Phage Therapy — A Solution To The Antibiotic Resistance Crisis?

This month, a patient has been successfully treated with genetically engineered phage. What does this mean for the future of medicine?

This month, for the first time in human history, an international team of researchers and clinicians have successfully treated a patient who had a bacterial infection with a cocktail of genetically engineered phages.

The patient, Isabelle Carnell-Holdaway, was a 15 year old girl with cystic fibrosis, who had been chronically infected with bacteria called Mycobacterium abscessus, and had been receiving treatment for her infection for 8 years. By age 14, her lung function had reduced to about 25–30%, so she underwent a lung transplant. She was given antibiotics and immunosuppressants for the surgery.

Unfortunately, she suffered severe side-effects following surgery and had to stop her antibiotic treatment. Shortly after, her surgical wound turned bright red, indicating that it was infected. The bacteria she’d been living with for years, M. abscessus, are able to grow in various parts of the body, and following this combination of an invasive surgery and a break in her antibiotic treatment, her lung infection had started to spread. Her liver started to fail, and lesions began forming across her body. She then began a more aggressive panel of antibiotics to try to get the infection under control. Sadly, the antibiotics didn’t clear the infection, and 7 months after surgery, she was discharged with a diagnosis of a disseminated M. abscessus infection. Antibiotic treatment was continued, but she was put on a palliative care plan, in anticipation of this infection proving lethal. Over the next 8 weeks, her infection continued to spread, and her condition got worse.

Mycobacterium abscessus are bacteria that can be found in soil and water, but also cause infections in humans when given the opportunity, for example when they encounter an open wound, or someone with a reduced ability to fight infections. Sadly, for people with cystic fibrosis, M. abscessus infections are becoming more common. These bacteria infect the lungs and establish long-term infections. They accelerate the rate of lung damage associated with progression of cystic fibrosis disease and can stop a patient from being able to get a lung transplant to extend their lives and improve their wellbeing. A major driver of this increase in infections appears to be improvements in treatment of cystic fibrosis patients, which have gifted them with longer lifespans (the current lifespan of a cystic fibrosis patient is around 37 years, double what it was in the ‘80s), but seems to have come at a cost of more antibiotic-resistant, hard-to-treat respiratory infections.

The continued improvement in outcomes for patients is threatened by the rise of a number of successful strains of M. abscessus which appear to be better suited to transmitting between patients and causing severe infections. It’s not clear how M. abscessus infects cystic fibrosis patients, but because the bacteria can be found in water, soil and household plumbing, they aerosolise easily, and have been found to hang around in rooms where cystic fibrosis patients have been treated, there are many situations in which a cystic fibrosis patient may be at risk. Recent evidence has shown that the bacteria can spread between cystic fibrosis patients treated in the same hospital, despite strict infection control measures which prevent these patients being in the same room together.

In addition to being so common in our environment, these bacteria are naturally resistant to a range of antibiotics. This resistance comes from a life in the soil, where competition with other microbes often involves exposure to naturally occurring antibiotics. These bacteria are tolerant of not only antibiotics, but also disinfectants and chlorination that’s commonly used to decontaminate water supplies and surfaces. As a result, they can be very hard to get rid of, infections can be incredibly hard to treat, and they often persist for the remainder of the patient’s life.

Around one third of cystic fibrosis patients who receive lung transplants die of infection. Because in this case, Isabelle’s infection was spreading quickly and threatening her life, phage therapy was considered as an emergency treatment option. The possibility was originally raised by Isabelle’s mother, who’d learned about phage therapy after searching the internet for possible treatments. One of the microbiologist consultants at the hospital had done their PhD thesis on phage therapy, and knew a phage therapist in the US, Graham Hatfull, who’d devoted his career to amassing an enormous collection of phage, so the team were in a unique position to arrange treatment. A sample of M. abscessus that was collected from Isabelle was sent to a laboratory and used to screen for phage that could kill it.

Phage surrounding and infecting a bacterial cell. Image source: Dr Graham Beards, via Wikipedia

Phage are viruses that infect bacteria, and don’t cause any harm to humans. They can be found in their trillions, all over the planet, for example in soil and water. They’ve been used clinically to treat bacterial infections for 100 years, and were used regularly to treat infections in the US and Europe in the pre-antibiotic era, but were abandoned in favour of antibiotics when the option arose. Today, they are only used routinely in Eastern Europe and Russia. They are often used to treat persistent infections that don’t clear up following treatment with antibiotics. While they fell out of favour in most parts of the world when antibiotics were discovered, they are in the midst of a resurgence now that antibiotics are starting to look like a non-sustainable option. Isabelle’s strain of bacteria was screened against a collection of phages that was produced as part of the SEA-PHAGES project, and undergraduate course that gets students to search the soil for new viruses. There were three phages in the cocktail that helped treat Isabelle. A feature of the project is that whoever finds the virus gets to name it, resulting in some colourful choices. The names of the phage used to treat Isabelle are Muddy, ZoeJ, and BPs, for instance. This program is run all over the world, and has even reached as far as my hometown, New Zealand.

