Therapeutic areas in focus
Resisting change: The pathway to better AMR planning
The latest global survey on antimicrobial resistance has seen a global plan initiated by WHO. ICON’s Caroline Forkin talks us through the various actions that should be taken to improve AMR planning
Antimicrobial resistance (AMR) is an urgent and growing public health threat. Since the transformative global adoption of antimicrobials in the last century, pervasive misuse and overuse has driven widespread AMR in pathogens, and rendered once reliable treatments ineffective. The drivers of AMR are multifaceted, with far-reaching consequences. Meanwhile, the development of alternative antimicrobials and interventions has been slow. With so many forces accelerating a problem that spans the globe, mitigation will require unprecedented social support, and coordinated, holistic action is needed to help combat the growing global public health crisis of AMR.
Reinforce understanding of AMR
Many antimicrobial drugs already have an ancient history of use and evolved resistance by microbes. Understanding the evolutionary relationship between antimicrobials and microbial resistance helps explain why acquired AMR can emerge so quickly following intensive antimicrobial use.
Microbial resistance is the result of a random genetic mutation or a combination of mutations impairing an antimicrobial’s utility. In the absence of an antimicrobial, resistance mutations tend to be disadvantageous because they are costly. However, when a population is exposed to antimicrobials, resistance mutations are often necessary for survival, and are likely to be passed from one generation to the next. Resistance genes can also be spread between unrelated microbes through horizontal gene transfer (HGT).
Because the presence of antimicrobials determines whether resistance mutations provide a competitive advantage or disadvantage, AMR prevalence is tightly correlated to the likelihood of antimicrobial exposure. Before widespread antimicrobial use by humans, AMR was generally contained to a small population of microbes that had natural, sustained exposure to an antimicrobial. However, when an antimicrobial is intensively applied by humans, the advantage of acquiring resistance becomes widespread.
Following sustained antimicrobial use in a clinical or agricultural setting, pre-existing resistance genes – which took generations of antimicrobial exposure to first evolve – can be rapidly and ubiquitously acquired through HGT by microbes in a shared environment. Microbes transported to other environments may then bring resistance with them.
Understanding AMR mechanisms is key to developing intervention strategies to disrupt AMR emergence and spread. In addition, comprehending why AMR occurs, and the risks it poses to public health, will support personal investment in initiatives to combat it.
Optimise antimicrobial use
The utility of antimicrobials in preventing infectious disease has transformed medicine and agriculture. Preventative antibiotics drastically reduced the risk of surgery, and common deadly diseases, including pneumonia and tuberculosis, suddenly became treatable. Moreover, antibiotics in agriculture made it possible to raise faster-growing livestock at higher densities.
Initially, the application of antimicrobials in these settings was indiscriminate.
However, the subsequent body of evidence linking antimicrobials to AMR motivated private initiatives and governmental regulations to temper antimicrobial use. Still, substantial progress must be made before antimicrobial application is optimised in healthcare and food production.
Up to 50% of all antimicrobials may be being used inappropriately in human healthcare.
Appropriate and restricted use of antimicrobials will require the implementation of diagnostics able to indicate which treatment is most likely to be effective, and reduce the number of antimicrobials prescribed. Diagnostics that can monitor a patient’s response to treatment may also help to prevent continued use of an ineffective treatment. Eventually, the adoption of treatment alternatives to existing antimicrobials may help ensure treatment efficacy when the risk of AMR is high. Optimised antimicrobial use also depends on patient compliance. Suspending treatment before an infection is entirely cleared can lead to a recurrence that is more resistant than an initial infection, and can increase the risk of AMR outbreaks. Here, clinicians play a critical role in educating patients about the importance of following an antimicrobial regimen.
Agriculture accounts for more than 75% of annual antimicrobial consumption in the EU and the US, and has been directly linked to AMR disease in humans.
