivery in practice, as well as inform key clinical questions for patient outcomes. The opportunity and ambition must be to implement this service nationally to ensure all NHS patients may benefit from this novel technology.