Funding science and providing incentives to spur innovation in antibiotics is crucial, but political support for stewardship and prevention of inappropriate use is just as important in ensuring availability of effective and affordable drugs that are used in a responsible way
Scientists and public health experts have been ringing alarm bells on the threat of antimicrobial resistance (AMR) for years, but although the problem is now on the political agenda, as yet little concrete progress has been made in averting the impending crisis.
At a meeting of healthcare stakeholders in Europe organised by Science|Business, policy makers, industry and medical experts agreed that addressing the AMR crisis requires political and economic effort at a global level.
Alexandra Aubry, professor of bacteriology at Sorbonne University underlined the extent of the problem, citing a UK government report published in 2016, which highlighted the need to tackle AMR globally. Without concerted action, “By 2050, superbugs will kill 10 million people a year,” Aubry said.
“The single biggest task of the Commission is to [present] AMR as a matter of economic survival, and not just a matter of health” said Xavier Prats Monné, director general for health at the European Commission. “This is not just an enormous threat to public health, it is also a major economic problem.”
Prats Monné suggested the warning that AMR could claim 10 million lives a year by 2050 might well become a reality if the public is not made aware of the threat posed by AMR. But because AMR strikes a case at a time there is no general understanding of the extent of the risk, or any widespread concern or pressure from the general public for action.
“The people that are dying because of AMR do not die at the same time,” Prats Monné said. Just as with climate change, a well-coordinated communications campaign is needed to convince the public and policy makers that the threat is serious and needs immediate action.
In addition, addressing the problem of AMR requires an interdisciplinary approach. People and organisations that are not used to working together will need to collaborate, Prats Monné noted.
Combatting AMR also calls for a trade-off between various economic interests. The fight against antimicrobial resistance will be lost without the right economic incentives, the right instruments for research and the right instruments for trade. “We need the help of health ministries and agriculture ministries,” said Prats Monné.
The reality that economics is at the core of the problem was brought into sharp focus by the UK study, which explored how to make investing in antibiotics more attractive to the industry and other funding bodies. The report made a series of recommendation on how to incentivize investment while rationing use, so that antibiotics remain effective for longer.
One positive note is that better technologies are now available for finding drug targets and for accelerating the drug discovery process. However, there is not enough investment to translate discoveries through to clinical development and onto the market, Stewart Cole, President of the Pasteur Institute told the meeting. “There’s hope from a scientific standpoint but my concerns come from ensuring sustainable funding,” he said.
Developing new drugs is a long-term process that needs long-term financial commitment. Money is available for early-stage discovery research, but it is difficult to attract funding to get a molecule over the translational gap. The high risks involved mean that, “classic funding agencies back off,” said Cole.
From the perspective of ensuring antibiotics maintain their effectiveness, rationing the use of new antibiotics, or holding them in reserve, “makes total sense” said Patrick Holmes, head of international policy for Europe and Canada at Pfizer. But as things stand, stewardship poses commercial challenges.
Apart from the problems of the imperfect market, pharmaceutical companies face other challenges in developing antibiotics. For example, recruiting clinical studies in antibiotics is complicated because there is uneven flow of patients. The majority of generic antibiotics are inexpensive, and the undervaluation of new antibiotics adds to the difficulties of justifying investment in antibiotics. “There is a 30-year gap in developing new classes of antibiotics,” said Holmes.
Taking all these factors together, it becomes “Hard to make a case for sustainable long-term investment in AMR,” Holmes said.
This was underlined by the findings of a €9.4 million EU study investigating ways to incentivise companies to invest in development whilst promoting sustainable use of approved antibiotics, which was published in January.
Drive-AB (Driving reinvestment in R&D for antibiotics and advocating their responsible use) concluded that a $1 billion market entry award, given in annual instalments of $200 million in the first five years after a product is approved, would significantly increase the number of new antibiotics.
Rather than four antibiotics with new mechanisms of action that are in pharmaceutical pipelines currently, there would be 16 – 20 innovative drugs in the next 30 years, Drive-AB concluded.
While some hospitals are putting in place advanced procedures for infection control, there is not enough attention being paid to the role that healthcare systems can play in preventing the spread of resistance. That is despite the direct impact AMR has on the cost of running a hospital, said Johan Van Eldere, medical director at the University Hospital Leuven. “Hospital managers do not have this sense of urgency that I think is needed,” he said
While there has been investment in campaigns to make hospital management more aware of the problem, to date, “The results have been disappointing, to say the least,” Van Eldere said.
Van Eldere believes the outcome measurements by which the quality of hospitals is assessed should be tied to infection control and antibiotic resistance. A key element of this would be to encourage and support doctors in identifying the cause of an infection, enabling targeted treatment with narrow spectrum antibiotics.