Addressing overuse and misuse of antimicrobials in agriculture will involve three strategies:
1. Abolition of trace antibiotics used in feed to promote growth
2. Abolition of continuous low-dose antibiotics for disease prevention
3. Using alternative antimicrobial treatments wherever possible
Antimicrobials also enable unhealthy agricultural practises promoting disease acquisition and transmission, such as overcrowding and inbreeding. Reintroducing practises that promote the health of livestock and crops could help reduce the number of infections, and help to minimise the need for preventative antimicrobials.
Governmental policies and initiatives supporting more sustainable food production practises can have a profound effect on optimising antimicrobial use in agriculture. For example, Vietnam’s National Action Plan for addressing AMR prompted the ViParc (Vietnamese Platform for Antimicrobial Reductions in Chicken Production) project. ViParc became the first large-scale intervention tackling antimicrobial overuse in Southeast Asian animal production systems.
ViParc offered small-scale poultry farms in Vietnam’s Mekong Delta veterinary care as an alternative to antimicrobials. The project determined that access to trained veterinarians reduced antimicrobial use by 66%, in a region where food production accounted for 72% of use overall.
Prioritise disease prevention
The risk of AMR emergence and transmission is especially acute in low-income countries and disadvantaged communities. Social and economic issues, especially overcrowded living conditions, unsanitary water, and limited healthcare access, increase the risk of acquiring and spreading AMR disease.
Reducing the incidence and spread of infectious disease in communities most vulnerable to AMR infection will be critical to combatting AMR.
Investments in public health resources may be even more effective with appropriate communication, awareness, and training, to promote understanding of AMR prevention. Informing healthcare and food production workers about the risk of antimicrobial overuse, and training them in measures to prevent contracting and spreading AMR disease, will help to prevent transmission from AMR hotspots to surrounding communities. Campaigns that engage a public audience, such as World Antimicrobial Awareness Week, are also key to encouraging awareness and best practises among the general public, health workers, and policy makers.
Establish funding for AMR research and development
While the problem of AMR has snowballed, the development of new antimicrobials has slowed. The incentive for pharmaceutical companies to develop new antibiotics is especially low, because antibiotic efficacy declines over time, and the upfront cost of drug development has risen to 1.5 billion dollars.
Implementation of financial incentives for pharmaceuticals may facilitate reduced reliance on traditional antimicrobials. The recent European Commission strategy document includes a programme to develop incentives for drug and diagnostic development, and marks the first time a major governing body has codified this approach.
Existing programmes for the funding of AMR research and development include the Global
AMR Innovation Fund (GAMRIF), a UK-based group with the goal of reducing the threat of AMR in low- and middle-income countries. GAMRIF has a goal of funding the development of two to four novel antibiotics and making them available to patients by 2030. State and local initiatives to combat AMR may be further supported by national efforts, such as the Antibiotic Resistance Solutions Initiative funded by the Centers for Disease Control (CDC).
Development of cheap, effective, and accessible diagnostics
The development of rapid, accessible, and low-cost diagnostics would enable the timely use of targeted therapeutics, and allow clinicians to better monitor treatment effectiveness over time. One diagnostic method uses polymerase chain reaction (PCR) to identify pathogens by their genetic fingerprint to diagnose disease. This method is substantially faster than traditional culturing methods. PCR diagnostics enable clinicians to diagnose tuberculosis within hours instead of weeks following the collection of a clinical sample.
However, PCR techniques require laboratory equipment and conditions that limit the technique’s application.
Adaptations of PCR technology, such as PCR Loop Mediated Isothermal Amplification (PCR LAMP), improve the practicality of PCR-based diagnostics by making them cheaper and transportable. The minimal equipment and speed of LAMP made it an ideal tool for rapid COVID-19 testing.
Improving AMR diagnostics will require simplifying diagnostic workflows, taking advantage of technologies such as nextgeneration sequencing (NGS) and artificial intelligence (AI). Researchers at the Oxford Biomedical Research Centre (OxBRC) are working on a modern diagnostic platform using whole genome sequencing analysis that is scalable and open-source.
The diagnostics platform aims to assist in outbreak response, infection control, and direct patient care on a global scale. Another global support system, the CDC’s AR Lab Network, helps laboratories enhance detection of AMR using DNA sequencing technologies.
