Antimicrobial drugs, including antibiotics, are the backbone of modern medicine. They are a primary treatment for a spectrum of ailments, from infected wounds to chest infections, sexually transmitted infections to pneumonia. They underpin treatments for people with compromised immune systems, for example those living with HIV or undergoing cancer treatments. Antibiotics have captured the public’s imagination as a fix-all drug.
However, times have changed. Antibiotics are, in many cases, much less effective at doing their job because their bacterial targets have become resistant to them, due, in part, to years of misuse and overuse.
Without new antibiotics, more people will die as their infections are no longer easily treatable, or their treatments no longer protected. The results of this antimicrobial resistance (AMR) are already evident: 4.95 million people were estimated to have died in 2019 due to antibiotic failure; experts estimate by 2050, annual deaths will reach 10 million, higher than those caused by cancer.
The obvious answer to this ‘silent pandemic’ is twofold: first, develop new antibiotics to replace those which have become ineffective and, second, be smarter in how we utilise the antibiotics that we have got.
This second answer, referred to as ‘stewardship’, has seen some positive results, including in the UK. However, stewardship itself is not a one-off activity, and we are yet to see how major disruptions, such as Covid-19, have affected antibiotic usage. Stewardship alone cannot overturn AMR – all it can do is hold back the rising tide for a while until new antibiotics come online to rebuild the defence.
And here, then, is the big problem: no one wants to make new antibiotics.
A broken market for antibiotics
Antibiotics are incredibly cheap to purchase compared to other drugs, and yet hugely expensive to develop, trial, and bring to market. Most estimates suggest it takes roughly 15 years to bring a new antibiotic to market. Given that the required investment is substantial, and return on investment meagre, how can we convince pharmaceutical companies to make new antibiotics? On top of that, a more fundamental barrier puts off investors: why make new antibiotics when we are trying so hard to stop people from using them?
Of course, stewardship is not about collapsing demand, but rather refining and structuring that demand so that the new antibiotics build up layers of defence, giving clinicians more options to treat resistant infections. This means that new antibiotics will not necessarily be used immediately, with some becoming a ‘last resort’ to prolong their effectiveness. Given that antibiotic purchase schemes have historically been on a pay-per-use basis, stockpiling them further collapses return on investment.
Efforts to fix the market
It has been clear to the UK, and many other countries, that the current market paradoxes are a major barrier in making headway in mitigating the effects of AMR. This has been reflected in the UK’s latest policy documents, for example, in the five-yearly strategies (2013-2018 and 2019-2024) and the 2019-2040 Vision.
If return on investment and profit can be assured, antibiotic development will be reinvigorated. One approach to achieving this is changing the pay-per-use model to a subscription model (often known as ‘the Netflix model’) in which companies are paid a regular, fixed amount for developing and producing antibiotics, regardless of whether they are used or not. This pull-incentive is, in principle at least, a win-win: pharmaceutical companies receive a dependable return for drug production, and societies receive antibiotics that can expand inventories.
The UK is currently running a pilot scheme in which it will pay £10m per year for ten years to both Shionogi, to produce Cefiderocol (Fetcroja), and to Pfizer, to produce ceftazidime with avibactam (Zavicefta). The UK’s scheme, and similar pull-incentive schemes in other countries, including the much-vaunted PASTEUR Act in the USA, provide promise for fixing the market and reinvigorating the industry. However, if these national schemes are to work, they will require international coordination to capture the global pharmaceutical market. Even then, it will take the best part of a decade or more to begin generating new antibiotics.
Is fixing the market enough?
While belief in the market’s ability to solve problems has contemporary political currency, it is unlikely that this alone will be enough.
In the UK, the last 15 years have seen the big pharmaceutical companies almost totally exit the antibiotic scene, taking with them their human and infrastructure resource, leaving only a handful of micro/SMEs working on antibiotics. Senior experts have either retired or moved to different therapeutic fields, such as cancer. Those remaining in the field report that the structure and levels of funding are currently inappropriate or insufficient to generate a healthy domestic antibiotic development pipeline. Fewer students are entering the field at PhD level, stoking concerns that the UK may face a skills shortage.
Experts, including during a UK AMR dialogue co-hosted by IDS in May 2022, have stressed that the potential long-term benefits from best-case-scenario international market pull-incentives can only be fully realised if the necessary human and infrastructural resources exist at the domestic level. This is not to imply that the field needs more funding but better funding that bridges development stages, and supports the long-term product development that is required to bring a new drug to market. Rebuilding the knowledge base, providing stability to the field, and investing in the next generation of antibiotic scientists is, for many, a prerequisite for ensuring that a functioning market actually has the stock to sell.
Moving forward
This major effort needs to be supported through emphasis on, and funding for, collaborative activities and resourcing, including public-private partnerships; better communicating the challenge; and coordinating the funding and actors to overcome structural impediments to ensure that pathways for promising ideas and products are not blocked.
Whilst our stewardship culture continues to strengthen our defence against rising resistance, and novel pull-incentives seek to reinvigorate the market, now is the time to work out how we can enhance national research and industry capabilities to stand a chance of navigating the paradox of the silent pandemic.