Some progress has been made in the Netherlands and Belgium, but also in other countries, where public authorities monitor the number of antibiotic prescriptions doctors write. More EU member states could take action to reduce the number of antibiotic prescriptions by shifting the paradigm in which doctors operate, said Van Eldere.
Doctors believe that saving patients is their prime goal and they will do everything to achieve this. But, doctors should also be incentivised to take into consideration the health of the populations at large. “There should be incentives for doing better diagnostics and financial consequences for prescribing certain drugs,” said Van Eldere.
Pathogens do not respect national borders
In January the World Health Organization published the first edition of the Global Antimicrobial Surveillance System, which it has set up in an attempt to standardise surveillance around the world.
The first edition mapped the occurrence of antibiotic resistance recorded in samples from 507,746 people with suspected bacterial infections across 22 countries. Among patients with suspected bloodstream infections, the number with bacteria resistant to at least one of the most commonly used antibiotics showed a huge difference from one country to another, ranging from 0 - to 82 per cent, while resistance to penicillin, used worldwide to treat pneumonia, ranged from 0 - 51 percent.
The most frequently reported antibiotic resistant bacteria were Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae, followed by various species of Salmonella, which cause some of the most common and potentially most dangerous infections.
As the WHO surveillance data illustrate, AMR is a global problem. Any progress made in Europe will have to be matched in other areas in the world. For example, in China, half the income of hospitals and doctors comes from prescriptions, incentivising inappropriate use, noted Prats Monné. “The easiest prescription a doctor can give is antibiotics,” he said.
EU’s role in promoting a One Health approach
In July 2017, the EU set out a five year plan for tackling AMR, including guidelines on the prudent use of antimicrobial drugs in humans. The overall aim is to make the EU a model of best practice, enabling Europe to shape the global agenda around a ‘One Health’ approach of simultaneously tackling AMR in humans, animals and the environment. Rather than being drawn up solely by the health ministry, agriculture, food safety, drug regulators, education and environment ministries, should all sign up in support of integrated AMR plans.
EU policies such as the ban on using antimicrobials as growth promoters in farm animals and the inclusion of AMR-related provisions in trade agreements, are making a practical contribution to tackling AMR at a global level, the Commission claimed when the plan was published.
Evidence that agitation by the EU, WHO and others is translating through to national action plans came in September 2016, when China hosted the G20 group of leading developed nations for the first time. AMR was on the agenda, and the Chinese government used the platform to announce its national action plan, saying it would increase spending on antibiotic research and development and take measures to curb misuse of antibiotics.
According to WHO’s China office, the country accounts for around a half of world antibiotic use, of which 48 per cent are consumed by people and the rest used in agriculture.
In addition to the pressure on doctors to make money from prescribing antibiotics because their salaries are so low, a number of other factors are promoting misuse. Amongst other measures, China’s plan says that by 2020 antibiotics will be available only on prescription; there will be greater supervision of veterinary use; and more education for healthcare professionals and the public on the appropriate use of antibiotics.
Reducing the consumption of antibiotics in farming is difficult because of the impact this has on the global trade in foodstuffs. The use of antibiotics in animal feed increases their metabolism, they consume more food and grow faster. From an economic point of view, it is more efficient to grow animals with antibiotics than without.
The EU banned the use of antibiotics as growth promoters in 2006, leaving farmers in Europe open to unfair competition from countries where antibiotics are still used in animal husbandry.
US farmers continue to use antibiotics as growth promoters and the US government accuses the EU of protectionism in limiting access of US meat products to the EU market. This underlines the difficulties in getting a global consensus on banning the use antibiotics in farming. It will be, “economically and politically expensive,” said Prats Monné.
Vaccines and public trust
While much of the focus in AMR is on the development of new antibiotics, by preventing infections taking hold in the first place, vaccines have a huge role to play in the battle against drug resistant bacteria.
The EU is facing an “extraordinary challenge on vaccination,” said Prats Monné. Scepticism towards vaccines is growing and coverage is going down.
Karin Kadenbach, MEP agreed. “One of the problems we have in health is the question of trust,” she said.
One stark case in point is measles, an infection that is entirely preventable through vaccination. However, lack of trust in the safety of vaccinations has seen immunisation rates fall to around 80 per cent. In particular, that leaves babies that are not old enough to be vaccinated and must be protected by ‘herd immunity’, exposed to infection.
Thirty-seven deaths due to measles were reported from across Europe during 2017. During the year, 14,600 cases of measles were reported, more than three times the number reported in 2016.
As a part its AMR strategy, the European Parliament’s committee on industry, research and energy (ITRE) is calling for more public funds to be invested in vaccine research. Lieve Wierinck, MEP suggested there should be targeted inducements to encourage development of vaccines against specific infections. “We could offer lump sums for promising research,” she said.