Developing alternatives to antimicrobials
Alternative treatment methods to antimicrobials include bacteriophages, probiotics, and vaccines. While all of these treatments have promise, vaccines may be especially impactful in the prevention of community disease spread and reduction of antimicrobial use in agricultural settings.
Unlike response-based treatments that can select for the most resistant microbes in an exposed population, vaccines facilitate an immune response that is early, targeted, and varied between individuals. Microbes are less likely to develop resistance to vaccines than to other targeted treatments.
However, until the COVID-19 vaccines, vaccine development was expected to take more than a decade. Now, vaccine development for AMR may be expedited by genetic sequencing technology, COVID- 19-informed models for accelerated clinical trials, and fast-tracked regulatory approval processes.
Research into antimicrobial alternatives will benefit from establishing combination treatments and treatment cycling, helping antimicrobials maintain efficacy, especially when AMR spread is likely. Determining the real-world efficacy and optimal use of diagnostics and treatments requires organised monitoring and surveillance of AMR by dedicated organisations.
Coordinate surveillance and monitoring of AMR
Coordinating observations of AMR emergence and spread helps identify key drivers of AMR and effective prevention strategies that can inform preventative action plans. The Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGISAR) started the development of WHO guidelines on the use of antimicrobials in food production, and contributed a guidance document on integrated surveillance of AMR.
The Transatlantic Taskforce on Antimicrobial Resistance (TATFAR) was chartered by the EU and the US in 2009 to improve peer collaboration, information exchange, and understanding of best practises for contending with AMR.
The Global Antimicrobial Resistance and Use Surveillance System (GLASS) outlines and facilitates standardised collection, analysis, interpretation, and sharing of AMR data to inform research. In 2021, 64,000 surveillance sites in 66 countries contributed data. Participation has grown exponentially since the system’s initiation in 2015.
Implement action plans
Governments and international groups have a pivotal role in developing and enforcing holistic action plans to combat AMR. The tripartite partnership of global organisations – WHO, the Food and Agriculture Organisation and the World Organisation for Animal Health – coordinated The Global Action Plan (GAP) to combat AMR in 2015, and encouraged countries to develop their own national plans.
The plan jumpstarted global initiatives such as GLASS, and the Interagency Coordination Group.
GAP has supported the development of national action plans to combat AMR in 144 countries. These national plans are well positioned to use insights from global AMR monitoring, and research efforts for locally tailored enforcement and multifaceted engagement strategies.
AMR is a problem of daunting scope, and we need to be prepared for the next disease-X type global threat. However, the evolutionary mechanisms and consequences of AMR are well characterised and understood. There are concrete actions that individuals, institutions, and governments can take to address the drivers of AMR and treat AMR infection. Working in concert, actions from diverse players will make it harder for microbes to evolve and sustain resistance to life-saving treatments.
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Dr Caroline Forkin
brings 26 years’ experience in clinical, pharmaceutical and global health settings, including extensive experience in Africa.
With a clinical background in Infectious Diseases, Caroline’s experience in Africa included senior roles as HIV/AIDS Advisor for both the World Bank and the Irish Government. These roles involved working with the Mozambican Ministry of Health, National AIDS Council, together with other global health entities such as the Clinton Foundation HIV/AIDS Initiative, the Global Fund for AIDS, TB, and Malaria, the President’s Emergency Plan for AIDS Relief. Dr Forkin’s pharma experience prior to joining ICON includes country medical lead for two biotech companies. Her role at ICON is Vice President for Clinical Research Services, with responsibility for all our studies in Africa and the Middle East.
