What is antimicrobial resistance?
Antimicrobial resistance is resistance of a microorganism to an antimicrobial drug that was originally effective for treatment of infections caused by it. These microorganisms include viruses (such as HIV), parasites (such as malaria), fungi (such as candida) and bacteria such as Staphylococcus aureus and Escherichia-coli. Since the discovery of penicillin in 1928 by Alexander Flemming at St. Mary’s hospital London, antibiotics have transformed healthcare leading many to assume that clinicians will always have an effective antibiotic at their disposal for any given bacterial infection.
However, the natural process of genetic mutation has led to the development of antimicrobial resistance following use (and misuse) of antimicrobial treatments. Put simply, exposure to antimicrobial products selects microorganisms with genetic mutations which give them full or partial resistance; it is these resistant microorganisms that survive and replicate thereby creating a larger population of resistant microorganisms. Bacteria have evolved to harness such mutations by sharing survival genes, even between bacterial species, on loops of bacteria DNA called plasmids (horizontal transfer).
The latest developments
Antimicrobial resistance (“AMR”) has frequently been in the news, most recently following the discovery in China of E-coli which are resistant to colistin, a so-called antibiotic of last resort (due to concerns regarding nephrotoxicity in humans). The discovery of resistance to colistin is not new per se, but the identification of the gene conferring colistin resistance, mcr-1, on plasmids allowing horizontal transfer of resistance to other bacteria has been described by scientists as a paradigm shift. Research into AMR has largely focussed on gram-positive bacteria such as MRSA, but there has been relatively little research into AMR in gram-negative bacteria such as E-coli, which has put scientists further behind the curve in relation to the mcr-1 gene.
AMR has also been in the news thanks to political initiatives to raise awareness and develop programs to tackle this global problem. In 2013, the UK government published its 5 year AMR strategy, and in 2014 the government commissioned the Review on Antimicrobial Resistance (the “Review”). Upon announcing the Review, David Cameron warned that, “if we fail to act, we are looking at an almost unthinkable scenario where antibiotics no longer work and we are cast back into the dark ages of medicine”. This echoes the warning from the WHO that, without urgent coordinated actions, the world is heading towards a post-antibiotic era, in which common infections and minor injuries, which have been treatable for decades, can once again kill. Former Goldman Sachs economist, Jim O’Neil, who is heading up the Review, is due to publish its results by summer 2016.
AMR strategies are also continuing to be advanced internationally. For example, the US launched its own 5 year plan and held a ‘superbug summit’ in May last year advocating better “stewardship” of antibiotics. So-called superbugs infect 2 million patients a year in the US and are responsible for 23,000 deaths. In response, President Obama has called for $1.2 billion in funding to implement an AMR strategy. Importantly, AMR has also made the agenda at both the G-7 and the G-20 summits,and , most recently, industry has come together to issue the Declaration by the Pharmaceutical, Biotechnology and Diagnostics Industries on Combating Antimicrobial Resistance which was launched at an event at the World Economic Forum in Davos, Switzerland.
In the UK, the AMR Review has published a series of detailed interim papers which have already triggered much debate. For example, the Review’s economists have published alarming estimates including a cost of $100 trillion if the world fails to act on AMR by 2050 by which time there would be an estimated 10 million deaths due to AMR infections every year.
Why a new market model for antimicrobials is needed
Historically, pharmaceutical companies have not been able to reliably recover their R&D spend on new antibiotic discovery which has severely hampered further research. A number of different factors are responsible for this, including the fact that newly developed antibiotics are used sparingly in order to minimise the development of resistance to the new product, and the treatment term for antibiotics is usually very short (unlike chronic conditions where treatment is continued over an extended period). On top of this, the development of clinical trials for novel antibiotics is often particularly challenging. All of these factors have an impact on revenue. The Review estimates that it would cost between $16-37 billion to bring 15 new antibiotics to the market place in the next 10 years.
