I worked at a pharmacy for over seven years. During that time, thousands of prescriptions for antibiotics came and went. From amoxicillin to treat a chest infection to doxycycline to treat acne, antibiotics were a staple of my dispensing career. I recently went back this local pharmacy to collect a prescription and noticed an infographic on the counter…
“Antibiotic Resistance – What you can do”.
While the intent of the notice is good, I think it is 50 years too late.
We all know the story of Alexander Fleming and the serendipitous discovery of penicillin in 1928, which figuratively and literally landed on his plate. Penicillin wasn’t used medically until 1941, when an Oxford policeman, who was exhibiting a serious infection with abscesses throughout his body, became the first person to receive it.
Just one year on from that release, the first penicillin-resistant strain was found. Since then, several other antibiotics have followed suit, and what was once considered our miracle treatment for bacterial infections has unfortunately led to one of the world’s biggest health threats.
In this blog, we explore the current landscape of antimicrobial resistance and highlight how viruses – yes viruses – may hold the key to our escape.
The AMR crisis
Run, run as fast as you can
At university, one of my immunology lecturers first introduced me to the Red Queen Hypothesis (Figure 1). It still fascinates me. I don’t know if it’s because I really like Lewis Caroll’s series of books about Alice and her adventures in Wonderland or I am intrigued by the intricacies of evolution, or both. For those who are unfamiliar, there is a sentence in Through the Looking Glass which reads:
“Now, here, you see, it takes all the running you can do, to keep in the same place.”
The concept of the Red Queen Hypothesis originated in the field of evolutionary biology and proposes that species must constantly adapt and evolve in order to survive when pitted against other ever-evolving species. In other words, species have to “run” or evolve in order to stay in the same place, or else they will go extinct.
This analogy can be extended to the arms race between humans and microbes.
With the discovery of penicillin, Fleming gave society a secret weapon to protect themselves in an evolutionary race. In fact, since antibiotics were first introduced at scale in the 1940s, deaths caused by infectious diseases have fallen by 70%. Unfortunately, microbes are able to ‘run’ very fast, with generation times often as short as 20 minutes. Over time, these disease-causing microbes have become resistant in their fight to adapt and evolve against these treatments., This has left society increasingly defenceless in this arms race.
It’s in the data
According to the World Health Organisation (WHO), antimicrobial resistance (AMR) is one of the top ten public health threats facing humanity today. The antibiotics that were once key to fighting bacterial infections are not just slowly becoming ineffective (Figure 2), but they are also becoming an unintentional killer.
The threat that the misuse of antimicrobial drugs poses on healthcare has been known for some time. In fact, even Fleming noted in 1945 that the overuse of penicillin could lead to forms of bacteria that would be resistant to its effects. And so, it did. If you sit down and pay attention to the data, it is scary:
- It is estimated that AMR infections cause 700,000 deaths each year globally.
- On average, hospitals spend an additional $10,000 to $40,000 to treat a patient infected by resistant bacteria in OECD (Organisation for Economic Co-operation and Development).
- Failure to address the problem of antibiotic resistance could result in an estimated 10 million deaths by 2050, as well as cost £66 trillion to the global economy.
The worst thing? Most of these effects are human led.
Although AMR occurs naturally over time through genetic changes, there are several main drivers. These include lack of access to clean water, sanitation and hygiene, poor infection and disease prevention and control, poor access to quality and affordable medicines and vaccines, lack of awareness, incorrect use of antibiotics and most importantly, over prescribing of antibiotics.
In 2016, it was reported that at least 30% of antibiotics prescribed in the United States alone were unnecessary. This issue has likely been exacceberated by the COVID-19 pandemic, whereby three-quarters of patients with COVID-19 received antibiotics. It is likely that the cases of unnecessary antibiotic use in patients with COVID-19 has been high.
Pharma abandons ship
With the continual rise of AMR and the diminishing effectiveness of most antibiotics, you would think that efforts would be intensely focused on developing new antibiotics.
Unfortunately, since the 1980s, no new classes of antibiotics have been discovered. And the future reality is even bleaker.
