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“We must consider the environmental dimension of antimicrobial resistance.”
James Anderson, Chair, AMR Industry Alliance
“Rebuilding momentum on antibiotics research, giving innovators a chance to pull through.”
Luka Srot, Manager, Health, Security, IFPMA
The misdiagnosis of sepsis is leading to an overuse of antibiotics, but early and accurate diagnostics using point-of-care biomarkers can address this problem.
The two main reasons for the use of antibiotics are the treatment and the prevention of bacterial infections.
Sepsis (a dysregulated reaction of the body to infection with 50 million cases per year) must be treated with antibiotics as soon as it is suspected — ideally, within the first hour. Antibiotics are thus easily administered at the slightest suspicion of infection, based solely on symptoms and in line with the latest international guidelines, despite bacterial infections being proven in only 30–40% of cases.
Inflammatory conditions with symptoms comparable to sepsis are often mistakenly treated with antibiotics. In addition, antibiotics are frequently given for the prevention of bacterial infections acquired in the hospital. Consequently, it has been estimated that up to 50% of antibiotic prescriptions are inappropriate or unnecessary. A way to reduce the burden of sepsis is to give timely, adequate antibiotics; and a way to reduce the burden of AMR is to withhold unnecessary antibiotics.
The measurement of biomarkers in the blood makes it possible to decide in just a few minutes whether to administer antibiotics or not.
The pancreatic stone protein (PSP) biomarker can be measured in under 10 minutes from a single drop of blood, thanks to an innovative point-of-care technology (abioSCOPE®, Abionic, Switzerland). PSP has shown the capacity to rule out sepsis (90–95% negative predictive value). It could be the biomarker, alongside others, to inform decisions to withhold unnecessary antibiotics.
Daily measurements of PSP in hospitalised patients have shown a unique ability to detect sepsis up to three days before signs and symptoms appear. This early warning provides a life-saving window of opportunity for the administration of antibiotics in patients who truly need them; while a negative result provides physicians with additional support in the decision to withhold antibiotics — making PSP an invaluable tool in the fight against AMR.
Dr Haileyesus Getahun Director, Global Coordination and Partnership Department, Division of Antimicrobial Resistance, World Health Organization and the Quadripartite (FAO, UNEP, WHO and WOAH) Joint Secretariat on AMR
The 2016 Political Declaration of the High Level Meeting (HLM) of the United Nations General Assembly (UNGA) on antimicrobial resistance (AMR) was a milestone that brought a paradigm shift in the global fight against AMR through galvanised political leadership.
Political declaration led to progress A 2019 progress report on implementing the political declaration highlights progress made by countries and international organisations, particularly in the development of National Action Plans for addressing AMR based on the Global Action Plan. The progress includes the 14 recommendations of the Inter-Agency Coordination Group on AMR (IACG) while underlining that urgent support and investments are still required to scale up responses at the national, regional and global levels.
The further actions needed were elaborated in the call to action, following the 2021 High-Level Interactive Dialogue on AMR, which was supported by 113 countries and 40 organisations. Despite these efforts, AMR still poses a major threat to human and animal health as well as food safety and security — contributing to the loss of nearly 5 million human lives annually.
The UNGA adopted a resolution in March 2022 to hold a HLM on AMR in 2024. Advocating for HLM on AMR to take stock of the 2016 Political
Declaration is a key performance indicator of the Global Leaders Group (GLG) on AMR in its action plan first published in July 2022. It seeks to transform the global response to AMR across the One Health spectrum in the aftermath of the Covid-19 pandemic.
The 2024 HLM on AMR should secure concrete, specific and bold commitments with aspirational targets and strengthened accountability. The outcome of the Third Ministerial Conference on AMR in November 2022 aims to support this process with proposed targets.
Disruptive measures are needed to avail the required financial resources to strengthen and transform human and animal health systems and the ecosystem for a strong pipeline of antimicrobials, vaccines and alternatives to antimicrobials.
In addition to leveraging existing internal and external financial resources for AMR by building the economic case, there is a call to establish a financing mechanism for global public goods that will benefit the AMR response.
The HLM in 2024 should legitimise and strengthen the mandate and structure of the Quadripartite organisations to coordinate multisectoral and sector-specific responses in humans, animals, plants and the environment.