The Review states that the volume of use of antimicrobials must be de-linked from profits in order to remove the commercial driver to sell antibiotics in large quantities and it calls for a new market model. The proposals include a $2 billion innovation fund to be supported by the pharmaceutical industry; streamlined regulation; and a new market entry reward scheme offering $1 billion or more for discovery of the most needed new antibiotics. The Review draws a distinction between these incentives and the usual pricing, market exclusivity and patent protection rewards.
A common theme across the various national 5-year strategies is that greater investment into rapid diagnostics is needed alongside new antibiotic discovery. Diagnostics have been stated to be the gateway to a new paradigm of precision antibiotic use rather than empirical treatment – the proposals therefore create real opportunities for the medical device industry.
The challenges to human and animal health sectors
In addition to the supply of new antibiotics, it is widely accepted that antibiotic use needs to be reduced. Both the human and the animal healthcare sectors have a very important role to play in this regard. In fact, the EU can be seen to lead the way in responsible use of antibiotics in agriculture and has taken a cautious approach in order to protect public health. In Pfizer Animal Health SA v Council (Case T-13/99), the Court of Justice of the European Union invoked the ‘precautionary principle’ in order to justify a ban on antibiotic feedstuff-additives used as growth promoters in animals based on a potential, unproven, risk to public health from AMR in this context.
The proposals for new veterinary Regulations in the EU (which will uncouple the regulation of human medicines and veterinary medicines – see an update here) already contain measures to tackle AMR and propose to empower the European Commission to restrict the use of antibiotics in animals. Whether restricting the availability of different classes of antibiotics (and therefore concentrating the use of other classes of antibiotics) is an effective strategy remains to be seen. However, a one size fits all proposal to reduce antibiotic use in animals by the introduction of targets to an agreed level per kilogram of livestock appears to be over simplistic as it does not make provision for an assortment of factors such as regional climatic differences and variations in potency per gram of antibiotic. Nevertheless, the emergence of the mcr-1 gene follows reports of widespread use of colistin in feedstuff-additives in China’s agricultural industry which has put the media spotlight squarely on the animal health industry for the time being. Notably, the EMA is now launching a review into the use of colistin in farming following a request from the Commission.
The reaction by industry and the potential way ahead
Overall, industry has been very supportive of the AMR initiatives, a fact which has been most recently demonstrated at Davos. However, concerns have inevitably been raised about some of the potentially unrealistic ‘blue-sky’ proposals. Securing international agreement on such initiatives and ensuring that they are supported to their conclusion, many years hence, are obvious challenges. Notwithstanding the support from industry, it is for the governments around the world to take responsibility, act decisively, and commit the necessary resources to address this problem. The crescendo of national initiatives and the increased international recognition of the huge significance of this problem suggest that there will be the political willpower to introduce radical new incentives to enable the innovation required to tackle AMR. On the other side of the coin, it is hoped that the flurry of national initiatives do not prove to be too overwhelming therefore preventing a more co-ordinated strategy. Indeed, many countries have already been striving to achieve the WHO’s global AMR plan over the last year, and it is possible that layer upon layer of additional initiatives could prove to be counter-productive.
Decision makers should also not be too quick to dismiss existing, highly effective methods of incentivising pharmaceutical innovation. For example, the market exclusivity afforded to orphan drugs for rare diseases has been incredibly effective and is well understood by industry. Whilst obvious distinctions can be drawn between tackling rare diseases and AMR, the Review and other investigations must carefully look at whether existing tried and tested models can be adapted to meet new challenges, rather than re-inventing the wheel with potentially unpredictable consequences. That is not to say that significant changes are not required – what can be certain is that as long as the responsibility and the risk of antimicrobial discovery and the development of diagnostics is placed on private industry, the necessary safeguards and/or incentives will have to be put in place to justify the huge costs of investment.
The discovery of a new antibacterial compound, texiobactin, in 2015 could be the first discovery of a new class of antibiotics for nearly 30 years and is an exciting example of the potential for new discovery. But new drug discovery alone will only postpone the development of AMR, and a truly global strategy that adopts the recommendations from the likes of the WHO will be necessary to ensure the continued availability and effectiveness of antimicrobials for future generations.