In 2019, drug resistant microbial infections claimed more than 1.3 million lives, and over the next 25 years, it is expected that more people will die from drug resistant infections than from cancer. New antimicrobials and alternatives to traditional chemotherapeutic agents are urgently needed to treat infections that are resistant to all current therapies, alongside rigorous policies and risk assessment procedures to safeguard the drugs we already have. In this article from our On Resilience publication, Dr Michael Bottery, Professor Michael Brockhurst, Professor Lucie Byrne-Davis, Professor Michael Bromley, and Dr Wendy Thompson explore ways to tackle antimicrobial resistance.

• Globally, increasing levels of antimicrobial resistance mean that crucial drugs are no longer effective for treating many bacterial, viral, fungal, and protozoal infections
• Researchers at The University of Manchester are developing new medicines – but a lack of coordinated regulatory approval between the medical and agricultural sectors means these drugs are being put at risk before they can be rolled out to patients.
• Meanwhile, national and global cooperation on antimicrobial safeguarding is needed to safeguard existing drugs, particularly in dentistry, where antibiotic prescription has increased since the COVID-19 pandemic.

Antimicrobials are lifesaving drugs. Since their introduction – alongside vaccines, improved public health, and better sanitation – deaths from infectious diseases have declined dramatically. Globally, however, increasing levels of antimicrobial resistance (AMR) mean that these crucial drugs are no longer effective for treating many bacterial, viral, fungal, and protozoal infections (such as malaria). Keeping antimicrobial drugs working has been highlighted as a global priority by the United Nations (UN) and World Health Organisation (WHO), and as an essential prerequisite for delivering the UN’s Sustainable Development Goals. In 2019, drug resistant microbial infections claimed more than 1.3 million lives, and during the next 25 years, it is expected that more people will die from drug resistant infections than from cancer. The University of Manchester’s AMR Network is working to better understand and discover new solutions to the crisis of antimicrobial resistance, to help safeguard our health and wealth in Greater Manchester, the UK, and globally.

The origins of resistance

Firstly, effectively using existing antimicrobial drugs requires us to better understand the molecular mechanisms of resistance, and the evolutionary processes leading to the emergence of AMR. The Manchester Fungal Infection Group has discovered new resistance mechanisms against clinical antifungals and has been central in showing how their use in the clinic and in crop protection creates an environment for resistance development. Meanwhile, bacteriologists have shown that the evolution of resistance to commonly used antimicrobials varies in predictable ways, according to conditions at the site of infection. This suggests new ways in which resistance emergence could be predicted – or even limited.

New antimicrobials and alternatives to traditional chemotherapeutic agents are urgently needed to treat infections that are resistant to all current therapies. Researchers from the University have been working to discover new ways to treat infections, such as tuberculosis, that block key infection processes and lessen the damage caused. Alternatives to antibiotics, such as phage therapy – which uses viruses that target bacteria to treat bacterial infections – are increasingly used as a last resort treatment. We are working to understand how resistance evolves against phages to guide the rationale design of phage therapies that best prevent resistance emerging.

It is critical to understand how and where drug resistance emerges. Without this knowledge, we cannot implement effective surveillance or antimicrobial stewardship (AMS). Of particular concern is the steady rise in antifungal resistance driven by the use of antifungals in crop protection. Alongside the University NHS Foundation Trust, we are working to understand the evolutionary mechanisms driving resistance in pathogenic fungi, so strategies can be developed to reduce resistance levels in patients and the wider environment. We are currently predicting that resistance will evolve to next-generation antifungals in agricultural settings before they are even put into clinical use.

In the clinic

AMS aims to optimise the use of antimicrobial drugs to ensure their effectiveness in the long run. Across the NHS, dentists are the second highest prescribers of antibiotics after GPs, and ahead of hospitals in the number of antibiotic items and net prescription costs in 2021-2022. Furthermore, dentistry was the only part of the NHS to increase antibiotic prescribing in 2020, due to COVID-19 restrictions on the provision of dentistry. Research led by The University of Manchester, with national and international colleagues, is developing and testing interventions for use by the UK Health Security Agency, NHS, and in other countries around the world to reduce unnecessary and inappropriate antibiotic prescribing by dentists.

Our researchers are also leading the development of international policy on antimicrobial stewardship, through the FDI World Dental Federation and through its influence with the WHO. Pioneering work on antifungal stewardship in intensive care units, by the University and the NHS Foundation Trust, has resulted in significant reduction (50%) in both antifungal consumption and mortality to bloodstream infection by Candida yeast (a common fungal infection).