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There are two common assumptions about how to tackle antimicrobial resistance (AMR): that the short-term answer is just to use fewer antibiotics, and that the long-term solution is all about new drugs. Reality, as ever, is more complicated.
Antibiotics are the backbone of modern medicine, treating millions of previously fatal infectious diseases and enabling routine surgeries or treatments where the immune system is temporarily suppressed.
WRITTEN BY Richard Saynor CEO Sandoz
The global spread of antimicrobial resistance, which occurs when microbes evolve to resist antimicrobial medicines, threatens to change all that. To quote Britain’s former CMO, Dame Sally Davies, failing to curb AMR could spell ‘the end of modern medicine.’
What can we do to stop that from happening?
Richard Saynor, CEO of leading global generics company Sandoz, says: “The starting point is simple: don’t kill the cure. There are two parallel threats facing the continued use of modern antibiotics, and we need to address both simultaneously.”
AMR: clear and present danger
WRITTEN BY Ian Ball Global Head Anti-Infectives Sandoz“The first is AMR, which threatens to take us all back to the days when a scratch from a rosebush could prove as deadly as falling off a cliff. This is a clear and present danger — but the solution is not to reduce access to essential medicines, it is to get access right.”
Ian Ball, Sandoz Global Head, Anti-Infectives, points to two numbers that should drive global decision-making priorities: “This year’s Lancet study estimates that nearly 1.3 million annual deaths are directly attributable to AMR, as many as malaria and HIV combined. Meanwhile, we still have 5.7 million people who die every year because of lack of access to antibiotics.”
Ball believes that to effectively combat AMR, we need a balanced approach combining responsible manufacturing, responsible access, responsible use and innovation. He highlights the importance of responsible access: ensuring the right antibiotic is available for the right patient at the right time.
This means ensuring the stable supply of a broad range of high-quality antibiotics, backed by stateof-the-art surveillance data and diagnostics to understand the real clinical need. Ball says: “We would need this without AMR — but evolving global resistance patterns, as well as significant regional differences, make it even more critical.”
A dysfunctional market
However, the AMR policy debate still focuses largely on incentives for new antibiotics, in what Saynor calls “a misguided search for a silver bullet.” This is a critical part of the global response strategy, “but it is not the strategy.”
The science is clear: new medicines will also face resistance once they enter clinical use: “It’s called evolution — you can delay it, but you can’t stop it.”
This imbalanced focus leads directly to the second major threat: the increasing dysfunctionality of the market framework for existing antibiotics.
Ball says: “Antibiotics today are treated largely as commodities, but with one big difference: producers have to supply at fixed price levels, regardless of supply and demand changes. This is simply not sustainable. We need to change the operating framework, to introduce basic concepts such as inflation-linked pricing and tenders with criteria that go beyond price.”
This year’s Lancet study estimates that nearly 1.3 million annual deaths are directly attributable to AMR, as many as malaria and HIV combined.
A new Hippocratic Oath?
Saynor says: “Beating AMR will require a concerted global response across all four pillars of the global response strategy.”
Patients must understand the threat of AMR and how to use antibiotics properly; healthcare providers must consider the consequences of every prescription; manufacturers must minimise environmental impacts and focus on reliable supply; and policymakers must prioritise the creation of stable, sustainable market frameworks.
Saynor concludes: “Just as physicians have an underlying duty to ‘first, do no harm,’ anyone serious about the future of modern antibiotics should start from the principle of ‘don’t kill the cure.’ Think of it as a new version of the Hippocratic Oath.”
When considering how to better address sepsis — which already affects 250,000 people in the UK each year, with 52,000 people dying as a result — we need to consider infection management holistically.1
The growing threat of antimicrobial resistance (AMR) is a critical public health concern and a major challenge in the treatment of sepsis. As more infectious pathogens become resistant to antimicrobials, more people are at risk of developing sepsis, and there are fewer opportunities for successful treatment.2 Without new antibiotics, this issue will only get worse.
Addressing the issue of AMR, as well as improving methods for clinicians to recognise and treat sepsis, will require collaboration between healthcare professionals (HCPs), health decision-makers, charities, industry, the Government and the general public. We can no longer afford to consider public awareness, pathogen surveillance, diagnostics, treatment options and prescribing habits in isolation. We need to understand and address all aspects of infection management in order to make necessary, lifesaving changes.
