Our Phavorite Solution? Phage

By Paul Turner, Ph.D., co-founder, Felix Biotechnology & Tyler Ford, Felix Biotechnology

Antibiotics have protected us from bacterial infections for nearly a century. Prior to the development of antibiotics in the 1940s, injuries and health problems that we rarely associate with infection today were often deadly. For example, the perhaps apocryphal story of the first person to be treated with penicillin in the UK claims that the patient was cut by a rose bush and the cut subsequently became infected.

Now, of course, we rarely consider tumbles with rose bushes to be life-threatening, but this may not be the case for much longer. The unfortunate truth is that many bacteria have become resistant to antibiotics and our defenses against infection are growing thinner and thinner. In fact, in the U.S. alone there were 35,000 deaths due to antibiotic-resistant infections in 2019.

Patients with illnesses that make them prone to infection are facing the brunt of the antibiotic resistance threat. For example, cystic fibrosis patients suffer from chronic lung infections. These patients are often dependent on antibiotics to control their infections but, in many cases, their antibiotics stop working. As Gunnar Esiason describes in this article from Pew:

“Between 2013 and 2018, when things were at their worst, I underwent nearly two dozen procedures while spending a cumulative year on intravenous antibiotics to control the infection and prevent my body from slipping into end-stage illness. Beyond my own experience, one of my best friends living with cystic fibrosis passed away in December 2018 when ‘the antibiotics stopped working.’”

All too often, the individuals who already fight the ravages of chronic illness also lead the way in fighting antibiotic resistance. For these individuals, phage therapy may offer a solution.

Phages are tiny viruses that specifically infect bacteria. In phage therapy, healthcare workers deliver these tiny viruses to patients with a bacterial infection. If successful, the viruses kill the bacteria and stop the infection. Phage therapies have the potential to replace, enhance, and/or augment antibiotics.

Phage therapies have already shown some success in small clinical trials and one-off treatments. Indeed, this quote from cystic fibrosis patient, Ella Balasa’s 2019 Huffington Post article about her experience with phage therapy highlights both the promise and challenges of phage therapy:

“It seemed that sitting on that clinic examination table with sweat soaking my armpits and my fingers clenched in anticipation had been totally unnecessary, because the experience appeared to have been entirely uneventful. However, about a week later, I started using a different cocktail of antibiotics, and within two days I was expelling all of the dead bacteria from my lungs. I had never cleared an infection so quickly before and I had used these antibiotics many times in the past, so I knew it couldn’t have just been the drugs doing their job.”

Phage therapies can definitely be successful, but we need to find effective and efficient ways to get the right phages to the right patients to clear their infections quickly and inexpensively. We need to give people like Ella confidence that phage therapies will work and that we know why they’ll work. At Felix Biotechnology, we hope to make phage therapies more effective and accessible to people like Ella.

Below you’ll learn a bit more about how we ended up here and how we and others are overcoming the obstacles facing phage therapy. We hope our efforts will bring phage therapies into the mainstream and get patients with antibiotic-resistant infections the solutions they deserve.

How did we end up here?

Humans were not the first creators of antibiotics. Indeed, penicillin, the first antibiotic used to treat an infection, comes from a fungus. Thus, bacteria have been confronting antibiotics and developing resistance to them for millennia. In fact, bacteria have many ways to share antibiotic resistance genes with one another. Our intense use of antibiotics has simply accelerated the development of large populations of antibiotic-resistant bacteria. There are a few reasons for this:

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• We often use antibiotics when they are not needed—e.g., a doctor may mistakenly prescribe an antibiotic for a viral infection (antibiotics cannot kill viruses). As a result, bacteria are exposed to antibiotics prematurely and develop resistance more quickly.
• We use antibiotics to increase livestock yields. For reasons that are not well understood, including antibiotics in livestock diets boosts growth. This is good for farmers in the short term, but once again exposes bacteria to antibiotics unnecessarily and causes resistance to spread.
• We use broad-spectrum antibiotics. Oftentimes, we use antibiotics that are capable of killing many different kinds of bacteria. Thus, all these different kinds of bacteria are driven to evolve resistance. Narrow spectrum antibiotics selectively kill only problematic bacteria. Using them would likely slow the development of resistance, but it can be difficult to diagnose which bacteria are the cause of an infection. As a result, broad-spectrum antibiotics are often the most expedient treatment option.
• Of course, you might think, “Can’t we just develop new antibiotics?” This is theoretically possible, but it is practically difficult for a couple of reasons:
  • Economics. In many cases, regulations cap the amount drug producers can charge for antibiotics. At the same time, new antibiotics are only used as a last resort in an attempt to save them for the most serious cases of antibiotic resistance. Thus, it can be very difficult to recoup the costs of antibiotic development.
  • Lack of “low-hanging fruit." We’ve essentially found all the antibiotics that are easy to produce and deliver to patients. It will take large, expensive research efforts to create more novel antibiotics.

• Economics. In many cases, regulations cap the amount drug producers can charge for antibiotics. At the same time, new antibiotics are only used as a last resort in an attempt to save them for the most serious cases of antibiotic resistance. Thus, it can be very difficult to recoup the costs of antibiotic development.
• Lack of “low-hanging fruit." We’ve essentially found all the antibiotics that are easy to produce and deliver to patients. It will take large, expensive research efforts to create more novel antibiotics.

Our phavorite solution: Phage

Phages, viruses that kill bacteria, are a potential solution to antibiotic resistance. The basic idea is, if a patient has an antibiotic-resistant infection, you find a phage that can kill the bacteria causing the infection. Then you produce a ton of this phage and deliver it to the patient. The phage then kills the bacteria and the patient is cured.