Unlike for Fleming, most antibiotics don’t appear out of thin air. Discovering and then developing new antibiotics is extremely challenging and costly. It can take 10 to 15 years to develop a new antibiotic and cost over $1 billion dollars. If this wasn’t enough to put you off – failure rates in most of these cases are high. Additionally, the average revenue generated from antibiotic’s sale is roughly $46 million per year. This is nowhere near the amount that would justify an investment. This has led many pharma companies to leave the market in pursuit of more profitable lines of drug development; one of the most prominent being cancer treatments (Figure 3). Without some reimagination it is likely that this market will be in jeopardy.
An old new solution
To devour
There are currently just four major pharmaceutical companies with active antibiotic research programmes. As a result, some smaller companies are striving to fill the gap. In addition, new initiatives are being launched, such as the AMR Action Fund, that aims to bring new antibiotics to the market by 2030. Despite these efforts, we still must not narrow our search. We must look elsewhere for solutions. One of those solutions is viruses.
Yes, viruses.
Viruses do not currently have a great reputation for obvious reasons. But they are, in fact, not all bad.
A bacteriophage, informally known as a phage, is a virus that infects and replicates within bacteria and archaea. The term is derived from the word bacteria and the Greek word φαγεῖν (phageîn) which means ‘to devour’. Not only do they have a cool name, visualising these structures under a microscope is just incredible – they look like something out of a science fiction novel (Figure 4).
Phage reborn
The first known therapeutic use of phages occurred in 1919. Félix d’Herelle, a microbiologist at the Institut Pasteur in Paris, and several hospital interns, gave a phage cocktail to a 12-year boy suffering with severe dysentery. The boy’s symptoms cleared up after a single dose and he fully recovered within a few days. However, d’Herelle did not publish his findings until 1931.
Phage therapy was extensively researched before World War II. However, with the advent of antibiotics, this technology was placed on the backburner. Over the past couple of decades, interest in phage therapy has been growing rapidly in laboratories and hospitals. Why? Well, phage therapy has some enthusiastic supporters. But it’s mostly because of deep concerns about AMR.
How does phage therapy work?
Phages work by injecting their genetic material (DNA or RNA) into the bacteria. After this stage, the phages undergoes replication where new phages particles are assembled. The phage can make up to 1000 new viruses in each bacterium. Finally, the cell undergoes lysis, releasing the newly formed phages into the environment, where they go on to find and infect other cells nearby.
Phages are often compared to antibiotics. However, in many ways they are more effective. For instance, unlike antibiotics, phages can penetrate a biofilm covered by a polysaccharide layer. This is important as it is the polysaccharide coating which gives bacteria its resistant properties. Even when effective antibiotics are available, they can have detrimental effects on the body’s communities of beneficial bacteria. Phages on the other hand are extremely precise. Any given phage only attacks a very particular strain of bacteria. This means that phage therapy can eliminate any individual’s infection without harming beneficial bacteria.
Nonetheless, this specificity is also a disadvantage. A phage will kill a bacterium only if it matches the specific strain. In addition, like everything in the Red Queen’s race, the deployment of phages can result in the emergence of bacterial resistance. Researchers have reported phage-resistant bacteria in up to 80% of studies targeting the intestines and 50% of studies using sepsis models. Phage-resistant variants have also been observed in human studies.
A potential way to treat both of these concerns would be the development of phage ‘cocktails’ to improve the chances of success. If the phage kills pathogens faster than they can replicate, then there is a lower risk of the development of bacteriophage-resistant bacteria. Genetic engineering may also provide a way to improve the diversity and targeting efficiency of phages for the avoidance of resistance.
Take it or leave it
Phage therapy is already being used therapeutically in some countries, such as Russia and Georgia, to treat bacterial infections that do not respond to conventional antibiotics. However, approval for use in humans in other Western countries has not been given. Meanwhile, phages have been investigated as a means to eliminate pathogens in the food industry. For example, two anti-Listeria phage cocktails were approved by the FDA and the Canadian Environmental Protection Agency (EPA) in 2007. They later also obtained authorisation from the European Food Safety Agency (EFSA).
