Press release written by Jason Clark, Chief Scientific Officer at NexaBiome.
The World Health Organization (WHO) has listed antimicrobial resistance (AMR) as one of the top 10 global public health threats. There is serious concern at the growing number of drug-resistant infections, caused by so-called ‘superbugs’, with AMR being dubbed ‘the silent pandemic’.
Overuse and misuse of antibiotic drugs mean they are becoming less effective, with bacteria, viruses, fungi and parasites evolving to evade treatments. Infections are becoming harder to treat, leading to an increased risk of severe illnesses or death. At least 1.27 million deaths have been directly attributed to drug-resistant infections globally since 2019. This number is expected to rise further, with up to 10 million annual deaths worldwide predicted by 2050.
These alarming forecasts are behind a global push to find viable new treatments and alternatives to antibiotics, both to reduce the usage of existing treatments and to find new ways to help stem the tide of superbugs. These factors have prompted a renewed interest in the potential of bacteriophage (phage) therapy in treating multidrug-resistant bacterial infections.
Making a comeback
Phages are the most common biological entities in nature. They are naturally occurring viruses that selectively target and kill harmful bacteria. They are found in huge quantities everywhere, from soil to water to the human body, including in faeces, saliva, sputum, blood and urine.
Discovered more than 100 years ago, phages were soon suggested as a therapeutic treatment for tackling bacterial infections. However, a lack of understanding of the biological nature of phages meant they were soon supplanted by the emergence of chemical antibiotic drugs, which were relatively easy to manufacture, ushering in a new era of modern medicine.
Antibiotics have been incredibly effective medicines and have a broad spectrum of activity, so can be prescribed to treat many different bacterial infections without knowing the exact cause of the problem. Phages are more specific, attacking a relatively narrow range of bacteria, so a more detailed understanding of the infection is required.
However, unlike chemical antibiotics, phages can evolve to kill resistant bacteria, so, in theory, there is an unending supply of therapeutics that can be tapped to address AMR, once the cause of an infection is identified. The urgent need to develop new ways to combat AMR, combined with improved methods for detecting and identifying bacteria, has led to a resurgence of interest in the therapeutic use of phages.
Today, the field of phage therapy has advanced considerably, thanks to continually evolving research and innovation, with significant developments in the ‘compassionate use’ of phages for patients in need of life-saving antimicrobial therapy, where conventional treatments have failed. This evolution has thrust the practice back into the spotlight as a potential supplement, or, in some cases, an alternative to antibiotics.
With this has come a renewed interest in the safety and efficacy of phage therapy. However, a substantial body of evidence from clinical trials and other human and animal applications exists to show that phage therapy is safe, with proven success in a variety of different applications.
‘Well tolerated and safe’
Phages are ‘good’ viruses, only targeting their bacterial host and otherwise being completely inert in humans and animals. They are found wherever bacteria exist, are naturally occurring and consist of genetic material in a protein coat; they are incapable of reproducing independently and depend on a bacterial host for their procreation. The fact that phages replicate at infection sites is a unique advantage as it ensures a continuous supply of the therapeutic until the target bacteria is removed. For these reasons, phages are generally considered to be safe to use therapeutically, particularly compared to chemical antibiotics.
A 2022 systematic review of observational clinical data from 52 studies looking at the safety of phage therapy reported it as “well tolerated and safe.” (1) Meanwhile, in 2020, another review shared that phage therapy has a long and proven history in the treatment of bone and joint infections, applied in both ‘cocktail’ and ‘personalised’ formulations (2).
Several further cases have been reported where phage therapy was successfully administered to patients, such as in treating staphylococcal lung infections, cystic fibrosis infections, eye, urinary tract and surgical wound infections, as well as neonatal sepsis (3).
A well-publicised case is that of a 68-year-old male diabetic patient from San Diego, California, who was infected with a multidrug-resistant strain of the bacteria Acinetobacter baumannii (4). Despite multiple antibiotic courses and other treatments, the patient deteriorated over a four-month period. In the absence of any effective antibiotics, nine types of suitable phages were identified from phage collections. These were administered and helped clear the A. baumannii infection. In the opinion of the clinician, this saved the man’s life when all other treatments had failed.