Diagnostics are critical to rapidly and accurately identify different pathogens of infection and inform antimicrobial usage.
To achieve better outcomes for sepsis and more broadly holistic infection management, continuous research and innovation is needed to fight new and evolving resistant infections, such as bringing in new antibiotics and increasing access to diagnostics. Diagnostics are critical to rapidly and accurately identify different pathogens of infection and inform antimicrobial usage. We must also change the way we gather and utilise data, which needs to capture every element of the patient experience. This information must be available across all healthcare settings, so that HCPs have a much better understanding of the patient no matter where they are in their journey. Furthermore, we need more accurate coding and death certifications of infections. This would lead to better identification and tracking of infection outbreaks, personalised care for patients, as well as better and more responsible antimicrobial prescribing.
The pandemic showed the world the benefits of a collaborative way of working. Implementing a holistic infection management strategy will require this same approach. With different stakeholders working in partnership, it can save on resources, improve patient experience and outcomes, as well as enable new legislation to continuously improve infection management practices.
References
1. The UK Sepsis Trust. Representing the UK Sepsis Trust. Available at: https://sepsistrust. org/wp-content/uploads/2019/01/UKST-volunteer-speaker-notes-2019.pdf. Last accessed November 2022
2. World Health Organisation. Antimicrobial Resistance. Available at: https://www.who.int/ news-room/fact-sheets/detail/antimicrobial-resistance. Last accessed November 2022
Tackling antimicrobial resistance (AMR) is truly like fighting a monster with many heads — AMR is a global threat, much like climate change with many causes and no single solution even for each country.
Diagnostic tests are an important tool to help reduce AMR. These tests are done on samples from the body such as blood, urine or saliva. While the tests are typically done in hospital laboratories, they may now be performed in other settings and by trained professionals other than a scientist.
Since our population has become used to testing themselves as a way of getting back to normal as the Covid-19 pandemic waned, there is a greater awareness of the role of diagnostic tests in healthcare. Treating infectious diseases and infection from wounds are the major uses for antibiotics, and we are seeing increasing pockets of resistance, even with antibiotics which have been saved to use as a last resort. This means diagnostic tests to identify which organisms are responsible for the infection are critical. Once identified, the patient can be treated with the right antibiotic, which not only helps reduce antibacterial resistance but also stops the infection and helps prevent sepsis.
Antibiotic prescription is often expected by patients in primary care settings. Hopefully, the knowledge we have gained from the Covid-19 pandemic will help people
understand why this expectation can’t be met — for example, if the cause of a respiratory infection is viral. This means testing needs to be done at the GP or locally, such as in a community pharmacy.
Changes to the way the NHS allocates funding from July this year, at least in England, should also mean NHS funds are accessible for diagnostic testing in the community. The diagnostic tests provide information to support doctors in making decisions on the right treatment.
Diagnostic tests can also help doctors find specific infections that could spread within hospitals. When these infections take hold, wards must be closed for deep cleaning. This causes a knock-on effect on admissions and surgery. Meaning, being able to find people with these ‘bugs’ using diagnostic tests before admission (or at A&E) can be lifesaving.
Information is power, and in helping control AMR, diagnostic tests are the way to produce the essential information doctors need to make the right treatment decisions for patients.
Accurate, rapid infection diagnosis supports healthcare teams to get people the care they need quickly and reduce the impact of AMR.
WRITTEN BY Dr Jane Freeman National Clinical Lead, AMR Diagnostics, NHS England WRITTEN BY Tony GreenwayAntimicrobial resistance (AMR) is a widespread concern in the UK; we must use current antimicrobials wisely to reduce the risk of AMR infections to patients. Accurate, rapid diagnostic tests support healthcare teams to identify infections and use the right dose and duration of targeted antimicrobials as quickly as possible. Diagnostic tests also help teams recognise when antimicrobials are not needed.
A highly targeted approach
Dr Jane Freeman, National Clinical Lead, AMR Diagnostics at NHS England explains: “If clinicians know exactly which bug is causing an infection and which antimicrobials it is susceptible to, they can treat it
in a targeted way without destroying the body’s beneficial bugs. Good diagnostics don’t just inform the most effective treatment plans. They can also reduce the risk of antimicrobial resistance developing.”