After receiving her phage cocktail, Isabelle felt sweaty and flushed in the first two days of treatment, but otherwise didn’t notice any adverse side effects. Her surgical wound showed signs of healing after 1 month, and 6 months on from treatment, her condition continued to improve, she had better lung function and gained weight. To date, Isabelle isn’t completely healed — she still gets lesions occasionally, but is hopeful that the infection will eventually clear completely. This is promising, and indicates the cocktail may have worked, but critically this is not conclusive proof — she may have recovered from the infection on her own. More patients will need to be treated in this way to show a true benefit from treatment.

The scientists who put this cocktail together pointed out it didn’t work on other M. abscessus, so the treatment would need to be reformulated for individual patients. They had to screen a database of over 10,000 phages to find three that could fight this particular infection. This is a common challenge in phage therapy, and is both a strength and a weakness. Each phage is quite specific in the strains of bacteria it can infect, meaning it won’t wipe out your microbiome like broad-spectrum antibiotics would, but also meaning that general purpose phage cocktails would be tricky to put together.

Not all phage kill bacteria, some just live inside them as parasites. This ended up being the case for two of the three phage initially discovered, meaning that more needed to be done to make this treatment effective for treating infection. To make their phage cocktail more effective, they genetically engineered the harmless phage to be deadly to the bacteria. This involved removing the gene that normally allows these phage to insert their DNA into the host’s DNA and enter a dormant state.

A close-up of two phage. Image source: Wikipedia

This work was a first in several respects. First, it was the first example of using genetically engineered phage for treating an infection, which is a huge boost for the field of synthetic biology in showing promise for producing life-changing practical applications. Second, it’s the first time phage therapy has been used to treat this type of bacteria. Other examples of phage therapy treatments vary. Following a treatment of another 22 year old patient, Paige Roger’s Pseudomonas aeruginosa infection, which she’d had since 2 years old, her symptoms began to improve after just 10 days, and a month later her infection was beginning to clear completely. Another patient, Mallory Smith, who was approved to receive phage treatment for a Burkholderia infection tragically died just days before a treatment could be found that worked, after a long process of seeking approval to treat her and finding appropriate phage.

Phage therapy comes with benefits that antibiotics don’t. Phage can evolve along with bacteria, meaning that the ability of bacteria to adapt and change to escape treatment can be met with an ability of the virus to change to infect the newly adapted bacteria. Some bacteria do survive treatment with phages, but in other common bacteria treated with this approach, bacteria that survive treatment have shown increased sensitivity to antibiotics, because the same mechanisms that provide resistance to the phage appear to reduce resistance to antibiotics. This suggests that phage therapy could rescue some of our available antibiotics, and the two could be used effectively in tandem.

A huge plus with phage therapy is its relative safety. Antibiotics that we take commonly are relatively benign. But, for infections that are resistant to our preferred antibiotics, this situation changes. Management of multi-drug resistant infections is more complex, costly and time-consuming compared to drug-sensitive infections. Treatment of multi-drug resistant tuberculosis is a clear example. Many people stop treatment of their drug-resistant TB because the side effects of these drugs can be hard to bear. TB treatment regimes are changing to try to minimise suffering for patients, but curing the infection is essential.

“The injection was like nothing I’d ever felt before. It burns from the second it starts — it is quite a thick serum so you can’t inject it in fast. It takes some time. The pain went down my legs and up to my back. It is so painful. No injection should be that painful. It is intense pain that never stops.”
“It is painful to get up. It is painful to go shower. It is painful to eat. It is painful to go to school. Everything is so difficult all day. And the next day when you go for your injection, you’re still in pain from the last injection”

Zolelwa Sifumba, TB patient

Phage therapy has been dismissed for a long time by many Western practitioners, however breakthroughs in treating patients with persistent, drug-resistant infections bolsters confidence in the approach. As our confidence in antibiotics wanes, this could signal a turning of the tides in the way we approach treating bacterial infections. There appears to be growing interest and investment in phage therapy projects and resources. A Center for Innovative Phage Applications and Therapeutics at UC San Diego was launched last year, with the aim of making phage therapy more widely available to patients. In 2010, Texas A&M University launched the Center of Phage Technology (CPT), which initially focussed on agriculture and animal husbandry, avoiding work on humans because of the regulatory hurdles involved, but is now hoping to do more work in humans. Johnson & Johnson also struck two deals this year to support research into phage therapy, a contrast to the dropping investment by pharmaceutical companies in the development of new antibiotics.

Currently, phage therapy hasn’t been approved by the FDA, and is hard to access. Cases of treatment in the US so far have involved efforts by the patient’s families and researchers to find compatible phages, and emergency approval by the FDA to use an Emergency Investigational New Drug. However, examples of successful phage treatments are growing, and phage therapy has recently been cleared for an FDA trial, meaning approval may be on the horizon. For the growing number of patients with multi-drug resistant infections, who are running out of options for treatment, this couldn’t come soon enough.

FDA approval would just be the first step. Discovery of appropriate phages may involve some genetic engineering, but currently mostly involves scouring nature for what we want. The SEA-PHAGES project has allowed people from all over the world to contribute phage to the treatment that lead to Isabelle’s recovery. Success stories like this may well encourage interest in joining the project and growing a larger resource for clinicians to draw from. As commercial providers get involved, sources of phage may change, but currently this presents an incredible opportunity for people around the world to contribute to a resource that can save lives.

Bioinformatician + data scientist, building machine learning algorithms for the detection of emerging infectious threats to human health

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