DATA IN CARE
A bold and ambitious plan: Harnessing data and improving health and care continuity for the next decade
The NHSX and DHSC draft strategy aims to improve patient outcomes, by placing them at the centre of the care journey. Dr Dipesh Hindocha at Doctor Care Anywhere explores how health data systems can be used to help patients directly engage with their care experience, and build trust in their providers
As the UK emerges from COVID-19 restrictions, some of the old debates are beginning to reassert themselves, and now the minds of politicians and the public are returning to long-term public health issues. In June, the publication of a draft strategy paper from NHSX and the Department of Health and Social Care (DHSC) was scarcely noticed by many. The paper threw into sharp relief the debate about where patient privacy should end, and where joining up NHS data across the NHS estate and beyond can be expected to drive better outcomes for patients and clinicians alike.
There will surely be many across the private and public sectors in healthcare and technology who will feel the publication of
marks a significant and welcome step. Harnessing the relatively untapped potential of joined-up patient data use brings closer the prospect of delivering significant health, social care, and services improvement across the NHS and elsewhere in the wider health system. The national public health emergency caused by COVID-19 has highlighted how effective data analytics can simultaneously save lives while driving efficiencies – both of significant value to the NHS. This has played a huge role in tracking the virus and infection hotspots, prioritising the distribution of critical resources, mapping regions and groups for mass vaccination and, most importantly, in the case of this latest initiative, accelerating the ease of access and sharing of patient care records.
It is therefore encouraging to see the importance that DHSC and NHSX is attaching to placing the patient at the centre of the care pathway. People should be closer to their own data, which will enable healthcare professionals to review the entire clinical journey from GP surgery through to patient aftercare, and ultimately improve outcomes.
This concept is something the private sector is rapidly innovating. We therefore feel well placed to provide our perspective and to assess this initiative through the lens of both a primary care clinician and a thought leader in the private, digital health space. We seek to strike a balance between someone embedded within the NHS, and an innovator outside it.
Putting patients at the centre of the care journey
The crucial point, from a patient perspective, is about building a system that can maintain trust, confidentiality, and transparency. It is also about building and maintaining the highest standards in data processing, which will be critical to building trust amongst patients, clinicians, and wider organisations.
The rapid rise of data use over the last ten years, and digitalisation of many aspects of our lives, has led, somewhat understandably, to concerns about the scope for data leaks, and the fear of inappropriate use being made of individuals’ data. To this end, developing and enabling a transparent health data system that allows users to see how and when their data is being used, is to be warmly welcomed.
Another question that needs resolving is how we come to a shared understanding of what ‘data’ mean to those using the system, ie the patient, and the care giver. Given the complex nature of health data, data privacy, data handling, and legalities surrounding data, if patients are going to ‘buy-in’ to the concept, they need to be persuaded of its value and indispensability for their own wellbeing. The Wellcome Trust’s Understanding Patient Data, a health data initiative working in partnership with the NHS, which seeks to bring transparency, accountability, and, crucially, understanding, will be an important tool in delivering this. However, further initiatives will be needed to bring all stakeholders onboard, such as clinicians and healthcare managers. Patients will increasingly engage with their data in the future. This is inevitable. But if participants, such as those clinical and care staff delivering healthcare, are not well positioned clearly or openly to explain or discuss this with their patients, then full acceptance cannot be guaranteed.
The ability to review such information in innovative and more efficient ways, can help clinicians, researchers, and healthcare managers make transfor mative differences to patient and public health outcomes
From a technical perspective, personal data stores, in whatever form they take, will only work if all the moving parts of the system are speaking the same health language and information can be contextualised by the person receiving or reviewing the information. The mass consolidation of data, and the joining up of all the constituent parts will require a unified governing framework and terminology system. Universally accepted clinical vocabulary systems, digital platforms and frameworks, such as
SNOMED CT, will of course help ensure there is ubiquitous language across all systems. But we would suggest more still needs to be done.
Access to patient data
Access to relevant patient data is hardly a new or groundbreaking concept. However, as witnessed acutely during the pandemic, access to substantially enhanced data sets and the ability to review such information in innovative and more efficient ways, can help clinicians, researchers, and healthcare managers make transformative differences to patient and public health outcomes.