Although it’s being used more widely in other industries, phage therapy also had the potential to provide great benefit to individuals’ health. For example, AMR is frequently seen in individuals who suffer with cystic fibrosis and who eventually die from antibiotic failures. Due to regular antibiotic use to control infections, cystic fibrosis patients are at high risk of AMR. As a result, many patients die from chronic resistant infection, typically by Pseudomonas aeruginosa and Staphylococcus aureus, which ultimately leads to lung function decline. In these cases, phage therapy represents a potential lifeline.
For instance, in 2019 a 15-year-old cystic fibrosis patient with a disseminated drug-resistant Mycobacterium abscessus infection was cured by the use of natural and synthetically modified phages. Another case study reported the success of a phage therapy in a 26-year-old cystic fibrosis patient who was awaiting lung transplantation and had developed multidrug resistant P aeruginosa. After receiving intravenous phage therapy, this individual had decreased supplemental oxygen use and sputum production, and subsequently received a lung transplant 9 months later.
With these emerging success stories, the number of trials and scientific publications on this subject are increasing significantly. Additionally, various microbiology conferences in recent years have given increasing attention to the therapeutic applications of phages.
The next phage
The future looks stark. AMR is increasing globally, and antibiotics are losing their effectiveness. As a result, there is an urgent need to develop new treatments. Whilst phage therapy has been researched for more than a century, the AMR crisis has reignited interest. Advanced technologies such as genetic engineering, whole-genome sequencing and metagenomics have also provided new tools that could help optimise these phage therapeutic strategies.
However, several issues remain with the use of phages as alternatives for antibiotics. These are mostly due to gaps in our knowledge and regulations. There is a clear lack of information regarding the clinical applications of phages for controlling bacterial infections and potentially replacing antibiotics. A lot of the clinical data published in countries where phage cocktails are available, such as Russia and Poland, are difficult to access due to security and language barriers. In addition, in comparison to conventional therapies, there are many challenges for scientists in obtaining regulatory approval for phage-based therapeutic applications.
Most importantly, there is a lack of established and validated protocols in relation to the routes of administration, dose frequency and duration of phage treatment. There are also several challenges relating to the genetic biosafety of phages. We still currently have an incomplete understanding of the function of all encoded phage genes. Alongside this, genetic engineering of phages will inevitably raise several safety concerns which will need to be addressed before its clinical application.
While the reasons for hesitancy surrounding the use of phage therapy are complex, one of the most prominent reasons preventing their adoption is a concern regarding the use of what, at the end of the day, is a virus. A lot of the difficulty in obtaining regulatory approval for scientists is because of the risks of using a self-replicating entity that has the capability to evolve. With everything that has happened in the past two years, it this anxiety will likely worsen.
Nonetheless, given the ongoing AMR crisis we need to be optimistic that these challenges will be overcome in the coming years. With ongoing attempts to raise awareness about AMR among healthcare professionals and the general public, we must also attempt to start looking at ALL of the options that are out there. Although viruses do not currently have the best reputation, they have become the topic of most people’s conversations. Viruses have taken centre stage. What better time for scientists to investigate and also educate people about how we could turn one of our current weaknesses into one of our future strengths.
Check out our recent interview with Olivia McAuliffe (Principal Scientist, Teagasc Food Research Centre, Ireland) who discusses the work her team are doing on bacteriophages.
References
- Principi N, Silvestri E, Esposito S. Advantages and limitations of bacteriophages for the treatment of bacterial infections. Frontiers in pharmacology. 2019 May 8;10:513.
- Brives C, Pourraz J. Phage therapy as a potential solution in the fight against AMR: obstacles and possible futures. Palgrave Communications. 2020 May 19;6(1):1-1.
- Romero-Calle D, Guimarães Benevides R, Góes-Neto A, Billington C. Bacteriophages as alternatives to antibiotics in clinical care. Antibiotics. 2019 Sep;8(3):138.
