Antimicrobial resistance – a global response to a global threat

The discovery and development of antimicrobial agents and particularly antibiotics is recognised as one of the greatest medical achievements of the 20th century. Since Sir Alexander Fleming discovered the antibiotic penicillin in 1928, antimicrobial agents have been used to save the lives of millions.

Not only do antimicrobial agents directly treat deadly infectious diseases they play a vital role in many modern clinical procedures (such as surgery, organ transplants and cancer treatments) by tackling opportunistic infections in patients with reduced immune response.

No new classes of antibiotics have been discovered since the “golden age” of antibiotic discovery from the 1950s to the 1970s.  New drugs developed since the 1970s have largely been derivatives of known molecules and these tend to suffer from the same problems of resistance as the original antibiotics. 

Antimicrobial resistance refers to the ability of a microbe to resist the effects of a drug that was previously used to treat it.  In other words, infections are ‘learning’ to ignore drugs like antibiotics and becoming so-called ‘superbugs’.

The rate at which resistance is emerging is thought to be speeding up.  Medical experts warn that if antibiotics lose their effectiveness it will spell the end of medicine as we know it: common medical interventions that we now take for granted would once again become incredibly ‘risky’. 

Global Threat

Research conducted by the Review on Antimicrobial Resistance estimated that AMR is responsible for 700,000 deaths per year globally. It is predicted that the number of global deaths could rise to 10 million per year by 2050 at the current rate at which resistance is emerging. In Japan, a 2017 study by the Center Hospital of the National Center for Global Health and Medicine in Tokyo estimated that 8,000 or more deaths in Japan were the result of AMR resistance of just two bacteria, Methicillin‑resistant Staphylococcus Aureus (MRSA) and fluoroquinolone-resistant salmonella.

The World Health Organisation (WHO) describes antimicrobial resistance as “one of the biggest threats to global health, food security, and development today.” This sentiment is echoed by many including England’s former Chief Medical Officer, Professor Dame Sally Davis who has warned in recent years of a “dreadful, post-antibiotic apocalypse”.

These recent warnings are not new and neither is the threat of antimicrobial resistant superbugs. In fact, the issue of antimicrobial resistance was understood and publicised back in the 1980s.

It is clear from the covid‑19 outbreak at the start of this year that tackling the spread of disease and treating disease is a global issue requiring a global response. Although this response will need to be tailored for the particular needs of local populations and countries as a whole, an informed and coherent global response is needed.

Global Response

In May 2015 the WHO set out a global action plan with five objectives aimed at tackling antimicrobial resistance. Four of these objectives broadly relate the sharing and gathering of information, reduction in infection rate and optimization of the use of antimicrobial agents through the information gathered. Effectively, these four objectives look to tackle the spread of the disease.

The fifth objective is to develop an economic plan for, and increase investment in, developing new antimicrobial medicines and other medical interventions for microbial infections such as diagnostics and vaccines. More on the economics of tackling AMR below but this is a particular area that WHO has recently identified as a problem

Economics of AMR

The economic reality for creating a new antimicrobial agent is fundamentally different to the economic model that commonly applies to the development of other medical treatments.

Other medical treatments typically meet a previously unmet need or provide an advancement on the existing treatment for a condition. As such, once approved, these treatments can be widely prescribed to the patient population generating revenue to compensate for the cost of their development.

Almost the opposite situation is true for antimicrobial agent. If a new antimicrobial agent is approved that can treat drug resistant microbes, the new antimicrobial agent should only be administered as a last line of defence (i.e. when all other treatment fails). This limited prescription of the new antimicrobial agent means that microbes have a very limited possibility of adapting to develop resistance. This treatment strategy means that the revenue generation which offsets the cost of development for other medical treatments does not occur in the same quantities for new antimicrobial agents.

The WHO has identified this as a key problem impeding research and development into new antimicrobial treatments.

Tackling the Economic Issues of AMR

One issue identified by the WHO was the cost of research being primarily met by private sector companies. This leads to less research in the area due to the low return on investment and subsequently leads to the relatively small drug pipeline for new antimicrobial.

The WHO published a report at the end of 2019 on the pipeline of new treatments for their priority AMR. As of 1 September 2019, there are 50 antibiotics and combinations (with a new therapeutic entity), and 10 biologicals in the clinical pipeline (Phase 1– 3) targeting the WHO priority pathogens (discussed below), Tuberculosis and C. difficile. By way of comparison, it is reported that in 2014 around 800 new cancer medicines were in clinical trials.