However, such innovative analytics will only be as good as the data being supplied. Transposing raw data, some high quality, some low quality, which will come from various sources including digital platforms and apps, will need extensive health analytics capabilities. And as patients are increasingly
likely to add their own data to the system, it is imperative that proper governance and validation frameworks are put in place to best inform the decision-making process, and provide clarity and reassurance both to patients and clinicians.
Building the right architectures and standards to allow third parties readily to innovate and share those learning with the NHS, and supporting this with a clearer pathway to achieving effective whole-of-market strategies, is exactly what the proverbial doctor ordered
We may see this when linking digital and remote assessment tech with real-time patient data collection, such as through home monitoring systems, which really could revolutionise care delivery to the most vulnerable patients in society. However, this will need to be supported by innovative analytics and thoughtful consideration of how and when this information flows back to healthcare workers. There would obviously be little value in having a set of data delivered that had not been through a considered process of analysis to ensure that information was being used effectively. Indeed, it would be possible to imagine poor outcomes being the result of a failure to achieve this.
Shared care records
Shared care records, i.e., the various constituent parts of the health and care system seamlessly sharing information about patients, has the potential dramatically to reduce errors being made from a clinician’s perspective. However, patients will in due course be likely to expect all parts of their health and care experience to be included in this process, both within the NHS as well as any private or thirdparty healthcare companies and providers. They will want all of their health data to sit within their central shared care record, and so naturally this needs to be underpinned by clear and well understood structures about how this data is used, in order to maintain transparency, honesty, and trust with our patients.
There will also be inevitable questions about what constitutes appropriate stewardship and curation of shared care records. And there will also be challenges. For example, how can this all be done coherently and effectively in the context of a shared record that intersects with different parts of the health system, some of which speak different ‘health’ languages? Who will be responsible and accountable for the overall curation of these records? Who will ensure critical information is kept up to date and made consistent with information previously data inputted? We would hope that, as a part of the consultative process on initiatives like Understanding Patient Data, the mobilisation and inputs of private and third sector groups are brought in to play in order to provide complete and compelling answers to these questions and create the best possible, and most sustainable, solutions and systems for the future.
Supporting local and national decision makers
We don’t believe this needs to be limited to public sector healthcare leaders. Where there is a legitimate reason, underpinned by the right consents, confidentiality, and governance systems and processes, organisations providing care beyond the NHS, but still critically important parts of the UK healthcare ecosystem, should have access to shared cared records. This is necessary to ensure clinical and social care continuity, especially as the delivery of services via digital platforms and operators continue to increase. In the event of a further lockdown or emergence of a new COVID-19 variant, this will be vital.
A good example would be patients attending private hospitals, referred to by their private health insurer but via an NHS GP, for surgical procedures. Of course, they, and their physician, would benefit medically from shared access to this information. As per the draft guidance, “where access to data is granted, having met these high thresholds, it must always have the explicit aim to improve the health and care of our citizens, or to support the improvements to the broader system.”
The plans included in this draft strategy are bold, ambitious, and necessary. But questions do arise. Are they achievable in the timeframes stated? How will the big propriety systems that are already contracted and providing services throughout the NHS come onboard? How will public and private sector organisations work together, without ever compromising or impairing the objective of improving patient outcomes?
The commitment to help innovators and health technology providers to work with health and care organisations is very much to be welcomed. Building the right architectures and standards to allow third parties readily to innovate and share those learning with the NHS, and supporting this with a clearer pathway to achieving effective whole-of-market strategies, is exactly what the proverbial doctor ordered.
We all want to achieve brilliant outcomes for patients and their care. Patients deserve no less. But those outcomes must be the right ones, as well as achievable and sustainable ones. As always, the devil is in the detail. So, we await with eager anticipation the next iteration of NHSX’s proposals.
Dr Dipesh Hindocha
, Clinical Innovation Director at Doctor Care Anywhere, started his career as a locum GP following his Master’s in Medical Sciences and Clinical Practice. In 2018 he began working with Doctor Care Anywhere as a Clinical Lead, moving on to become Head of Clinical Product Development, before being promoted to Clinical Innovation Director in 2021.
Redbow Consulting Group