Interestingly, phage therapy has been around for even longer than antibiotic use. Félix d’Herelle discovered phages in 1917 and they were used to treat bacterial infections soon thereafter (Hence the name Felix Biotechnology). While the discovery of penicillin later usurped the role of phages in treating bacterial infections in the West, countries of the former USSR have used phages therapeutically through the present day. Indeed, there are a few Phase I and II clinical trials indicating that phage therapy can be successful. These also show that phage therapies are generally safe (see review here). More recently, a variety of phage therapy centers have popped up around the world and many one-off treatments point to the promise of phage treatment.

Nonetheless, there are several key challenges the phage research community must overcome in order to bring phage therapy into the mainstream. First off, there have been no Phase III clinical trials for phage therapy. In addition, other trials have rarely compared phage therapy to traditional antibiotic therapy. Outside of these broad concerns, some of the key challenges and their potential solutions include:

• Bacteria can become phage resistant. As with antibiotics, bacteria have been in an evolutionary arms-race with phages since far before we started using them to treat infections. Thus, bacteria have many mechanisms through which they become phage resistant.
• Potential solutions: There is a large natural reservoir of phages. Many believe that, if resistant bacteria arise, we should still be able to find new phages that can kill them.

In addition, researchers (those at Felix Biotechnology in particular) are specifically looking for phages that infect bacteria using the factors that make bacteria antibiotic-resistant or virulent. If these bacteria evolve phage resistance by getting rid of such factors, they should become antibiotic sensitive and/or become less virulent as a result. Thus, even if such bacteria become phage resistant, they should be easier to treat.

• Phages are narrow-spectrum. Phages generally infect certain strains of bacteria very selectively. This could be a problem if the bacteria causing an infection are difficult to identify. In these cases, it will be hard to find a phage that can actually treat an infection if we don’t know what bacteria are causing the infection.
• Potential solutions: There have recently been rapid improvements in infectious disease diagnostics. Some of these have been spurred by the COVID-19 pandemic. Others are a product of research technologies like DNA sequencing decreasing in cost over the last few decades. As a result, many hope it will soon be relatively easy to identify the bacteria causing antibiotic-resistant infections. If this is true, narrow-spectrum will actually be a benefit. This is because having phages that only target specific strains makes it less likely that large populations of bacteria will evolve phage resistance. Narrow-spectrum can also prevent phages from killing the beneficial bacteria found in our body's microbiome. In addition, some researchers are coming up with creative ways to force phages to have broad-spectrum targeting.
• Phage delivery and distribution to target tissues are poorly studied. Although a phage may be great at killing a pathogen in the lab, that doesn’t mean it will be effective at doing so in the body. How the phage is administered, how much phage dose is administered, whether the immune system will recognize it, whether bacterial killing results in the production of many more phages, and how the body clears the phage will all alter the efficacy of a phage therapy. There have not been extensive studies on these topics in humans. Phage administration is generally safe and doesn’t cause particularly dangerous immune reactions (inflammation for example), but larger studies are needed.
• Potential solutions: While there haven’t been large clinical studies looking at phage delivery and distribution in humans to date, we do have some general strategies that can improve phage delivery and distribution. For example, we can:
  • Use genome sequencing technologies to identify phages that are likely to rapidly kill bacteria and produce more phages rather than inserting themselves into bacterial genomes (identify “lytic” phages as opposed to “lysogenic” phages).
  • Engineer phages so they are less likely to be recognized by antibodies.
  • Use modern phage purification techniques to make sure there are no substances in phage preparations that will provoke negative immune responses.
  • Identify infections (such as pulmonary infections) that are particularly easy to reach with phage treatment.

• Use genome sequencing technologies to identify phages that are likely to rapidly kill bacteria and produce more phages rather than inserting themselves into bacterial genomes (identify “lytic” phages as opposed to “lysogenic” phages).
• Engineer phages so they are less likely to be recognized by antibodies.
• Use modern phage purification techniques to make sure there are no substances in phage preparations that will provoke negative immune responses.
• Identify infections (such as pulmonary infections) that are particularly easy to reach with phage treatment.

With these general strategies in hand, we are well poised to conduct larger studies that monitor phage delivery and distribution.

• Economics. As with traditional antibiotics, it will be very expensive to run large-scale clinical trials for phage therapies. It is not clear that these clinical trials will be cost-effective in the long run.
• Potential solutions: Phage therapies may not be subject to the same usage restrictions as traditional antibiotics. With successful clinical trials, physicians may therefore use new phage therapies more readily than new antibiotics. This will make it easier for phage developers to recoup costs.

In addition, initial phage therapies can target so-called “orphan” diseases. These are rare diseases for which there are few therapies available. Therapies for orphan diseases often have smaller, less expensive clinical trials. There are also tax and monetary incentives for the developers of orphan disease therapies. These make therapy development more economically feasible.

The future of phage therapy

The challenges of phage therapy are not minor, but we are better prepared to face them than ever before. Modern technologies enable us to quickly identify new kinds of phages from various environments. We can also rapidly discover which bacterial strains they infect and, crucially, how they infect these strains. With this information in hand, and modern genome engineering techniques, we can create phages that are especially good at killing dangerous, antibiotic-resistant bacteria. We can even find good phage/antibiotic pairs for more effective therapies.

Large clinical trials clearly demonstrating the efficacy of phage therapy are a must. Backed by our determination to help patients and find a solution to the looming antibiotic resistance crisis, we believe successful phage therapy trials are just around the corner.