 To address this issue of funding for early stage research a number of (inter‑) governmental, non‑profit and university led initiatives have arisen.

For example, CMBI, the MRC centre for Molecular Bacteriology and Infection, is a research initiative at Imperial College London funded by the Medical Research Council. In Japan, the Japanese government established the AMR clinical reference centre (AMRCRC) to implement its action plan on AMR. The aims of the AMRCRC include large scale public awareness campaigns and data collection as well as research and development and international cooperation.

Another, multinational example, is Carb‑X, an acronym for “Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator”, which was started in 2016 and is led by Boston University. The aim of Carb‑X is to provide business, scientific and technical expertise to product developers in order to facilitate and accelerate the development of new antimicrobials through to Phase I clinical trials. Funding for Carb‑X is provided by the US, German and UK governments, charities such as Wellcome Trust and Bill and Melinda Gates Foundation showing the range of support there is, and is needed, to tackle AMR.

To fully reconcile the economics of developing new antimicrobials, it is also important to address the issue of revenue generation. Of course, patent protection for these newly developed treatments, vaccines and diagnostic testing methods will be incredibly valuable to innovators in terms of recovering the cost of their development. But patents alone will not do this.

The good news is that governments are taking steps in this area too. For example, in the UK, new funding models were introduced in 2019 that will effectively pay not for volume of a drug used but for making the drug available. This is aimed at providing revenue generation for new antimicrobial agents despite the low usage of those agents.

The Microbes

 The term antimicrobial resistance applies to any microbe that acquires resistance. However, there are some key microbes that pose a real threat due to their resistance to most if not all known treatments. The WHO published a list of priority pathogens with the aim of guiding research efforts to tackle these most problematic microbes. They are broken up into three categories depending on, for example, their resistance level:

Priority 1: CRITICAL

• Acinetobacter baumannii, carbapenem-resistant
• Pseudomonas aeruginosa, carbapenem-resistant
• Enterobacteriaceae, carbapenem-resistant, ESBL-producing

Priority 2: HIGH

• Enterococcus faecium, vancomycin-resistant
• Staphylococcus aureus, methicillin-resistant, vancomycin-intermediate and resistant
• Helicobacter pylori, clarithromycin-resistant
• Campylobacter, fluoroquinolone-resistant
• Salmonellae, fluoroquinolone-resistant
• Neisseria gonorrhoeae, cephalosporin-resistant, fluoroquinolone-resistant

Priority 3: MEDIUM

• Streptococcus pneumoniae, penicillin-non-susceptible
• Haemophilus influenzae, ampicillin-resistant
• Shigella, fluoroquinolone-resistant

Other offenders that are targeted by the WHO in their antimicrobial resistance are tuberculosis and C. difficile.

The six bacterial pathogens most commonly associated with antimicrobial resistance are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae (an Enterobaceriaceae), Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. These six are often referred as ESKAPE an acronym for their names and a reference to their ability to escape the effects of commonly used antibiotics through evolutionarily developed mechanisms.

New Technologies

So what are the new technologies in the pipeline aiming to produce antimicrobial agents to treat these priority pathogens and in particular the tricky ESKAPE pathogens?

Here are just a few that show promise as replacement antimicrobials or entirely new treatment protocols.

New Antimicrobial Agents

 The existing stock of antibiotics have in their time been highly effective and saved countless lives. Some of the new technology looks to replicate this type of success by designing new classes of antibiotics which microbes currently have no defence against.

One such new class currently being developed by scientists from Northeastern University, looks to nature for inspiration specifically entomopathogenic nematodes. The researchers found that Photorhabdus released by the nematodes destroy any harmful bacteria on the surface of the nematode larvae including drug resistant E. Coli, K. pneumoniae, and P. aeruginosa. 

Darobactin is formed of 7 amino acids and is a large molecule (as far as antibiotics go). This means that Darobactin cannot permeate the outer membrane of gram-negative bacteria.  Therefore the researchers reasoned that Darobactin’s target must be on the surface of the cell.  Further studies revealed the target was BamA, an essential protein in the outer membrane of gram-negative bacteria and one that continues to be a promising target for new antibiotics.  The success of activity against such a surface protein encourages investigations of other essential surface targets.

Importantly, Darobactin proved effective against strains which are resistant to known antibiotics althought it will be some time before Darobactin or related compounds are seen in clinic.