Improving how we diagnose bloodstream infections
NHS England is working hard to improve the way we diagnose infections. This includes refining the blood culture pathway which diagnoses infections in the bloodstream. When a blood culture sample is taken, many are involved in getting it to the lab to be analysed as quickly as possible — including ward staff, hospital porters, transport staff and the lab team. Each contribution should not be
underestimated, notes Dr Freeman. “One of the things we are doing is creating education packages around the blood culture pathway so that different staff groups understand the importance of their role within it, whether that is taking the recommended volume of blood or getting it to the lab analysers quickly,” she says. “They are part of a bigger picture that is critical to patient care.”
While using current diagnostic technologies more efficiently, the NHS England team are also introducing new technologies into the pathway, where appropriate, to ensure it is working as well as possible for patients.
Developing the existing blood culture pathway and early identification of bloodstream infections can reduce deaths from sepsis. Sepsis is the body’s extreme response to a bloodstream infection which can cause life-threatening organ and tissue damage.
The UK Sepsis Trust highlights that there are 48,000 deaths related to sepsis yearly. “We have made big improvements in how we recognise sepsis clinically,” says Dr Freeman. “Identifying the microbiological pathogen that causes sepsis — and if bacterial, which antibiotic it is most susceptible to — can improve our ability to treat it. That helps bring the best patient care possible, while also helping prevent AMR.
Much of the global coordination on combatting AMR has rightly been focused on incentives, appropriate use, stewardship, diagnostics and other tools. But we must also consider the environmental dimension of antimicrobial resistance.
With over 100 members, the AMR Industry Alliance is the largest life-sciences coalition providing sustainable solutions to curb AMR, including awareness raising and adoption of responsible manufacturing practices. That is why we developed the first-ever Antibiotic Manufacturing Standard to minimise environmental emissions from antibiotic manufacturing plants.
Many factors contribute to antimicrobial resistance, such as poor infection control, misdiagnosis, misuse and overuse of antibiotics. However, it is accepted that, in sufficient concentration, the presence of antibiotics in the environment may increase selection pressure on bacteria to develop resistance.
While the major source of antibiotics in the environment results from human and animal use of medicine and subsequent excretion, other sources may include emissions from the manufacturing of antibiotics. Depending on a facility’s emission treatment program, antibiotic production processes involve a risk that antimicrobials can leave manufacturing plants through wastewater and enter the environment.
Given the interconnected nature of human, animal and environmental health, the AMR Industry Alliance has developed a proactive approach to minimizing the release of antibiotics from manufacturing operations. The first thing was to work with leading scientists to define the minimum concentration targets for a range of antibiotics below which they are unlikely to drive resistance. These targets are extremely low — often in the order of a couple of pills in a swimming pool full of water.
Many factors contribute to antimicrobial resistance, such as poor infection control, misdiagnosis, misuse and overuse of antibiotics.
Earlier this year, in partnership with British Standards Institution (BSI), the Alliance created an Antibiotic Manufacturing Standard, which will be followed by a forthcoming certification scheme, that establishes and formalises a set of requirements and independent assessment for manufacturers in the global antibiotic supply chain. This standard and certification aims to validate that the discharge from an antibiotic’s production is at such a level that the substance will not have an adverse effect on its environment. This independent certification will give confidence and provide further transparency to purchasers, financial investors and other policymakers.
While pharmaceutical manufacturing is heavily regulated around the world, regulations typically do not address the environmental impact such concentrations of antibiotic waste can have.
Together with industry stakeholders and the assistance of BSI, we have developed a solution for the next chapter of responsible antibiotic manufacturing. Only together can we fight the spread of AMR and ensure the viability of our lifesaving medicines.
The discovery of penicillin 94 years ago revolutionised bacterial infection treatments. However, germs adapt; and today, antimicrobial resistance is one of the most significant threats to public health worldwide.
Antimicrobial resistance (AR) is a growing global health threat. AR occurs when germs like bacteria and fungi develop the ability to defeat the drugs designed to kill them. Before the Covid-19 pandemic, the United States was making steady progress in reducing healthcare-associated infections, including those caused by antimicrobial-resistant germs. Those numbers reversed in 2020, partly due to the inappropriate use of antibiotics and overwhelmed healthcare systems focused on battling Covid-19. Preventing infections and improving antibiotic and antifungal use are crucial to stemming the resistance tsunami facing all of us.