Phage treatment has also been used as a safe and effective option for diabetic foot ulcers. In Edinburgh and Glasgow, phage therapy was made available to 10 patients with diabetes who were suffering from diabetic foot infections (5). In the opinion of the clinicians providing the therapy, in 6 out of 10 patients, phage treatment facilitated the healing of the infection and prevented amputation.
There is a growing body of evidence that suggests with further research and investment, real-world application of phages as a treatment for hard-to-treat chronic illnesses is not only viable but can be made more accessible to a larger number of patients. Phages have the potential to transform our approach to treating bacterial infections and addressing AMR.
All this explains why the idea of using these viruses as a tool to tackle infections and reduce reliance on antibiotics is developing traction, both in the UK and abroad.
In a significant development, Health Improvement Scotland (HIS), part of the Scottish National Health Service, earlier this year endorsed the use of bacteriophages as a treatment option in critical cases (6). Patients with infections that no longer respond to conventional antibiotics can now potentially be treated with phages, with the main limiting factor being the availability of phages produced to a standard that can be applied to humans.
There is also growing interest at the UK level, too. Earlier this year, MPs on the House of Commons Science, Technology and Innovation Committee held an inquiry into the antimicrobial potential of bacteriophages(7). The inquiry explored the role of phages in the UK’s AMR strategy, the regulatory environment and potential barriers to development, and the lessons that can be learned from other countries on phage research and deployment. The findings of this committee are due to be published this year.
Globally, several countries – including Belgium and Australia – have already allowed the use of phage therapy, albeit in a limited or controlled manner, and usually in cases where all standard treatments have failed. Patients have also been treated on a compassionate use basis in the USA, and in 2021 the National Institute of Health (America) awarded a $2.5m grant to 12 institutes around the world researching to support phage therapy.
In the fast-evolving phage field, momentum is building. While there is a large and growing body of data to suggest that phages can be effective if appropriately applied, even in cases where all other treatments have failed, this is currently restricted to compassionate use, on a small scale. Further investment and development are therefore needed to facilitate clinical trials, and the development of licensed phage-containing medicines, which are ultimately required for the wide-scale, commercial use of phages.
In the UK, the limited availability of manufacturing to the standard of Good Manufacturing Practice (GMP), a pre-requisite for clinical trials and licensed products, is one of the main limitations to the development of licensed phage therapeutics. While phages themselves are safe, the processes by which they are manufactured must also be demonstrated to be safe for their widespread use.
To rapidly develop this manufacturing capacity in the UK (for example, establishing a central UK phage manufacturing facility), it is likely that both public and private investment is needed. Without this support, progression of clinical trials is still achievable, but manufacture would likely need to occur in the EU or US.
Public support for phage manufacturing infrastructure would greatly expand the availability and safety of compassionate use treatments and facilitate the exploitation of phages as therapeutics. This will further mobilise phage research, discovery, process development and production, invigorating the field and cementing the UK’s position as a global leader in this exciting sphere.
The significant progress in and growing support for phage therapy has propelled the practice back into the spotlight. Its potential as a viable supplementary therapeutic treatment for bacterial infections now widely recognised. Substantial evidence exists to demonstrate the success of compassionate phage therapy in treating AMR infections and it has a well-established safety record.
The UK phage industry has come a long way in recent years. The Phage Innovation Network at Innovate UK KTN works to bring together academics, companies and regulators to address how to move the field forward with a concerted voice. The University of Leicester has recently set up the Centre for Phage Research to address fundamental questions about phage and phage biology and to provide a repository for phage collections. NexaBiome (formerly Fixed Phage) and other phage companies in the UK continue to commercially develop phages, addressing regulatory pathways, manufacture to GMP standard, scale-up and formulation – with the ultimate goal of progressing to clinical trials.
Maintaining collaborations and investment will be critical to support further research and discovery, clinical trials, and process production and manufacturing. This will ensure that phage therapy can continue to shape the future of medical science and realise its full potential in addressing the challenges raised by AMR.