Others such as Japanese pharmaceutical company, Shionogi, have reimaged the mode of action when designing their new antibiotic cefiderocol which is now approced in the US.

 Cefiderocol is a novel cephalosporin-based antibiotic for the treatment of drug-resistant gram-negative bacteria including pseudomonas aeruginosa (commonly associated with pneumonia). While not a member of a new class of antibiotics (cephalosporins have been around since the mid-20th century), its new mode of action made a splash in the news.

Cefiderocol acts by ‘tricking’ bacteria into bringing it inside themselves. The main active part of the molecule is bonded to a siderophore. Siderophores are secreted by bacteria to seek out, bind, and return with iron, and are vital for the bacteria’s survival.

In the case of cefiderocol, the siderophore is recognised by the bacteria and the gates of the city opened, allowing the antibacterial to walk straight in. Thus the antibacterial avoids the bacterium’s natural defences and the drug has been hailed as a “Trojan horse” antibiotic.

Shionogi have a clear drive to address the issue of antimicrobial resistance, partnering with the CMBI at Imperial College London in 2018 to support early stage research into the mechanisms that make AMR microbes hard to treat. Shionogi were also the first Japanese company to join Carb‑X in 2018 to further their work in treatment for AMRs.

Phage Therapy

As well as knew classes of antibiotics, whole new ideas about the way we treat microbial infections are also gaining traction.

Bacteriophages, phages for short, are viruses that have naturally evolved to attack bacteria. Phage therapy is an old idea that pre-dates chemical antibiotics and is now experiencing a resurgence in interest.

Put simply, phage therapy involves infecting the bacterial infection with a bacteriophage virus that is selected to target only the bacterium and not the host.

Some of the issues that prevented early adoption of phage therapy have been overcome by modern technology, such as whole genome sequencing and automated high-throughput screening. Pharmaceutical companies are also showing renewed interest in phages.

Phage therapy offers many benefits including requiring only a few doses, combination therapies and the ability of the phage to adapt with the bacteria. But phage therapy has limitations like all forms of treatment. Each infection must be screened to select the best phage and sometimes multiple phages are administered together to improve the chances of success.

In the US and the UK, there have already been a number of isolated instances of phage therapy successfully being used as a last resort in critical situations, such as in the UK to treat a highly resistant bacterial infection arising after a lung transplant. At the time of writing, there are not any approved phage therapies the UK, Japan or the US but this is changing, for example in 2019 the FDA approved the first US clinical trial of intravenously administered bacteriophage therapy.

Targeting Transcription

Carb‑X partner with a large number of companies to meet its aim of accelerate a diverse portfolio of clinical product (vaccines, antimicrobials, diagnostics etc.). One of these companies is Procarta who are developing a “new mode of action” antibiotic which targets specific bacteria’s transcription process.

Procarta’s technology works differently to normal antibiotics. Its proprietary delivery mechanism inserts short pieces of DNA into the infectious bacteria causing, then blocking, a stress response. This sequence of events kills the bacteria. Procarta have developed a platform technology that will allow them to produce many different antibiotics rapidly which can be designed to attack a specific bacterial strain. If this technology reaches the market, it has the ability to revolutionise treatment of AMR infections.

Summary

A huge amount of effort has been expended over the past years and decades to tackle the problem of AMR from research and development to logistic and regulatory support.

But there is still work to do.

 Some of this work will require collection and dissemination of information, for example to increase public awareness. A worrying 2000 study shows why: over two thirds of people when surveyed thought that antibiotics could be used to treat viral infections such as colds and flu. This over prescribing and incorrect use of antibiotics needs to be vastly reduced or stopped in order to slow down the rise in antimicrobial resistance and provide time for the development of new antimicrobial agents. Whilst the AMRCRC in Japan has put a huge amount of work in this area over the past 5 years, more can and needs to be done to raise awareness across the globe.

 The WHO’s report on new antimicrobials in the pipeline published at the end of 2019 concluded that there are simply not enough new treatments in the pipeline. More new treatments, and therefore research, will also be vital to tackle the threat posed by AMR.

 The good news is that governments, industries and charities around the world are assuming the mantle of tackling this global crisis.  With the increased awareness of governments, individuals, charities and researchers there is increased vigour for tackling AMR. Coupled with the improved funding models to incentivise the original research and provide revenue for new antibiotics there is hope for the future. 

This article was originally published by the Japan Patent Attorneys Association (JPAA). View the original article in Japanese.