Antimicrobial resistance killed at least 1.27 million people worldwide and was associated with nearly 5 million deaths in 2019. In the United States alone, CDC’s 2019 ‘AR Threats Report’ estimated more than 3 million antimicrobial-resistant infections occur each year, with 48,000 deaths.
During the first year of the Covid-19 pandemic, resistant infections and deaths increased by at least 15% compared to 2019 in the U.S. This significant rise represents at least 29,400 lives lost from AR commonly associated with healthcare. The overall burden of AR in 2020 is likely much higher, as the pandemic created gaps in the data collected. It is a sobering thought to know that many of these infections are preventable.
During the first year of the Covid-19 pandemic, resistant infections and deaths increased by at least 15% compared to 2019 in the U.S.
We know what works to fight antimicrobial resistance — preventing infections in the first place. CDC reported in 2019 that dedicated prevention and infection control efforts drove down deaths from antimicrobial-resistant infections by 18% overall and by nearly 30% in hospitals from 2012 through 2017 in the United States.
The data shows that these reductions continued until 2020. However, the pandemic created challenges, including stress on healthcare systems, the spread of more resistant infections, increased antibiotic use and fewer data and preventive actions. To turn the tide, we must focus on preventing infections and improving antibiotic/ antifungal use wherever they are used. You can protect yourself, your family and your loves ones and help slow antimicrobial resistance.
For more information, visit cdc.gov/drugresistance/
WRITTEN BYThe pace of resistance to existing antibiotics is outpacing the rate at which new ones can reach the market and be used against difficult-to-treat infections.
According to the WHO, on average, resistance is reported to most new agents two to three years postmarket entry.
Difficult environment to develop antibiotics
Research into new antibiotics is a long-haul journey: it takes 10–15 years to progress an antibiotic candidate from the preclinical to the clinical stages. For antibiotics in existing classes, on average, only one of every 15 drugs in preclinical development will reach patients. For new classes of antibiotics, only one in 30 candidates will reach patients. And even many that reached the market in the last decade continued to face existential challenges.
Sustaining research in this space requires patience, but more importantly, it requires financial resources and incentives. And that’s what most scientists and investors from big and small companies alike are calling for.
There is a clear lack of funding for antibiotic R&D, particularly in the later and more resource-intensive stages. Many have taken on a mission to tackle the scientific barriers, but few have managed to stay afloat despite having a successful product.
That’s the paradox with antibiotics: They need to be used appropriately to preserve their effectiveness and slow the development of resistance. Therefore, new antibiotics would be used only rarely, but we still need them to be available when nothing else works.
The biopharmaceutical industry stepped in to provide relief through the creation of the AMR Action Fund — a USD 1 billion fund aiming to bring to market two to four new antibiotics by 2030.
But the Fund is a band-aid solution — we need an urgent, larger overhaul of how the antibiotic R&D ecosystem is stimulated. The most impactful solution lies in so-called ‘pull incentives,’ and it’s encouraging to see more political momentum build up.
Several countries are piloting or considering different policy reforms and rethinking the value new antibiotics bring to society. Eyes are turned towards the US and the discussions on the PASTEUR Act. There is potential for a sea change at a global level. As attention turns towards the next UN high-level meeting on AMR in 2024, we need to set an expectation for all leading countries to implement impactful reforms of their own.
Rebuilding momentum on antibiotics research, giving innovators a chance to pull through
Luka Srot Manager, Health Security, IFPMA
Antimicrobial resistance (AMR) is an alarming wake-up call — with the potential to set healthcare back by decades. “We can’t afford to underestimate the impact of AMR on global health,” says Amalia Adler-Waxman, SVP, Global Head, ESG, and Head of International Markets at Israel-headquartered Teva, a pharma company which manufactures 83% of antibiotics/ anti-infectives listed on the WHO’s Essential Medicine List.