An antimicrobial stewardship project aimed at the education of secondary care teams is led by the Division of Medical Education. AMS TEACH is an NIHR Policy Research Programme funded collaboration between The University of Manchester, UCL, the University of Newcastle, and Public Health England. The project aims to understand how, and to what extent, education and training interventions for health professionals about AMS use behavioural science and, crucially, to develop policy recommendations to improve the impact of education and training on stewardship behaviours.

What can – and should – be done?

AMR has been recognised by the UK government as “one of the most pressing global health challenges” faced this century. The UK’s 20-year AMR vision highlights that low-and-middle-income countries will be worst affected, but more affluent nations will also see higher mortality and longer lasting infections.

COVID-19 sharply demonstrated that diseases are not limited to a single nation, and tackling antimicrobial resistance requires global cooperation. As a start, international bodies like the UN, WHO, and the EU should provide detailed guidance on the use of antimicrobials in agriculture. This should include risk assessments on the likelihood of cross-resistance evolving because of the dual use of the same types of antimicrobials across agriculture and the clinic, to limit the risk posed by AMR evolving in the environment.

Key to tackling AMR is understanding the scale of the risk. International programmes are in place to monitor the emergence of resistance, but more can be done on predicting evolution, and the impacts of commercial use of antimicrobials on resistance in the clinic. This is particularly true for novel antimicrobials, where new drugs may be deployed in agriculture before they are approved for clinical use.

Regulators should ensure that before a new antimicrobial is permitted for commercial use, independent assessment has been made of the potential impact on clinical use. In the UK, this will require cooperation between the Environment Agency, the Medicines and Healthcare products Regulatory Agency (MHRA), and the UK Health Security Agency; establishment of a cross-agency working group would help to facilitate this. The PATH-SAFE programme may provide a useful template for this, in bringing together public and private sectors.

At a departmental level, UK policymakers should make the most of Britain’s regulatory divergence from the EU to drive research into phage therapies. The Department of Science, Innovation and Technology should make phage therapies a priority research area, and coordinate expertise and regulatory development across the UK, in partnership with the Department for Health and Social Care, the National Institute for Health and Care Excellence, and the MHRA. In an inquiry response via the Microbiology Society, we recommend that one pathway to doing so is to increase the number of phage-specific funding opportunities, alongside investigating the use of phages in agriculture and animal medicine, where there are few regulatory hurdles for research.

Lastly, widespread study of the behavioural and social science aspects of antimicrobial use, and the development of evidence-based behavioural interventions to influence this, is needed. Our research highlights the need for a widely available evidence-based resource, to guide the reporting for AMR and AMS behaviour change interventions. A simple, standardised reporting framework will help the delivery of robust training to health professionals on how to responsibly manage antimicrobial use.

Lessons and opportunities from COVID-19

Our research has found that the 25% increase in antibiotic prescribing by dentists during the COVID-19 pandemic was driven by system-level influences, which left dentists feeling frustrated that they were unable to provide safe and effective care in line with clinical guidance. Remote management of urgent dental patients (tele-dentistry) was found to underpin the problem. The study found that this approach continued to be used by dental services commissioners in some parts of the country to manage the problem of poor access to NHS dentistry, and more recently, it has been included within the NHS England commissioning strategy for urgent dental care.

Targets for optimising antibiotic prescribing into the future should be at the system (commissioner) level and should focus on improving access to – and the delivery of – safe and effective care for people with acute dental problems, in accordance with the long-standing national guidelines and the WHO’s more recent antibiotics book. Focusing antimicrobial stewardship activities on reducing antibiotic prescribing alone may result in unsafe and ineffective care as, left untreated, dental infections can quickly become life-threatening.

Where next?

The future UK AMR strategy should draw on research from The University of Manchester and others, by identifying new ways to help conserve the effectiveness of antimicrobials for future generations. For their part, research bodies should aim to shape targets within, and support delivery of, the UK’s national AMR action plan and the WHO’s Global Action Plan on AMR, including through our global health research and education activities in LMICs.

Antimicrobial resistance is an existential threat, and one that is intimately entwined with the risks posed by climate change and overconsumption. For AMR, as with the climate crisis and resource scarcity, the solution lies in a mix of new innovations, and smarter guarding of current assets.