Teva’s approach to addressing AMR focuses on producing antimicrobial compounds responsibly while minimising their discharge to the environment from manufacturing facilities and supply chain, supporting innovative research and science through the AMR Fund established by several pharmaceutical companies; helping ensure affordable access to — and appropriate use of — antibiotics. It has joined forces with more than 20 companies to launch the USD 1 billion AMR Action Fund, aiming to support biotech firms in bringing two to four new antibiotics to patients by 2030.
The crisis is so multifaceted that no one sector can solve it alone, stresses Adler-Waxman — which is why the work of the Fund is so crucial. “We need to ensure the public, private and not-for-profit sectors are all joining forces,” she says.
While currently available antibiotics fight infection, they have side effects, including the emergence of antimicrobial resistance (AMR). Pathogen-specific antibiotics may represent a new paradigm to combat AMR.
The development of antibiotics was one of the most lifesaving medical interventions in history, agrees Ricardo Chaves, M.D., Executive Medical Director, Infectious Diseases, at biopharmaceutical company Debiopharm in Switzerland.
Targeted antibiotics
While broad-spectrum antibiotics kill a range of pathogens causing infection, these drugs are — by nature — untargeted. Meaning, they can disrupt the finely balanced gut microbiome — a complex community of microorganisms that provides a wealth of essential functions for healthy living and protects us from disease.
“This means that broad-spectrum antibiotics can facilitate certain infections,” says Dr Chaves. For example, the use of antibiotics is associated with Clostridioides difficile colitis (inflammation of the large
It’s important to face up to the market failure of antibiotics, says Adler-Waxman. “Companies are reluctant to get involved in antibiotic research and development because the business model is unsustainable. Unfortunately, this reduces the availability of antibiotics and, ultimately, increases barriers to access.”
One of the Fund’s aims is to incentivise pharma to invest in antibiotic R&D. “The question now is: will governments be willing to pay for new antibiotics?” says Adler-Waxman. “Because at the moment, this medication is too cheaply available. If antibiotics were priced properly, the business model would be more sustainable and may also allow for additional options which could ultimately reduce misuse and overuse of certain options.”
We also feel that new economic models should be investigated. Some ideas are already under discussion and worth exploring with all stakeholders.
Adler-Waxman is cautiously optimistic. “During the pandemic, the focus shifted away from AMR and onto Covid-19, and rightly so because of the threat we faced,” she says. “But it taught us that when the world is confronting a crisis, everyone can come together to find a solution very quickly. We need to see the same sense of urgency regarding the development of new antibiotics.”
“But in cases where the cause of infection is known, it’s important to spare the microbiome and administer narrow-spectrum — ideally, pathogen-specific — antibiotics, for patient health and to prevent AMR development. Rapid microbiological diagnosis is key for the use of these drugs.”
intestine) following destabilisation of the normal healthy bacterial population of the gut.
Broad-spectrum antibiotics can also lead to selection and overgrowth of antibiotic-resistant organisms that are difficult to treat.
To curb the emergence of AMR, Dr Chaves believes in restricting the use of antibiotics that harm the microbiome. He calls for a paradigm shift in antibiotic research, to focus on developing pathogen-specific antibiotics that have a low ecological impact — and can be used for common infections without harm.
Pathogen-specific antibiotic solution
The use of broad-spectrum antibiotics is vital in some cases, admits Dr Chaves. “ If a patient has sepsis, and the causing pathogen is unknown, broad-spectrum antibiotics need to be administered quickly, otherwise the result could be fatal.”
Pathogen-specific antibiotics do as their name suggests: target individual disease-causing organisms — while preserving the microbiome. Dr Chaves says that this ‘one drug for one bug’ approach is an exciting innovation; currently, there is no approved pathogen-specific antibiotic, but they are in development. He believes that pathogen-specific antibiotics will be approved within the next few years, and regulators should now lay the ground for approval including assessments of microbiome endpoints in clinical trials.
Two problems solved
Debiopharm is developing a novel class of pathogen-specific antibiotics, called FabI inhibitors, to treat Staphylococcus spp, Neisseria gonorrhoeae and Acinetobacter baumannii, including multi-resistant strains.
“If we imagine a future where multiple pathogen-specific therapies exist, all common infections would be treatable — and AMR would be preventable,” says Dr Chaves. “We could be solving two different problems at once.”
The question now is: will governments be willing to pay for new antibiotics?
